UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PA TENT TRIAL AND APPEAL BOARD
`
`WATSON LABO RA TORIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORP.
`
`
`Patent Owner
`
`Cases1 IPR.2017-01621;
`
`Patent 9,358,240
`
`
`IPR 2017-01622; Patent 9,339,507
`
`
`
`SECOND DECLARATION OF DR. WERNER SEEGER
`
`
`
`
`
`1 The word-for-word identical paper is filed in each proceeding identified in the
`
`
`
`
`
`heading.
`
`UNITED THERAPEUTICS, EX. 2098
`
`
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01621
`Page 1 of 11
`
`IPR2021-00406
`United Therapeutics EX2071
`
`
`
`BEFORE THE PA TENT TRIAL AND APPEAL BOARD
`
`WATSON LABO RA TORIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORP.
`
`
`Patent Owner
`
`Cases1 IPR.2017-01621;
`
`Patent 9,358,240
`
`
`IPR 2017-01622; Patent 9,339,507
`
`
`
`SECOND DECLARATION OF DR. WERNER SEEGER
`
`
`
`
`
`1 The word-for-word identical paper is filed in each proceeding identified in the
`
`
`
`
`
`heading.
`
`UNITED THERAPEUTICS, EX. 2098
`
`
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01621
`Page 1 of 11
`
`IPR2021-00406
`United Therapeutics EX2071
`
`
`
`}PR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`I, Dr. Werner Seeger, hereby declare as follows:
`
`1.
`
`I am a named inventor of U.S. Patent No. 9,358,240 (“the ’240
`
`patent”) and U.S. Patent No. 9,399,507 (“the ’507 patent”), which are based upon
`
`U.S. provisional patent application No. 60/800,016 filed May 15, 2006 (“our patent
`
`application”) (Ex. 2034). I amthe director of University of Giessen and Marburg
`
`Lung Center (““UGMLC”), a research center at the University Hospital Giessen
`
`studying pulmonary hypertension.
`
`2.
`
`Lama paid consultant for United Therapeutics Corporation in
`
`connection with IPR2017-01621 and IPR2017-01622. My compensation does not
`
`depend on the content of this declaration, the substance of any other testimonythat
`
`I may offer in connection with this proceeding, or the disposition ofthis
`
`proceeding.
`
`3.
`
`[am aco-author of the German languagearticle: Hossein Ardeschi
`
`Ghofranie7 al. “Neue Therapieoptionen in der Behandlung der pulmonalarteriellen
`
`Hypertonie,”” Herz, 30, 4 (June 2005): 296-302 (“the Ghofraniarticle”) (Ex.
`
`2103). I understand that Watson Laboratories, Inc. (“Watson”) submitted an
`
`* Thetitle is translated as “New therapies in the treatment ofpulmonary
`
`hypertension” in Exhibit 1005.
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`English language translation of the Ghofraniarticle in this proceeding as Exhibit
`
`1005, which I have reviewed along with the original German article (Ex. 2103).
`
`4.
`
`As stated in my previous declaration (Ex. 2020), the Ghofraniarticle
`
`was an overview review article, drafted under my direction and control by
`
`members of myresearch center at University Hospital Giessen. The intent of the
`
`article was to compile and review information regarding treatment of pulmonary
`
`hypertension, not to communicate primary data or to teach any specific therapeutic
`
`regimen.
`
`5.
`
`As detailed in my previous declaration, Dr. Voswinckel and I
`
`contributed the following inhaled treprostinil section of the Ghofrani article:
`
`Initial trials in Giessen have shown proofofefficacy 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
`treprostinil (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 thatit
`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 numberinhalations necessary to up to four per day; the
`inhalation period can be reduced to < | min. by selecting a suitable
`device. Additionally, the initial data showsthatit is technically
`feasible for there to be only one to two breaths in an application.
`
`(Ex. 1005, p. 3). Although the information in this excerpt for the article was
`
`compiled and composed by Dr. Voswinckel and myself, the individuals who
`2
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`designed the underlying clinical studies with inhaled treprostinil are the same as
`
`the oneslisted as inventors on the patents, as explained in more detail below. We
`
`of course performed the studies discussed in the Ghofraniarticle, wrote the excerpt
`
`quoted above, and submitted it for publication before it was published in June 2005
`
`based upon our work together designing the clinical study.
`
`6.
`
`Regarding dosage of inhaled treprostinil, the above excerpt from the
`
`Ghofrani review article notes that patients were “administered inhaled treprostinil
`
`(15 meg/inhalation).” The word “inhalation” in that sentence (in both German and
`
`English) does not mean “breath,” but rather, refers to an inhalation event. This is
`
`clear under ourtypical use of that terminology and because the above excerptis
`
`citing the reference of endnote “[6]” for support, which used an inhalation period
`
`of six minutes (reference [6] of Ex. 1005 is Ex. 1046, and p. 5 of Ex. 1046 states
`
`that “6 min” was used). An inhalation event of six minutes indicates that a
`
`continuous nebulizer was being used (without pulsing or an opto-acoustical
`
`trigger), as in the first two studies using Optineb discussed below.
`
`7.
`
`Although Ghofranistates that treprostinil showed a strong pulmonary
`
`selectivity “so that it is possible to increase the dosage to up to 90 meg (absolute
`
`inhaled dose per inhalation exercise),”it does not report that this dosage was
`
`applied in human pulmonary hypertension patients, which is evident from
`
`reviewing the cited reference, “[6]” (Ex. 1046), in which this this dosage is not
`
`+2
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`reported. Rather, the Ghofrani review article states only that it “is possible”
`
`(“méglichist” in Ex. 2103). This statement was intended to convey the ideathatit
`
`maybepossible to increase the dosageto that level, not that the referenced study
`
`actually performedthat particular test. Similarly, the Ghofrani review article states
`
`that due to certain unique properties of treprostinil, “it is possible [“ist es méglich”
`
`in Ex. 2103] to reduce the number[of] inhalations necessary to up to four per day”
`
`and that the inhalation period “can be” reduced [“lasst sich bei” in Ex. 2103] to < 1
`
`min. and thatit “is technically feasible [“technisch realisierbar sein wird” in Ex.
`
`2103] for there to [sic] only one to two breaths in an application.” These
`
`statements of possibilities do not report any conclusion of studies performed,
`
`whichis evident from reviewing the cited reference, in which 6 min inhalation
`
`time was reported “[6]” (Ex. 1046), but rather, suggest only future paths for
`
`clinical studies.
`
`8.
`
`In sum, the Ghofrani review article does not explain or teach any
`
`particular therapeutic regimen or necessary parameters. It merely provides a high-
`
`level overview ofearly investigations into inhaled treprostinil and some
`
`speculation for additional research. Similarly, the two Voswinckel references
`
`provided by Watson as Ex. 1003 and 1046, both of which are abstracts and not
`
`primary study reports, report only select and incomplete information of different
`
`studies. Although the specific parameters used and particulars ofthe studies
`
`4
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`performed by my groupare not fully reported, any study that formed the basis of
`
`our discussion ofinhaled treprostinil in these three references (Ex. 1005, 1003, and
`
`1046) was performed by me in conjunction with my ongoing collaboration with
`
`Drs. Voswinckel, Olschewski, Rubin, Schmehl, Sterritt, and Roscigno. Indeed in
`
`both Voswinckel abstracts at Ex. 1003 and Ex. 1046 wenote that the study was
`
`“supported by Lung Rx.” In particular, as to any of these relevant inhalation
`
`studies with inhaled treprostinil, Drs. Voswinckel, Olschewski, Rubin, Schmehl,
`
`Sterritt, Roscigno, and I determined the dosage amounts of administered inhaled
`
`treprostinil to give to patients, determined the inhalation time and/or number of
`
`breaths employed, determined what equipment and administration devices and
`
`methods to use, and identified the spacing between inhalation events, as well as
`
`analyzed the hemodynamic and pharmacokinetic effects over time. The other
`
`authors listed in the Ghofrani review article — Drs. Ghofrani, Reichenberger, and
`
`Grimminger — did not participate in the design of any ofthe studies, did not select
`
`the dosing regimen, and did not conduct analysis of patient results discussed in the
`
`Ghofrani review article or the two Voswinckelabstracts.
`
`9.
`
`Drs. Ghofrani, Reichenberger, and Grimminger were named as co-authors
`
`because it was and continues to be the practice of our group, as an academic and
`
`research group, to include as co-authorsall individuals working in our group that
`
`run the center, assist with trials, and engage in clinical routine management and
`
`5
`
`
`
`IPR2017-01621; [PR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`administration, even when that group is broader than the individuals actually
`
`involved in inventing methods or devices and designingthe trials. More
`
`specifically, even though Ghofrani, Reichenberger, and Grimmingerdid not design
`
`the inhaled treprostinil clinical trials, they did perform support work including help
`with identifying potentially eligible patients out ofthe group ofpatients in our
`
`pulmonary hypertension clinic. Because patients with severe pulmonary
`
`hypertension have multiple needs beyondtheir participation in clinical trials, such
`
`as treatments involving their background medications(e.g. diuretics, anti-
`
`coagulation, other pulmonary hypertension targeted co-medications, antibiotics,
`
`etc.); and support for some general needs(e.g. administrative matters with
`
`insurance or helping with other family members,etc.), they also carried out this
`
`type of work. In still other cases, patients who discontinuedclinical trials, require
`
`immediate transitioning back to their normal clinical care again, which wasalso
`
`part of their responsibilities.
`
`10.
`
`Dr. Voswinckel and my collaboration with Drs. Rubin and
`
`Olschewski and Lung Rx began in 2003. On September 30, 2003, I entered into a
`
`Services Agreement (Ex. 2101) with Lung Rx, Inc. under which I served as co-
`
`chair with Dr. Lewis Rubin for the development program for treprostinil
`
`inhalation. As reflected in the Services Agreementitself, work included
`
`developing the outline and timeline for the development program,and also
`
`6
`
`
`
`1PR2017-01621; [PR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`designing the pilot and pivotal trials. Jd. I worked directly with Drs. Rubin,
`
`Voswinckel, Olschewski, Schmehl, Roscigno, and Sterritt on this collaboration,
`
`which resulted in the three clinical studies mentioned below that becamethe basis
`
`of our patent application leading to the °240 and °507 patents.
`
`11.
`
`In particular, I recall a meeting in New York in 2003, Oct 22"which
`
`included me, Dr. Rubin, and Dr. Olschewski, as well as participants from United
`
`Therapeutics, and together we discussed the design ofclinicaltrials with inhaled
`
`treprostinil to treat pulmonary hypertension patients. A copy of the agenda from
`
`this meeting, which describes a detailed work plan,is attached. Ex. 2102. Certain
`
`action items indicated in this agenda involved me or my co-inventors as reflected
`
`by ourinitials (“LR” is Lewis Rubin, “WS”are myinitials, “HO”is Horst-
`
`Olschewski, “RR” is Robert Roscigno, and “CS”is Carl Sterritt).
`
`12.
`
`Following this initial meeting in New York, my co-inventors and I
`
`investigated various devices and alternativesto deliver inhaled treprostinil as
`
`described in our patent application. One possible method involved the use of a
`
`particular kind of metered dose inhaler (Ex. 2100, par. [0037] and [0047]-[0055]).
`
`A different, and unrelated, alternative was the use of an ultrasonic nebulizer(id. at
`
`[0066]). We beganaseries of studies with a particular ultrasonic nebulizer called
`
`the Optineb device, which are summarized in our patentapplication (id. at [0062]-
`
`[0089]). The first two studies initially used a 6 min. inhalation period, meaning
`
`7
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`that patients breathed continuously while nebulization occurred overthis time
`
`period, without pulsing of aerosol generation and without an opto-acoustical
`
`trigger (Ex. 2100, par. [0066], [0070], and [0071}).
`
`13. Unexpectedly, when we usedtreprostinil at a much higher dose in our
`
`second study with the Optineb ultrasonic nebulizer device, we discovered that
`
`treprostinil has a slower transpulmonary transit time (time of drug “spillover”into
`
`the blood to reach peak plasma concentration) of 10 to 15 minutes when
`
`administered to pulmonary hypertension patients (id. at Fig. 12), compared to
`
`iloprost (Ex. 1029, p. 1, “rapid entry of iloprost into the systemic circulation was
`
`noted, peaking immediately after termination of the inhalation maneuver”). This
`
`particular pharmacokinetic data is disclosed in our patent application (Ex. 2100 at
`
`Fig. 12), but is not reported in either of the Voswinckel abstracts (Ex. 1003 or
`
`1046) or the Ghofrani publication (Ex. 1005). This slower time to reach peak
`
`plasma concentration is important. It obviously allows: a) to avoid major systemic
`
`side effects even whenhightotal inhalation doses are used (nevertheless the high
`
`local concentrations in the lung already provide the desired therapeutic effect); b)
`
`to reduce the inhalation time to even a few breaths (made possible by switching to
`
`a pulsed ultrasonic nebulizer in the further course of the studies); and c) to increase
`
`the overall inhaled treprostinil dose more than one order of magnitude over the
`
`overall inhaled tolerable iloprost dose.
`
`
`
`[PR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`14.
`
`Ina subsequenttrial, we modified the Optineb device to include both
`
`pulsing and an opto-acoustical trigger, while using a high enough concentration of
`
`pre-aerosolized treprostinil solution to permit high dosing in a smal! numberof
`
`breaths coordinated with each of the aerosol pulses (Ex. 2100, par. [0072], [0079]-
`
`[0081] and [0088]), which dramatically shortened the overall time of each
`
`treatment session. Drs. Voswinckel, Olschewski, Schmehl and I were involved in
`
`guiding the design of these changes to the Optineb device and workingto
`
`implement them into the treatment regimen. The co-inventors andI, therefore, had
`
`to work directly with Nebu-tec, the manufacturer of the Optineb device, to guide
`
`modifying the device to achieve all of the necessary features. Because we moved
`
`to such a high concentration oftreprostinil in the aerosol, the opto-acoustical
`
`trigger to guide the patient’s breathing and synchronize it to each pulse of aerosol
`
`was especially important. To my knowledge, the Optineb device we created was
`
`_ not one that was publicly available or otherwise publicly disclosed prior to our
`
`patent application. Although the Voswinckel publication references a “pulsed”
`
`Optineb nebulizer, it does not disclose any of the modifications we made,
`
`including the importance of the opto-acoustical trigger for coordinating each
`
`patient’s breath with each pulse of aerosolat these high treprostinil concentrations.
`
`15.
`
`[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;
`
`9
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Werner Seeger
`
`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: A fn 14 = 2018
`
`Dr. Werner Seeger
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
