UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`WATSON LABORATORIES, INC.
`Petitioner
`
`V.
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`UNITED THERAPEUTICS CORP.
`
`Patent Owner
`
`Cases1 IPR2017n01621; Patent 9,358,240
`{PR 2017-01622; Patent 9,339,507
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`SECOND DECLARATION OF DR. WERNER SEEGER
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`l The word-for-word identicai 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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`lPR201?-01621; IPR2017-01622
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`Declaration of Dr. Werner Seeger
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`1, Dr. Werner Seeger, 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 (“the ’240
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`patent”) and U.S. Patent No. 9,399,507 (“the ”507 patent”), which are based upon
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`US. provisional patent application No. 60f800,026 filed May 15, 2006 (“our patent
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`application”) (Bx. 2034). i am the director of University of Giessen and Marburg
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`Lung Center (“UGMLC”), a research center at the University Hospital Giessen
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`studying pulmonary hypertension.
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`2.
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`I am a paid consultant for United Therapeutics Corporation in
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`connection with IPR2027-0162l and 1PR2017-01622. My compensation does not
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`depend on the content of this declaration, the substance of any other testimony that
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`I may offer in connection with this proceeding, or the diSposition of this
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`proceeding.
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`3.
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`I am a co-author of the German language article: Hossein Ardeschi
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`Ghofrani er al. “Neue Therapieoptionen in der Behandlung der pulmonalarteriellen
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`Hypertonie,”2 Herz, 30, 4 (June 2005): 296-302 (“the Ghofrani article”) (Ex.
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`2103). I understand that Watson Laboratories, Inc. (“Watson”) submitted an
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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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`lPR2017-0162l; lPR2017-0i622
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`Declaration of Dr. Werner Seeger
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`English language translation of the Ghofrani article in this proceeding as Exhibit
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`1005, which I have reviewed along with the original German article (Ex. 2103).
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`4.
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`As stated in my previous declaration (Ex. 2020), the Ghofrani article
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`was an overview review article, drafted under my direction and control by
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`members of my research center at University Hospital Giessen. The intent of the
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`article was to compile and review information regarding treatment of pulmonary
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`hypertension, not to communicate primary data or to teach any specific therapeutic
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`regimen.
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`5.
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`As detailed in my previous declaration, Dr. Voswinckel and I
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`contributed the following inhaled treprostinil section of the Ghofrani article:
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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 pre-
`capillary pulmooary hypertension were administered inhaled
`treprostinil (15 meg/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].
`Dee 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.
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`(Ex. l005, p. 3). Although the information in this excerpt for the article was
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`compiled and composed by Dr. Voswinckel and myself, the individuals who
`2
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`IPR2OZY-01621; [PENN-01622
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`Declaration of Dr. Werner Seeger
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`designed the underlying clinical studies with inhaied treprostinil are the same as
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`the ones listed as inventors on the patents, as explained in more detail below. We
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`of course performed the studies discussed in the Ghofrani article, wrote the excerpt
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`quoted above, and submitted it for publication before it was published in June 2005
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`based upon our work together designing the clinical study.
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`6.
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`Regarding dosage of inhaled treprostinil, the above excerpt from the
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`Ghofrani review article notes that patients were “administered inhaled treprostinil
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`(15 meg/inhalation)” The word “inhalation” in that sentence (in both German and
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`English) does not mean “breath,” but rather, refers to an inhalation event. This is
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`clear under our typical use of that terminology and because the above excerpt is
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`citing the reference of endnote “[6]” for support, which used an inhalation period
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`of six minutes (reference [6] of Ex. 1005 is Ex. 1046, and p. 5 of Ex. "1046 states
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`that “6 min” was used). An inhalation event of six minutes indicates that a
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`continuous nebuiizer was being used (without pulsing or an opto-acousticai
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`trigger), as in the first two studies using Optineb discussed below.
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`7.
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`Although Ghofrani states that treprostinii showed a strong pulmonary
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`selectivity “so that it is possible to increase the dosage to up to 90 meg (absolute
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`inhaled dose per inhalation exercise),” it does not report that this dosage was
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`applied in human pulmonary hypertension patients, which is evident from
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`reviewing the cited reference, “[6]” (Ex. 1046), in which this this dosage is not
`1‘
`.3
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`reported. Rather, the Ghofrani review article states only that it “is possible"
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`(“moglich ist” in Ex. 2103). This statement was intended to convey the idea that it
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`may be possible to increase the dosage to that levei, not that the referenced study
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`actually performed that particular test. Similarly, the Ghofrani review article states
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`that due to certain unique properties of treprostinil, “it is possible [“ist es moglich”
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`in Ex, 2103] to reduce the number [of] inhalations necessary to up to four per day”
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`and that the inhalation period “can be” reduced [“lasst sich bei” in Ex. 2103] to < 1
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`min. and that it “is technically feasible [“technisch realisierbar sein wird” in Ex.
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`2103] for there to [sic] only one to two breaths in an application.” These
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`statements of possibilities do not report any conciusion of studies performed,
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`which is evident from reviewing the cited reference, in which 6 min inhalation
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`time was reported “[6]” (Ex. 1046), but rather, suggest only future paths for
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`clinical studies.
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`8.
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`In sum, the Ghofrani review article does not explain or teach any
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`particular therapeutic regimen or necessary parameters. It merely provides a high—
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`levei overview of early investigations into inhaled treprostinil and some
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`speculation for additional research. Similarly, the two Voswinckel references
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`provided by Watson as EX. 1003 and 1046, both of which are abstracts and not
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`primary study reports, report only select and incomplete information of different
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`studies. Although the specific parameters used and particulars of the studies
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`4
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`performed by my group are not fully reported, any study that formed the basis of
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`Our discussion of inhaled treprostinii in these three references (Ex. 1005, 1003, and
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`1046) was performed by me in conjunction with my ongoing collaboration with
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`Drs. Voswinckel, Dischewski, Rubin, Schmehl, Sterritt, and Roscigno. Indeed in
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`both Voswinckel abstracts at Ex. 1003 and EX. 1046 we note that the study was
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`“supported by Lung Rx.” In particular, as to any of these relevant inhalation
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`studies with inhaled treprostinil, Drs. Voswinckei, Olschewski, Rubin, Schmehl,
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`Sterritt, Roscigno, and I determined the dosage amounts of administered inhaled
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`treprostinil to give to patients, determined the inhalation time and/or number of
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`breaths employed, determined what equipment and administration devices and
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`methods to use, and identified the spacing between inhalation events, as well as
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`analyzed the hemodynamic and pharmacokinetic effects over time. The other
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`authors listed in the Ghofiani review article — Drs. Ghofrani, Reichenberger, and
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`Grimminger — did not participate in the design of any of the studies, did not select
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`the dosing regimen, and did not conduct analysis of patient results discussed in the
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`Ghofrani review article or the two Voswinckei abstracts.
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`9.
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`Drs. Ghofrani, Reichenberger, and Grimminger were named as co—authors
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`because it was and continues to be the practice of our group, as an academic and
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`research group, to include as co-authors alt individuals working in our group that
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`run the center, assist with trials, and engage in clinical routine management and
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`5
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`administration, even when that group is broader than the individuals actually
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`involved in inventing methods or devices and designing the trials. More
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`specifically, even though Ghofrani, Reichenberger, and Grimminger did not design
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`the inhaled treprostinil clinical trials, they did perform support work including help
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`with identifying potentially eligible patients out of the group of patients in our
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`pulmonary hypertension clinic. Because patients with severe pulmonary
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`hypertension have multiple needs beyond their participation in clinical trials, such
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`as treatments involving their background medications (cg- diuretics, anti-
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`coagulation, other pulmonary hypertension targeted co—medications, antibiotics,
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`etc); and support for some general needs (e.g. administrative matters with
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`insurance or helping with other family members, etc.), they also carried out this
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`type of work. In still other cases, patients who discontinued clinical trials, require
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`immediate transitioning back to their normal clinical care again, which was also
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`part of their responsibilities.
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`10.
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`Dr. Voswinckel and my collaboration with Drs. Rubin and
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`Olschewski and Lung Rx began in 2003. On September 30, 2003, I entered into a
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`Services Agreement (Ex. 2101) with Lung Rx, Inc. under which I served as co-
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`chair with Dr. Lewis Rubin for the development program for treprostinil
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`inhalation. As reflected in the Services Agreement itself, work included
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`developing the outline and timeline for the development program, and also
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`6
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`designing the pilot and pivotal trials. 1d.
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`I worked directly with Drs. Rubin,
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`Voswinckel, Olschewski, Schmehl, Roscigno, and Sterritt on this collaboration,
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`which resulted in the three clinical studies mentioned below that became the basis
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`of our patent application leading to the ’240 and ’507 patents.
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`ii.
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`In particular, I recall a meeting in New York in 2003, Oct 22’”, which
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`included me, Dr. Rubin, and Dr. Olschewski, as well as participants from United
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`Therapeutics, and together we discussed the design of clinical trials with inhaled
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`treprostinil to treat pulmonary hypertension patients. A copy of the agenda from
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`this meeting, which describes a detailed work plan, is attached. Ex. 2102. Certain
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`action items indicated in this agenda involved me or my co-inventors as reflected
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`by our initials (“LR” is Lewis Rubin, “WS” are my initiais, “HO” is Horst -
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`Oischcwski, “RR” is Robert Roscigno, and “CS” is Carl Sterritt).
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`12.
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`Following this initial meeting in New York, my co—inventors and I
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`investigated various devices and alternatives to deliver inhaled treprostinil as
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`described in our patent application. One possible method involved the use of a
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`particular kind of metered dose inhaler (EX. 2100, par. [0037] and [0047]-[0055]).
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`A different, and unrelated, alternative was the use of an ultrasonic nebulizer (id. at
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`[0066]). We began a series of studies with a particular ultrasonic nebulizer called
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`the Optineb device, which are summarized in our patent application (id. at [0062]-
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`[0089]). The first two studies initially used a 6 min. inhalation period, meaning
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`7
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`that patients breathed continuously while nebutization occurred over this time
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`period, without pulsing of aerosol generation and without an opto-acoustical
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`trigger (Ex. 2100, par. [0066], [0070], and [007l]).
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`13. Unexpectedly, when we used treprostinil at a much higher dose in our
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`second study with the Optineb ultrasonic nebulizer device, we discovered that
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`treprostinil has a slower transpuirnonary transit time (time of drug “spillover” into
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`the biood to reach peak piasma concentration) of 10 to 15 minutes when
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`administered to pulmonary hypertension patients (id. at Fig. 12), compared to
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`iloprost (Ex. 1029, p. 1, “rapid entry of iIOprost into the systemic circulation was
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`noted, peaking immediately after termination of the inhalation maneuver”). This
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`particular pharmacokinetic data is disclosed in our patent application (Ex. 2100 at
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`Fig. 12), but is not reported in either of the Voswinckel abstracts (Ex. 1003 or
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`1046) or the Ghofrani publication (Ex. 1005). This slower time to reach peak
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`plasma concentration is important. It obviously allows: a) to avoid major systemic
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`side effects even when high total inhalation doses are used (nevertheless the high
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`local concentrations in the lung already provide the desired therapeutic effect); 1))
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`to reduce the inhaiation time to even a few breaths (made possible by switching to
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`a pulsed ultrasonic nebulizer in the further course of the studies); and c) to increase
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`the overall inhaled treprostinil dose more than one order of magnitude over the
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`overail inhaled tolerable iloprost dose.
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`14.
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`In a subsequent trial, we modified the Optineb device to include both
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`pulsing and an opto—acoustical trigger, while using a high enough concentration of
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`pre-aerosolized treprostinil solution to permit higlt dosing in a small number of
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`breaths coordinated with each of the aerosol pulses (Ex. 2100, par. [0072], [0079]-
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`[0081] and [0088]), which dramatically shortened the overall time of each
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`treatment session. Drs. Voswinckel, Olschewski, Schmehl and I were involved in
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`guiding the design of these changes to the Optineb device and working to
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`implement them into the treatment regimen. The co-inventors and I, therefore, had
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`to work directly with Nebu-tec, the manufacturer of the Optineb device, to guide
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`modifying the device to achieve all of the necessary features. Because we moved
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`to such a high concentration of treprostinil in the aerosol, the opto-acoustical
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`trigger to guide the patient’s breathing and synchronize it to each pulse of aerosol
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`was especially important. To my knowledge, the Optineb device we created was
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`not one that was publicly available or otherwise publicly disclosed prior to our
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`patent application. Although the Voswinckel publication references a “pulsed”
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`Optineb nebulizer, it does not disclose any of the modifications we made,
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`including the importance of the opto-acoustical trigger for coordinating each
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`patient’s breath with each pulse of aerosbl at these high treprostinil concentrations.
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`15.
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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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`9
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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: fig};
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`.
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`, a
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`/,2 ,2013
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`Dr. Werner Seeger
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`10
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