UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`
`WATSON LABORATORIES, INC.
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION
`Patent Owner.
`
`_____________________________
`
`Case IPR2017-01621
`Patents 9,358,240
`_____________________________
`
`EXPERT DECLARATION OF MAUREEN D. DONOVAN, PH.D.
`
`
`
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 1 of 91
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`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`
`WATSON LABORATORIES, INC.
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION
`Patent Owner.
`
`_____________________________
`
`Case IPR2017-01621
`Patents 9,358,240
`_____________________________
`
`EXPERT DECLARATION OF MAUREEN D. DONOVAN, PH.D.
`
`
`
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 1 of 91
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`I.
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`INTRODUCTION
`1.
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`I, Maureen D. Donovan, Ph.D., hereby submit my expert declaration on
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`behalf of Defendant Watson Laboratories, Inc. (“Watson”).
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`2.
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`I have been retained by Watson to provide technical expertise and
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`expert opinions regarding U.S. Patent No. 9,358,240 (“the ’240 patent”).
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`3.
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`The opinions to which I will testify at trial, if asked, are set forth in this
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`report. My opinions in this report are based upon the information that I have
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`received to date. They may be supplemented or modified if additional information
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`is received. They also may be supplemented to reply to additional information or
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`opinions provided by the parties (or witnesses retained by the parties) and issues that
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`may arise at trial.
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`4.
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`I may rely on demonstrative exhibits at trial to assist in explaining my
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`trial testimony.
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`II.
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`PERSONAL BACKGROUND AND EXPERT QUALIFICATIONS
`5.
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`I am a Professor in the Division of Pharmaceutics and Translational
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`Therapeutics at the University of Iowa College of Pharmacy. I have more than 25
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`years of experience working and consulting in the field of pharmaceutics. My
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`curriculum vitae is attached to this report as Exhibit A.
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`6.
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`I am an expert in pharmaceutics. I received my Bachelor of Science in
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`Pharmacy from the University of Minnesota College of Pharmacy in 1983 and my
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`Ph.D. in Pharmaceutics from the University of Michigan in 1989.
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`7. My professional experience includes working as a Staff Pharmacist for
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`Clark Professional Pharmacy from 1986 until 1989 and as a Visiting Scholar for
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`SmithKline Beecham Pharmaceuticals in 1991. From 1989 through the present, I
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`have held various positions at the University of Iowa College of Pharmacy.
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`Specifically, in the Division of Pharmaceutics, I was an Assistant Professor from
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`1989 until 1996, and an Associate Professor from 1996 until 2008. I was promoted
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`to the rank of Professor in 2008 in the College of Pharmacy, and I currently hold this
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`position. From 2008 until 2013, I was the Division Head for the Division of
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`Pharmaceutics. In 2013, I became the Associate Dean for Undergraduate Programs
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`at the College of Pharmacy, and I currently hold this position.
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`8.
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`I have over 25 years of experience in pharmaceutical research and
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`development
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`including actively
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`teaching drug delivery, pharmaceutical
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`preformulation, and compounding to pharmacy students and graduate students, and
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`directing research programs focused on drug absorption, nasal drug delivery, and
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`alternative routes of drug delivery and delivery systems.
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`9.
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`I have published numerous articles, book chapters, and abstracts in the
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`area of pharmaceutics, drug absorption, drug delivery, and materials
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`characterization. I also belong to several professional societies for pharmaceutical
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`science and technology, including the American Association of Pharmaceutical
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`Scientists and the Controlled Release Society.
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`10.
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`I am being compensated for my work at $250 per hour for general
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`document and background review; $400 per hour spent preparing reports; and a daily
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`rate of $5,000 when testifying. No part of this compensation due or received is
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`contingent upon the outcome of this matter or the pending litigation.
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`11.
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`In addition to my knowledge, education, and experience in the field of
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`pharmaceutical formulation, in forming the opinions I express in this report, I
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`reviewed the full list of materials cited herein.
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`III.
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`SUMMARY OF OPINIONS
`12. As explained in detail in section VII.C., each of the asserted claims of
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`the ’240 patent would have been obvious in light of the prior art as of May 15, 2006,
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`which collectively teach and motivate a person of ordinary skill in the art to make a
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`kit comprising a therapeutically effective amount of treprostinil by inhalation in an
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`aerosol form in a pulsed ultrasonic nebulizer utilizing an opto-acoustical trigger,
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`with instructions for use.
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`IV. LEGAL STANDARDS
`13. While I am neither a patent lawyer nor an expert in patent law, I have
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`been informed of the applicable legal standards for patent invalidity. I have relied
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`upon these legal principles, as explained to me by counsel, in forming my opinions
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`set forth in my report.
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`14.
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`I understand that clear and convincing evidence must be presented to
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`render a patent claim invalid. I understand that evidence is sufficiently clear and
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`convincing if it leaves the fact-finder with a definite and firm belief in the truth of a
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`fact.
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`15.
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`I understand that, even if a single prior art reference does not disclose
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`each and every limitation of the claim, a patent claim may still be invalid as obvious.
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`I have been informed that the standard for obviousness for the patent-in-suit, which
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`was filed prior to the effective date of the AIA, is set out in pre-AIA version of 35
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`U.S.C. §103(a), which is quoted below:
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`A patent may not be obtained though the invention is not
`identically disclosed or described as set forth in section 102 of
`this title, if the differences between the subject matter sought to
`be patented and the prior art are such that the subject matter as a
`whole would have been obvious at the time the invention was
`made to a person having ordinary skill in the art to which said
`subject matter pertains. Patentability shall not be negatived by
`the manner in which the invention was made.
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`
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`16.
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`I have been informed that in order for a patent claim to be considered
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`obvious, at the time the invention was made, each and every limitation of the claim
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`must be present within the prior art, or within the prior art in combination with the
`4
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`general knowledge held by a person of ordinary skill in the art (“POSA”), and that
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`such a person would have a reasonable expectation of success in combining these
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`teachings to achieve the claimed invention. I also understand that the reason to select
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`and combine features, the predictability of the results of doing so, and a reasonable
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`expectation of success of doing so may be found in the teachings of the prior art
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`themselves, in the nature of any need or problem in the field that was addressed by
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`the patent, in the knowledge of a POSA in the field at the time, as well as in common
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`sense or the level of creativity exhibited by a POSA. There need not be an express
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`or explicit suggestion to combine references. I understand the combination of
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`familiar elements according to known methods is likely to be obvious when it does
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`no more than yield predictable results.
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`17.
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`I understand that an analysis of whether a claim would have been
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`obvious to a POSA at the time of the invention requires an analysis of at least four
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`criteria: (i) the level of ordinary skill in the art, (ii) the scope and content of the art,
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`(iii) any differences between the prior art and the patent claims, and (iv) any
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`objective indicia of non-obviousness. I have been informed that Plaintiff may rely
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`on objective evidence of non-obviousness, and that I will have an opportunity to
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`rebut any evidence that Plaintiff puts forward.
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`18.
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`I understand that an analysis of whether a claim would have been
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`obvious to a POSA at the time of the invention includes an analysis of any objective
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`indicia of non-obviousness. To be relevant to an obviousness analysis, I understand
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`there must be a nexus between the secondary consideration of nonobviousness and
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`features of the patent-in-suit that are both novel and actually claimed in the patent.
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`In other words, evidence of a secondary consideration is only relevant if it relates to
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`a claim element that is unique to the patents-in-suit, and not already disclosed by the
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`prior art.
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`19. A prior art reference can be said to teach away when a POSA would be
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`discouraged from following the path set out in the reference, or would be led in a
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`direction divergent from the path that was taken in the claimed invention. The mere
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`disclosure of more than one alternative does not constitute a teaching away from
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`alternatives that are not disclosed when the prior art does not criticize, discredit, or
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`otherwise discourage the solution claimed in the alleged invention. Similarly, a prior
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`art reference that merely expresses a general preference for an alternative invention
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`does not teach away.
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`20.
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`I have relied upon this understanding of the applicable legal standards
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`in reaching my opinions set forth in my report.
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`V.
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` BACKGROUND AND TUTORIAL
`21. The patent-in-suit relates to the treatment of pulmonary hypertension
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`using a drug called treprostinil. Specifically, the treprostinil treatment is delivered
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`by inhalation, using a nebulizer. The background below and tutorial serves as a
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`primer to explain the background of the development of treprostinil for therapeutic
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`use and the background in the development of the technology used to deliver drugs
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`via inhalation.
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`1.
`Pulmonary Hypertension
`22. Pulmonary hypertension can be described as an increase in “resistance
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`to pulmonary blood flow” and “an elevation of pulmonary arterial pressure over
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`normal levels.”1 Other measureable hemodynamics associated with pulmonary
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`hypertension include left atrial pressure, central venous pressure, systemic arterial
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`pressure, heart rate, and cardiac output.2
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`23. Pulmonary hypertension “can be a manifestation of an obvious or
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`explicable increase in resistance, such as obstruction to blood flow by pulmonary
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`emboli, malfunction of the heart’s valves or muscle in handling blood after its
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`passage through the lungs, diminution in pulmonary vessel caliber as a reflex
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`response to alveolar hypoxia due to lung diseases or high altitude, or a mismatch of
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`vascular capacity and essential blood flow, such as shunting of blood in congenital
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`abnormalities or surgical removal of lung tissue.”3
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`1 Ex. 1001 at col. 2, ll. 6-8.
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`2 Ex. 1018 at col. 7, ll. 25–33.
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`3 Ex 1001 at col. 1, ll. 41-49.
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`24. Pulmonary hypertension may be either acute or chronic.4 Acute
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`pulmonary hypertension may be a reversible condition triggered by “hypoxia (as in
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`high-altitude sickness), acidosis, inflammation, or pulmonary embolism.”5 “Chronic
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`pulmonary hypertension is characterized by major structural changes in the
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`pulmonary vasculature.”6 The causes for chronic pulmonary hypertension include
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`“chronic hypoxia, thromboembolism, collagen vascular diseases, pulmonary
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`hypercirculation due to left-to-right shunt, HIV infection, portal hypertension or a
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`combination of genetic mutation and unknown causes.”7
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`25. Life expectancy for patients with pulmonary hypertension is extremely
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`short and death is often sudden due to failure of the right side of the heart.8
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`Compounds that are effective in the treatment of pulmonary hypertension, therefore,
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`have been the subject of significant research and development.
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`4 Ex. 1001 at Col. 2, l. 22.
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`5 Id. at ll. 23-27.
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`6 Id. at ll. 28-36.
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`7 Id.
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`8 Ex. 1028 at 820.
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`2.
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`Early Development of Treprostinil for the Treatment of
`Pulmonary Hypertension
`26. Treprostinil is a part of a sub-class of prostacyclin analogs called
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`benzindene prostaglandins.9 Prostacyclin is “an endogenously produced compound
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`in mammalian species.”10 It is both “structurally and biosynthetically related to the
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`prostaglandins.”11
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`27. The beneficial pharmacological effects of prostaglandins have been
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`known for decades. Prostacyclin was first synthesized in the 1970s and was
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`discovered to act as a strong local vasodilator that inhibits the aggregation of blood
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`platelets.12
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`28.
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`In 1981, U.S. Patent No. 4,306,075 (“Aristoff ’075”) taught that
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`benzidene prostaglandins were found to “have useful application as antithrombotic
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`agents, anti-ulcer agents, and anti-asthma agents”13 due to their ability to “produce
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`9 Ex. 1019 at col. 1, ll. 16–24.
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`10 Id. at col. 1, ll. 25–26.
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`11 Id. at col. 1, ll. 26–27.
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`12 See Ex. 1028 at 820 (noting that “[i]ntravenous prostacyclin is a potent pulmonary
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`vasodilator in patients with primary pulmonary hypertension”).
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`13 Ex. 1019 at col. 12, ll. 35–37.
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`various pharmacological responses, such as inhibition of platelet aggregation,
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`reduction of gastric secretion, and bronchodilation.”14 These prostacyclin analogs
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`“produce certain prostacyclin-like pharmacological responses” and formulas
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`containing these analogs “are used as agents in the study, prevention, control, and
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`treatment of diseases, and other undesirable physiological conditions, in mammals,
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`particularly humans.”15
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`29.
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`In 1989 EP 0347243 A1 taught “prostaglandins for use in the
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`prophylaxis, treatment, or diagnosis of pulmonary hypertension.”16 EP ’243
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`identifies treprostinil17 as a “particularly preferred compound[]” with “exceptional
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`pulmonary anti-hypertensive properties.”18
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`30. Likewise, in 1992, U.S. Patent No. 5,153,222 (“Tadepalli ’222”)
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`disclosed and claimed the use of treprostinil in the treatment of pulmonary
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`14 Ex. 1020 at col. 1, ll. 22–25.
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`15 Id. at col. 12, ll. 27–32.
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`16 Ex. 1021 at 2, ll. 3-5.
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`17
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`Identified
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`as
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`“9-deoxy-2’,9α-methano-3-oxa-4,5,6-trinor-3,7-(1’,3’-
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`interphenylene)-13,14-dihydroprostaglandin F1.”
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`18 Ex. 1021 at 3, ll. 60-62.
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`hypertension.19 Specifically, Tadepalli ’222 disclosed the results of certain animal
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`studies finding that treprostinil, “reduce[d] hypoxia-induced increase in pulmonary
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`arterial pressure and pulmonary vascular resistance in a dose-related manner without
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`appreciably affecting cardiac output or heart rate.”20 The inventors observed that
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`“[t]he hypoxia-induced vasoconstriction did not return to its control value within 15
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`minutes of terminating the final infusion indicating a relatively long duration of
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`action for [treprostinil].”21 In another study, the inventors observed “a dose-
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`dependent fall in systolic and diastolic pressures were observed for a period of up to
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`8 hours after administration
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`indicating
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`that [treprostinil] had good oral
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`bioavailability.”22
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`31. Tadepalli ’222 explained that, like prostacyclin, treprostinil acts as a
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`potent vasodilator that widens the blood vessels and decreases pulmonary arterial
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`pressure. It also was found to have little effect on cardiac output and heart rate, two
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`beneficial traits for the treatment of pulmonary hypertension.23
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`19 Ex. 1025 at Cover 6, ll. 27-50.
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`20 Id. at col. 6, ll. 27–32.
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`21 Id. at col. 6, ll. 35–39.
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`22 Id. at col. 6, ll. 47–50.
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`23 Id. at col. 6, ll. 30–31.
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`32.
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`In 1993, U.S. Patent No. 5,234,953 (“Crow ’953”) disclosed that
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`“[c]ompound A [i.e., treprostinil] was found to [be] a potent pulmonary
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`vasodilator… [that] markedly attenuated the pulmonary vasoconstriction induced by
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`hypoxia.”24 It further discloses other “acute beneficial hemodynamic effects” of
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`treprostinil including “substantial reductions in pulmonary vascular resistance,
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`pulmonary arterial pressure, systemic vascular resistance and mean arterial blood
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`pressure and increases in cardiac output and stroke volume.”25 Crow ‘953 teaches
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`the use of treprostinil in patients with congestive heart failure which is accompanied
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`by pulmonary hypertension.
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`3.
`Drug Delivery by Inhalation
`33. Delivery of drugs by inhalation has been utilized for hundreds of years.
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`In particular, inhalation has been known and used as an effective method of drug
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`delivery to the lungs. Since at least the early 1950s drug delivery by inhalation was
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`considered to be “an important means of treating a variety of conditions, including
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`such common local conditions as bronchial asthma and chronic obstructive
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`pulmonary disease and some systemic conditions, including hormone replacement,
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`24 Ex. 1054 at col. 7, ll. 19–22.
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`25 Ex. 1054 at col. 7, ll. 22–28.
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`pain management, cystic fibrosis, etc.”26 Several advantages are associated with
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`inhalation delivery.27 First, inhalation allows the drug to be delivered “directly to
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`the site of drug action.”28 Inhalation also results in “rapid onset of the therapeutic
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`effect, compared with other routes of administration, such as intramuscular and oral
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`routes.”29 Additionally, inhalation may be beneficial “[f]or drugs which are
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`susceptible to breakdown in the gastrointestinal tract.”30
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`34. The active drug can be formulated as a solution, suspension, or a solid.
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`In the first case, “the drug is dissolved in a suitable solvent which can be aerosolized
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`to form a small-particle mist.”31 By 2006, the existing devices that could aerosolize
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`the solution included at least a pneumatic nebulizer, ultrasonic nebulizer, or “a self-
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`contained nebulizer containing a pressurized, fluorocarbon propellant.”32 Pneumatic
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`nebulizers—also known as jet nebulizers—are powered by compressed air or
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`26 Ex. 1022 at col. 1, ll. 10-15; Ex. 1023 at p. 2, ll. 4–9.
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`27 Ex. 1024 at col. 1, ll. 36–46; col. 15, ll. 39–45.
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`28 Id. at col. 1, ll. 36–39.
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`29 Id. at col. 1, ll. 39–41.
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`30 Id. at col. 1, ll. 42–46.
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`31 Id. at col. 1, ll. 49–67.
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`32 Id.
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`another gas. Ultrasonic nebulizers utilize a source of ultrasound acoustically
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`coupled to a liquid in a nebulization chamber to generate an aerosol of small liquid
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`droplets to be delivered in controlled doses to a patient.33
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`35. To determine the optimal nebulizer, formulators would often compare
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`jet and ultrasonic nebulizers to determine which could ideally deliver the target dose
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`in an efficient manner.34 These device-comparison studies showed that ultrasonic
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`nebulizers consistently produced a higher output of drug aerosol.35
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`36. Most nebulizers operate by inserting or emptying an ampoule
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`containing a solution of the active ingredient and optional excipients into the
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`chamber.36 Once the ampule is inserted into the nebulizer and it is turned on, the
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`solution is nebulized at a certain rate. This rate is typically a constant rate, however
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`the rate of nebulization was adjustable in some devices.37
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`33 Ex. 1026 at col. 1, ll. 5–26.
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`34 Ex. 1027 at Abstr., 15.
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`35 Id.
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`36 Ex. 1018 at col. 8, l. 39–col. 9, l. 3.
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`37 The Nebu-Tec website explains that the OptiNeb® has a nebulization rate of <0.6
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`mL/min. (Ex. 1014 at B-2 at 26.) In one particle size test, the output of the
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`OptiNeb® ultrasonic nebulizer was 173±3 μL/min. (Id. at 31.)
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`37. By 2006 the delivery of a pharmaceutical product via nebulizer used at
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`least two different methods to administer the prescribed dose—either a constant or
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`a pulsed delivery. As opposed to a constant stream of aerosol delivery, a pulsed
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`nebulizer only dispenses drug intermittently.38 Because some 50% of any aerosol
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`produced by a continuous dose nebulizer is lost while a patient is exhaling, a pulsed
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`nebulizer offers the benefits of less drug waste and lower costs through greater
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`efficiency.39
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`38. For example, a 2003 paper reported tests conducted with a nebulizer
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`called “HaloLite:”
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`The HaloLite is a new electronically controlled device, applying
`aerosol pulses only in a preset period during early inspiration,
`with delivery adjusted to the breathing pattern. These aerosol
`pulses are added up, and the device stops automatically when the
`target dose has been delivered. The main advantages of the
`system are the virtual absence of aerosol delivered to the airway
`dead space, the fact that the predefined drug dose will be applied
`irrespective of the breathing pattern, and the low volume of
`inhalation solution necessary for sufficient nebulization.
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`
`
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`38 E.g., Ex. 1029 at 1301-02.
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`39 See Ex. 1030 at 322–23.
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`39. While complicated and expensive devices like HaloLite used advanced
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`computer systems to calculate the amount of drug delivered,40 other pulsed
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`nebulizers provided sensory cues to the patient, telling him/her when and how to
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`breathe.41
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`4.
`
`The Development of Inhaled Treprostinil for the Treatment
`of Pulmonary Hypertension.
`40. Because of its ability to administer drugs directly to the lungs,
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`inhalation delivery has proven to be especially beneficial for the treatment of
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`pulmonary conditions, including pulmonary hypertension.
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`41. By the early 1990s, investigators had begun researching the delivery of
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`prostacyclin and its analogues via inhalation for the treatment of pulmonary
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`hypertension.
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`40 See id.
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`41 See Ex. 1031 at col. 34:57-35:14. (“[t]he timing device can be electrically
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`connected with visual display signals as well as audio alarm signals. Using the
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`timing device, the microprocessor can be programmed so as to allow for a visual or
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`audio signal to be sent when the patient would be normally expected to administer
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`respiratory drug.”)
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`42. For example, Crow ’953 disclosed the use of treprostinil, including in
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`the treatment of patients with congestive heart failure that was accompanied by
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`pulmonary hypertension.42 Crow further disclosed that treprostinil could be
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`delivered via pulmonary inhalation and disclosed formulations, nebulizers and
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`droplet sizes for doing so.43
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`43. Similarly, a 1996 paper by Olschewski, et al. reported on “the effects
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`of aerosolization of prostacyclin and its stable analog iloprost with those of nasal
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`oxygen, inhaled nitric oxide, and intravenous prostacyclin on hemodynamics and
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`gas exchange in patients with severe pulmonary hypertension.”44 This trial found
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`that “[a]erosolized prostacyclin achieved the same reduction in pulmonary vascular
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`resistance [as with intravenous prostacyclin] with a smaller increase in cardiac
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`output but a significant decline in pulmonary artery pressure.”45 Thus, the authors
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`concluded that aerosolized prostacyclin achieved “selectivity for the pulmonary
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`circulation…as indicated by a substantial decrease of pulmonary artery pressure and
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`42 Ex. 1054 at col. 3, l. 59–col. 4, l. 11.
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`43 Ex. 1054 at col. 5, ll. 50–53.
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`44 Ex. 1028 at 820.
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`45 Id. at 822.
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`17
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 18 of 91
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`a smaller effect on systemic arterial pressure.”46 Olschewksi also reported that “the
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`stable prostacyclin analog iloprost caused nearly identical changes in hemodynamics
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`and gas exchange [as that of aerosolized prostacyclin].”47 Thus, iloprost had been
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`shown to improve survival, exercise capacity, and hemodynamics in patients with
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`severe pulmonary hypertension.48
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`44. By the early 2000s, Cloutier disclosed and claimed the administration
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`of a therapeutically effective amount of treprostinil by inhalation for the treatment
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`of pulmonary hypertension.49 The Cloutier patents included claims directed to the
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`treatment of pulmonary hypertension in humans via aerosolized treprostinil
`
`delivery.50
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`45. Cloutier observed that aerosolized treprostinil could be given in high
`
`doses without significant non-lung effects—i.e., heart rate and cardiac output.51 In
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`particular, aerosolized treprostinil had no effect on systemic arterial pressure or
`
`
`46 Id.
`
`47 Id. (emphasis added).
`
`48 Ex. 1033 at 58S.
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`49 Ex. 1018 at cl. 6-8.
`
`50 Id.
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`51 Id. at col. 10, ll. 50–57.
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`
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`18
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 19 of 91
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`cardiac output.52 Cloutier also observed that administration of treprostinil by
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`inhalation has a much greater potency than intravascular administration:53
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`46. A number of commercial products for the treatment of pulmonary
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`hypertension were approved in the mid-2000s as well. For example, in 2002, FDA
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`approved Remodulin® an
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`injectable
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`treprostinil product (i.e., continuous
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`subcutaneous infusion) that was indicated for the treatment of pulmonary
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`hypertension.54 Remodulin® is supplied in 20 mL multi-use vials in four
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`concentrations, containing either 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, or 10 mg/mL
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`of treprostinil.55
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`47. Ventavis, an inhaled iloprost product for the treatment of pulmonary
`
`hypertension, was first approved in Europe in September 2003 for marketing by
`
`Schering AG.56 Originally, Ventavis was approved for use with two commercially
`
`available jet nebulizers, the Prodose and HaloLite.57 Pre-approval studies, however,
`
`
`52 Id. at col. 11, ll. 23–44; col. 12, ll. 28–61; figs. 4, 5, 8, 11, 12 & 15.
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`53 Id. at col. 8, ll. 5–12.
`
`54 See Ex. 1035.
`
`55 Id. at 4.
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`56 See Ex. 1036; Ex. 1037.
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`57 See Ex. 1038.
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`
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`19
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 20 of 91
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`
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`were conducted using six different nebulizers, one of which was the OptiNeb®
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`ultrasonic nebulizer and another of which was the OptiNeb-ir ultrasonic nebulizer.58
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`The use of the OptiNeb® line of ultrasonic nebulizers with iloprost was also reported
`
`in 2003 in Anesthesiology,59 and 2004 in the European Journal of Anaesthesiology.60
`
`48. The Venta-Neb® nebulizer was also used to deliver iloprost/Ventavis
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`as early as February 2004.61 Indeed, the Nebu-Tec website included information
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`about the Venta-Neb® nebulizer and its use with Ventavis as early as June 2004.62
`
`49.
`
`In September 2005, Schering obtained approval to add the Venta-Neb®
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`nebulizer to the Ventavis label in Europe.63 After the label was approved, the Venta-
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`Neb® nebulizer was used to deliver Ventavis to patients for the treatment of
`
`pulmonary hypertension.
`
`50. After approval of Ventavis with Venta-Neb®, the Ventavis label
`
`included the following information about the use and characteristics of the Venta-
`
`
`58 Ex. 1039.
`
`59 Ex. 1040.
`
`60 Ex. 1041.
`
`61 See Ex. 1007.
`
`62 See Ex. 1014 at Ex. B-3 at 42, 49.
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`63 Ex. 1043; Ex. 1044; Ex. 1045; see also Ex. 1038.
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`
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`20
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 21 of 91
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`
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`Neb®: “Venta-Neb prompts the patient to inhale by an optical and an acoustic
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`signal.”64 The label further instructed patients to “refer to the instruction manual of
`
`the Venta-Neb nebulizer” for additional details.65
`
`51. The Venta-Neb®-ir A-I-C-I User Manual indicates that it is a “Mobile
`
`Ultrasonic Nebulizer for VENTAVIS® Inhalation.”66 The manual is directed to
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`patients in connection with their “treatment with the VENTANEB-ir.”67 The Venta-
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`Neb® User Manual details the functionality of the Venta-Neb® nebulizer.
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`Specifically, it confirms that Venta-Neb® included Nebu-Tec’s A-I-C-I technology,
`
`which stands for active intermittent controlled inhalation.68 This functionality was
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`publicly known at least as early as 2004.69 The Venta-Neb®-ir A-I-C-I User Manual
`
`also explains that the A-I-C-I functionality includes an optical and acoustic signal to
`
`guide a patient’s inhalation:70
`
`
`64 Ex. 1009 at 3, 30.
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`65 Id.
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`66 Ex. 1008 at 1.
`
`67 Id. at 2.
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`68 Id. at 32.
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`69 See e.g. Ex. 1014 at Ex. A-1 at 4.
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`70 Ex. 1008 at 32.
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`
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`21
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 22 of 91
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`52. The Venta-Neb®-ir A-I-C-I User Manual also explains that “[d]ue to
`
`this to this inhalation-scheme, a more efficient and a precise dosage can be
`
`
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`guaranteed.”71
`
`53. Ventavis was subsequently approved in the United States in 2004 and
`
`is indicated for the treatment of pulmonary hypertension. As the first commercially
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`available inhalation treatment for pulmonary hypertension, Ventavis demonstrated
`
`the potential for future inhalable drugs for the treatment of pulmonary hypertension.
`
`54. Another pulsed ultrasonic nebulizer manufactured by Nebu-Tec,
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`known as OptiNeb®, was also known to be used to deliver inhaled treprostinil by
`
`the mid-2000s.
`
`55. Specifically, in the Fall of 2004, researchers at the University of
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`Giessen in Germany—including Robert Voswinckel and Hossein Ghofrani—
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`published their initial findings of a study involving the use of OptiNeb® to deliver
`
`
`71 Id. at 33.
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`
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`22
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 23 of 91
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`
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`treprostinil.72 Specifically, the results were published in an October 2004
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`supplement to Circulation, naming Voswinckel as the lead author.73 The abstract
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`was published in advance of presentation of the study at the 2004 American Heart
`
`Association conference in New Orleans, which was held from November 7-10,
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`2004.74
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`56. This Voswinckel study observed the effects of inhaled treprostinil in 17
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`patients with severe pulmonary hypertension.75 Using a “pulsed OptiNeb®
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`ultrasound nebulizer,” and a solution containing 600 µg/mL of treprostinil, each
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`patient took three single breaths from the device and was observed for two hours.
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`Voswinckel’s study also observed the effects from two patients who received four
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`of these doses per day. Voswinckel concluded that inhaled treprostinil “resulted in
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`a sustained, highly pulmonary selective vasodilation over 120 minutes.” Further,
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`“[t]olerability is excellent even at high drug concentrations and short inhalation
`
`
`72 Ex. 1003 at 7; see also Ex. 1046 at 22 (disclosing the results of a test of inhaled
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`treprostinil administered to 21 patients using an OptiNeb® ultrasonic nebulizer and
`
`measuring effects for 180 minutes).
`
`73 Id.
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`74 Ex. 1048 at 1, 3.
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`75 Ex. 1003 at III-295.
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`
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`23
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1002, p. 24 of 91
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`times (3 breaths). Long-term treatment effects are very promising.” Voswinckel’s
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`findings gained immediate interest, as they were cited in a 2005 paper by Sulica and
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`Poon in Expert Review of Cardiovascular Therapy.76
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`57. Voswinckel and others published a second paper in 2004 discussing the
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`use of OptiNeb® to deliver inhaled treprostinil.77 This study also used an “Optineb
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`ultrasound nebulizer” but in a continuous administration mode, producing a constant
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`stream of aerosol for six minutes.78 This study administered treprostinil to 21
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`patients (8 receiving placebo), using formulations containing 16, 32, 48, or 64
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`µg/mL of treprostinil.79 The patients were observed periodically for 180 minutes
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`following inhalation, and Voswinckel similarly concluded that “[t]reprostinil
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`inhalation results in a significant long-lasting pulmonary vasodilation.”80
`
`58. Some of the same researchers published another paper in June 200
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