IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`UNITED THERAPEUTICS
`CORPORATION,
`
`v.
`
`Plaintiff,
`
`C.A. No. 1:20-cv-00755-RGA
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`Defendant.
`
`EXPERT REPORT OF DR. IGOR GONDA
`
`IPR2021-00406
`United Therapeutics EX2091
`
`

`

`Table of Contents
`
`Page
`
`I.
`II.
`III.
`IV.
`
`V.
`
`VI.
`
`INTRODUCTION ............................................................................................................. 1 
`MATERIALS CONSIDERED .......................................................................................... 1 
`BACKGROUND AND QUALIFICATIONS ................................................................... 1 
`LEGAL PRINCIPLES ....................................................................................................... 3 
`A.
`Claim Construction ................................................................................................ 3 
`B.
`Level of Ordinary Skill in the Art .......................................................................... 4 
`C.
`Obviousness ........................................................................................................... 5 
`D.
`Anticipation............................................................................................................ 6
`E.
`Written Description ................................................................................................ 6 
`F.
`Enablement ............................................................................................................ 6 
`G.
`Indefiniteness ......................................................................................................... 7 
`BACKGROUND TO THE ART ....................................................................................... 8 
`A.
`History of Inhalation Therapy ................................................................................ 8 
`B.
`Inhaled Treprostinil and Its Analogues ................................................................ 10 
`C.
`Well Known Considerations for Inhalation Therapies ........................................ 12 
`’793 PATENT .................................................................................................................. 16 
`A.
`The Specification ................................................................................................. 16 
`B.
`The Claims of the ’793 Patent ............................................................................. 17 
`VII. SUMMARY OF OPINIONS ........................................................................................... 18 
`VIII. SUMMARY OF PRIOR ART ......................................................................................... 19 
`A.
`’212 Patent ........................................................................................................... 19 
`B.
`Voswinckel JESC................................................................................................. 21 
`C.
`Voswinckel JAHA ............................................................................................... 22 
`D.
`Voswinckel 2006 ................................................................................................. 24 
`APPLICATION OF THE PRIOR ART TO THE CLAIMS ........................................... 24 
`A.
`Claims 1, 4, and 6-8 Are Obvious Over ’212 Patent in Combination with
`Voswinckel JESC and Voswinckel JAHA .......................................................... 25 
`Claims 1-8 Are Obvious Over ’212 Patent in Combination with
`Voswinckel JESC................................................................................................. 29 
`Claims 1 and 8 Are Rendered Obvious by Voswinckel JAHA in
`Combination with Ghofrani ................................................................................. 29 
`
`IX.
`
`B.
`
`C.
`
`-i-
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`

`

`D.
`
`X.
`
`Claims 4 and 6-8 Are Obvious Over Voswinckel 2006 in Combination
`with the ’212 Patent ............................................................................................. 30 
`Objective Evidence of Non-Obviousness ............................................................ 34 
`E.
`THE DISCLOSURE OF THE ’793 PATENT IS INSUFFICIENT ................................ 35 
`A.
`A POSA Would Not Understand That the ’793 Patent Inventors Were in
`Possession of a Treprostinil Powder Formulation of Suitable for
`Administration in a Dry Powder Inhaler .............................................................. 35 
`THE ASSERTED ’793 PATENT CLAIMS ARE NOT ENABLED .............................. 40 
`A.
`The Specification of the ʼ793 Patent Does Not Enable a Powder
`Formulation of Treprostinil or its Salt ................................................................. 40 
`XII. RESERVATION OF RIGHTS ........................................................................................ 61 
`
`XI.
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`-ii-
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`
`
`I.
`
`INTRODUCTION
`
`1. My name is Igor Gonda and I have been retained by Liquidia Technologies Inc.
`
`(“Liquidia”) as an expert in United Therapeutics Corporation v. Liquidia Technologies Inc., Case
`
`No. 1:20-cv-00755-RGA in the District of Delaware.
`
`2.
`
`I reserve the right to prepare exhibits to summarize and demonstrate my testimony
`
`at trial.
`
`3.
`
`4.
`
`I have not testified as an expert in the past 4 years.
`
`I was paid my customary rate of $850 per hour for my study of this matter and for
`
`any time I might spend testifying. My compensation is in no way dependent on the outcome of
`
`the case.
`
`II. MATERIALS CONSIDERED
`
`5.
`
`In forming my opinions, I have considered the materials specifically cited in my
`
`report as well as the documents identified in Attachment B.1
`
`III. BACKGROUND AND QUALIFICATIONS
`
`6.
`
`I am currently the founder and CEO of Respidex LLC, which has offered consulting
`
`services to pharmaceutical and medical device companies since 2018. Before founding Respidex
`
`LLC, I held leadership positions at several pharmaceutical companies, including Aradigm
`
`Corporation, a company that focused on developing inhalation therapies for the prevention and
`
`treatment of serious respiratory and systemic diseases.
`
`7.
`
`In 1971, I received my Bachelor of Science in Chemistry from the University of
`
`Leeds. In 1974, I received my Ph.D. in Physical Chemistry from the University of Leeds. After
`
`
`1 I understand that counsel for UTC has not yet permitted Liquidia to take the deposition of
`Dr. Robert Roscigno, a named inventor on the ’793 patent, and also a corporate deposition
`concerning the conception and reduction to practice of the invention claimed in the ’793 patent. I
`reserve the right to supplement my expert reports, if needed, to consider this information.
`
`
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`

`

`129.
`
`XI.
`
`THE ASSERTED ’793 PATENT CLAIMS ARE NOT ENABLED
`
`A.
`
`The Specification of the ʼ793 Patent Does Not Enable a Powder Formulation
`of Treprostinil or its Salt
`
`130.
`
`To the extent UTC contends that the asserted claims of the ’793 Patent are not
`
`obvious, it is my opinion that the ’793 Patent specification does not teach a POSA how to formulate
`
`a treprostinil (or a pharmaceutically acceptable salt of treprostinil) powder formulation suitable for
`
`-40-
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`
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`administration via dry powder inhaler (let alone one with particles less than 5 micrometers in
`
`diameter) or a dry powder inhaler capable of administering the treprostinil dry powder formulation
`
`as required by claims 1, 4, 6 and 7 of ’793 Patent without undue or excessive experimentation.
`
`131. As discussed above in Paragraph 25, it is my understanding that the “full scope” of
`
`the ʼ793 Patent claims must be enabled. This would include a treprostinil dry powder formulation
`
`suitable for administration via a dry powder inhaler, as required by claims 1, 6, and 7 of the ʼ793
`
`Patent. This would also include a dry powder inhaler suitable for delivery of the claimed
`
`treprostinil dry powder formulation, as required by claims 1 and 4. I further understand that the
`
`“enablement” requirement requires that a skilled artisan assess several factors, including the
`
`breadth of the claim, the nature of the invention, the state of the prior art, the level of skill in the
`
`art, the level of predictability in the art, the amount of direction provided by the specification, the
`
`existence of working examples, and the quantity of experimentation needed to make and use the
`
`invention. See ¶¶ 22-26, above.
`
`132. Here, claim 1 of the ’793 Patent does not specify a specific type of formulation
`
`suitable for administration by inhalation and thus a POSA would understand the full scope of
`
`claim 1 to include both solutions and powder formulations of treprostinil or a pharmaceutically
`
`acceptable salt of treprostinil. Ex. 1 (’793 Patent) at claim 1. Claim 4 recites a “method of claim
`
`1, wherein the inhalation device is a dry powder inhaler.” Id. at claim 4. Claim 6 recites a “method
`
`of claim 4, wherein the formulation is a powder.” Id. at claim 6. Claim 7 recites a “method of
`
`claim 6, wherein the powder comprises particles less than 5 micrometers in diameter.” Id. at claim
`
`7. The dependent claims of the ʼ793 Patent confirm a POSA’s understanding that the full scope
`
`of claim 1 includes powder formulations of treprostinil and its pharmaceutically acceptable salts.
`
`
`
`
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`-41-
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`
`1.
`
`Applying the “Enablement” Factors, a POSA Would Have to Engage
`in Undue Experimentation to Formulate a Powder Treprostinil
`Formulation Suitable with an Appropriate Dry Powder Inhaler for
`Effective Administration in General and for the Treatment of PH in
`Particular
`
`133. Applying the “enablement” factors discussed above in Paragraph 24, it is my
`
`opinion that a POSA would have to engage in excessive (undue) experimentation to develop a
`
`treprostinil powder formulation and corresponding dry powder inhaler that achieve effective
`
`administration of treprostinil as required by claims 1, 4, 6, and 7 of the ʼ793 Patent. The following
`
`is a summary of the factors a POSA considers for enablement and further discussion is provided
`
`in the paragraphs that follow.
`
`a. Breadth of the Claim: As discussed in Paragraphs 118-119, claim 1 of the ’793
`
`Patent is broad and encompasses formulations of treprostinil or its pharmaceutically
`
`acceptable salt in solution and powder forms. Moreover, claims 4, 6, and 7
`
`specifically claim treprostinil powder formulations and use of dry powder inhalers.
`
`Additionally, the asserted claims of the ’793 Patent encompass all treprostinil free
`
`acid and salt forms. Accordingly, it is my opinion that the asserted claims of the
`
`’793 Patent are broad.
`
`b. Existence of Working Examples: As described in greater detail below, the ’793
`
`Patent specification provides no working examples of dry powder treprostinil
`
`formulations or a dry powder inhaler, or a combination of the two for delivery of
`
`treprostinil or its salts. With respect to the formulation, there is no method of
`
`preparation of such powders described in ’793 Patent. Further, the ʼ793 Patent does
`
`not describe any excipients that can be used in dry powder formulations, and none
`
`of the Examples in the ’793 Patent utilize a dry powder formulation of treprostinil
`
`or its salt. Ex. 1 (’793 Patent) at 8:58-18:11. The only guidance provided by the
`-42-
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`
`
`
`
`
`
`’793 Patent as to the powder formulation is to a particle size of “less than 10
`
`micrometers in diameter or less than 5 micrometers in diameter” (id. at 7:24-26),
`
`which was already well-known in the art as of May 15, 2006. Ex. 25 (Telko &
`
`Hickey 2005) at 1219; Ex. 7 (Clark) at 375 (Table 1).
`
`c. Nature of the Invention: The nature of the invention is a “method’ for treating
`
`pulmonary hypertension, but that method requires administration by inhalation of
`
`a “formulation” of treprostinil or its pharmaceutically acceptable salt using an
`
`“inhalation device.” Ex. 1 (’793 Patent) at claim 1. Further, that method requires
`
`from 15 micrograms to 90 micrograms of treprostinil or its pharmaceutically
`
`acceptable salt to be inhaled in 1-3 breaths. Id. Thus, while the nature of the
`
`invention is treating pulmonary hypertension, that treatment must be accomplished
`
`by, among other things, a powder formulation of treprostinil or its salt and a specific
`
`dry powder inhaler, which operates in a much different manner than inhalers that
`
`administer solutions such as nebulizers, soft mist inhalers, or metered dose inhalers
`
`that use propellants to form aerosols containing treprostinil (these could be
`
`solutions or suspensions of treprostinil in the propellants). Almost without an
`
`exception, dry powder inhalers use the energy of the patient’s inspiration to elicit
`
`the drug from the device and disperse it into particles suitable for inhalation into
`
`the lungs. Ex. 24 (Atkins) at 1306-1307 (“Currently available DPIs are all passive
`
`systems, meaning that the patient must provide the energy to disperse the powder
`
`from the device.”). This differs from other types of inhalers where the device itself
`
`(e.g., using electricity or the energy of a compressed gas) generates the small
`
`particles or droplets. Therefore, a POSA would need to identify a dry powder
`
`-43-
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`
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`inhaler that suits the needs of the specific patient population (i.e., PH). Id. at 1307-
`
`1308 (“[I]t is important that physicians recognize that these [DPI] devices will
`
`deliver different amounts of drugs to different patients, and the lung delivery
`
`depends on patient factors, such as inspiratory flow, patient inhalation technique,
`
`and device resistance.”).
`
`d. Especially considering the PH population suffers from a severe lung disease,
`
`identifying a suitable dry powder inhaler and treprostinil powder formulation for
`
`the PH population would require substantial time and effort. Additionally, although
`
`several DPIs were available for the treatment of asthma and COPD, there was no
`
`experimental work reported on the use of DPIs in PH patients. For instance, a
`
`POSA would have to determine that a PH patient could inspire at a high enough
`
`inhalation rate and volume for the powder formulation to disperse and fully inhale
`
`an adequate dose. And conversely, a POSA would have to find the appropriate
`
`combination of DPI and formulation to effectively deliver treprostinil in a dry
`
`powder form to PH patients. It was well-known that different DPIs had different
`
`flow resistance and therefore required different inspiratory effort to be functional.
`
`See Ex. 54 (Clark & Hollingworth 1993) at 102; Ex. 24 (Atkins) at 1307 (“[T]here
`
`are important differences in resistance among the DPIs, and this difference in
`
`resistance causes differences in drug delivery efficiency between these devices.”).
`
`e. Level of Unpredictability in the Art: Considering the significant number of factors,
`
`discussed herein, involved in developing a dry powder formulation and suitable dry
`
`powder inhaler device, the level of unpredictability in the art was high. As
`
`explained below, powders present unique design challenges. Ex. 25 (Telko &
`
`-44-
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`

`

`Hickey 2005) at 1211-1212 (“The aerodynamic behavior, which has a profound
`
`effect on the disposition of drug from a DPI, is particularly sensitive to powder
`
`properties.”). Formulation of dry powders requires ensuring that the particle will
`
`not change in structure, crystallinity, size, or density during manufacture, storage,
`
`and administration. See ¶¶ 147-153 below. With especially potent drugs like
`
`treprostinil, moreover, a POSA would need to ensure that a consistent amount of
`
`active drug is delivered to the desired parts of the respiratory tract. See ¶ 139 below.
`
`f. State of the Prior Art: While solutions of treprostinil and other prostacyclins like
`
`iloprost for inhalation were known by May 2006, no treprostinil powder
`
`formulation suitable for delivery using a dry powder inhaler had been developed or
`
`disclosed as of May 15, 2006. Accordingly, the state of the prior art as it pertains
`
`to powder formulations of prostacyclin and its analogs, including treprostinil, for
`
`delivery via a dry powder inhaler in general and for PH patients in particular as of
`
`May 15, 2006 was relatively minimal.
`
`g. Level of Skill in the Art: The level of skill in the art was high. As I explained
`
`above in Paragraph 14, a POSA as of May 2006 with respect to inhaled
`
`formulations used in a method of treating pulmonary hypertension would be a Ph.D.
`
`in pharmaceutical science or a related discipline like chemistry or medicinal
`
`chemistry, plus two years of experience in pharmaceutical formulations, including
`
`inhaled products, or equivalent (e.g., an M.S. in the same fields, plus 5 years of
`
`experience).
`
`h. Quantity of Experimentation: As discussed herein, to formulate a powder
`
`formulation of treprostinil suitable for administration via a dry powder inhaler, a
`
`-45-
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`

`
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`POSA would have to engage in a significant amount of experimentation. Among
`
`other reasons, a POSA would need to test such formulations in suitable powder
`
`inhalers. Further, the combination of the inhaler device and the formulation would
`
`have to accommodate for variations in patients’ ability to breathe correctly to
`
`ensure that the correct amount of active drug is delivered to the desired parts of the
`
`respiratory tract for each patient. See Ex. 54 (Clark & Hollingworth 1993) at 102.
`
`A POSA would have to ensure that the formulation was sufficiently stable to
`
`withstand storage and administration without altering the size, shape, and density
`
`and other properties, such as water content, that might affect the clinical
`
`performance (inhaled dose and its particle size distribution) of a dry powder inhaler
`
`product delivering treprostinil.
`
`2.
`
`The ’793 Patent Provides No Guidance or Working Examples as to
`How a POSA Would Formulate a Powder Formulation of Treprostinil
`
`134. As discussed in Section X above, the ʼ793 Patent only includes the use of solutions
`
`of treprostinil and its salts for inhalation. The only formulation details provided in the ʼ793 Patent
`
`pertain to aqueous solutions (Ex. 1 (’793 Patent) at 7:39-46), and generally discloses the use of
`
`water, ethanol or a mixture thereof. There is no disclosure of any specific excipients that could be
`
`used to make a powder formulation of treprostinil suitable for a dry powder inhaler. In fact, the
`
`Examples of the ʼ793 Patent provide no formulation details other than the fact that the treprostinil
`
`was administered as a solution with concentrations described in µg/ml. Id. at Examples 1 and 2.
`
`135. All of the Examples provided in the ’793 Patent describe clinical studies involving
`
`the administration of treprostinil solutions via soft mist inhalers and pulsed nebulizers. Id. at 8:57-
`
`16:54. For instance, Example 1 describes a clinical study in which treprostinil solutions were
`
`administered to humans via a soft mist inhaler. Id. at 8:57-11:67. The ’793 Patent explains that
`
`
`
`
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`-46-
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`
`
`“[t]he solution used for aerosol generation was prepared from treprostinil sodium salt . . . .” Id. at
`
`10:23-25 (emphasis added). Similarly, Example 2 describes three clinical studies in which
`
`treprostinil solutions (in concentrations described in µg/mL) were administered to humans via
`
`pulsed ultrasonic nebulizers. Id. at 12:58-59 (“All inhalations were performed with the
`
`OPTINEB® ultrasonic nebulizer (Nebutec, Elsenfeld, Germany).”) (emphasis added). As its
`
`manual makes clear, the OPTINEB® ultrasonic nebulizer is used for nebulization of solutions and
`
`cannot be used to administer dry powders. Ex. 49 (OPTINEB-ir Translation) at 30 (noting
`
`“[d]evice does not generate any aerosol” when “[n]o liquid (medication solution) in the medication
`
`cup”).
`
`136. The sole sentence in the ’793 Patent that discusses powder formulations provides
`
`no details as to the formulation other than particle size. See Ex. 1 (’793 Patent) at 7:22-26 (“The
`
`inhalation device can also be a dry powder inhaler. In such case, the respiratory drug is inhaled in
`
`solid formulation, usually in the form of a powder with particle size less than 10 micrometers in
`
`diameter or less than 5 micrometers in diameter.”). As discussed further below, this bare-bones
`
`disclosure would be insufficient to teach a POSA to develop a treprostinil dry powder formulation
`
`and corresponding dry powder inhaler device. Such experimentation would have been challenging
`
`because of treprostinil’s high potency and the need for precise dosing to match PH patients’ needs
`
`with respect to efficacy and tolerability
`
`3. Without Guidance, Formulation of a Treprostinil Powder Suitable for
`Administration via a Dry Powder Inhaler Would Require Undue
`Experimentation
`
`137. Without guidance from the ʼ793 Patent, a POSA would be unable to formulate a
`
`treprostinil powder suitable for administration via a dry powder inhaler for PH patients without
`
`excessive experimentation. First, it is well-accepted in the field that nebulized solutions like that
`
`disclosed in the ’793 Patent are not compatible with dry powder inhalers. Conversely, a dry
`
`-47-
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`
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`powder inhaler cannot deliver solutions. Second, because treprostinil is highly potent, a POSA
`
`would need to formulate treprostinil with a compatible carrier to ensure that a precise amount of
`
`the active drug is delivered to the targeted areas of the respiratory tract. That experimentation
`
`would not be routine as the interaction of each type of carrier with each type of solid form of
`
`treprostinil or its salt used for these experiments would need to be undertaken, including the
`
`chemical and physical stability of such combinations during processing and storage. Third, a
`
`POSA would need to investigate the ability of the PH patients to breathe adequately through a dry
`
`powder inhaler and across the range of disease severity to ensure delivery of reproducible
`
`treprostinil doses to the lungs using the precise device-formulation combination. Furthermore,
`
`dose content uniformity for a highly potent drug like treprostinil is also challenging, i.e., making
`
`sure that the powder formulation in each inhaled dose contains the same amount of Treprostinil
`
`delivered to the lung. Fourth, a POSA would need to ensure that the formulation is sufficiently
`
`stable to prevent changes to the chemical composition and particles’ size, shape, density, and water
`
`content, as they all have been found to impact the performance of dry powder inhalers in terms of
`
`the delivered dose and its reproducible dispersibility into particles suitable for deposition in the
`
`human respiratory tract. Again, such experimentation, even with the knowledge possessed by a
`
`POSA as of May 2006, would not have been routine.
`
`138. First, nebulized solutions like that disclosed in the ’793 Patent are not compatible
`
`with dry powder inhalers. I understand that named inventor Dr. Rubin testified:
`
`Q. Could you use a solution in a dry powder inhaler?
`
`A. No, they’re completely different. Solution is a formulation that includes liquid.
`The medication in this case is put into solution to create a solution of a certain
`amount on concentration to be used to deliver through a delivery vehicle that is
`designed to deliver particles in a mist, particles of a certain size delivered through
`a mist to the patient. So that could be a nebulizer. It could be a soft mist or a
`metered dose inhaler. They all would use the same principle of creating a
`breathable hydrated formulation of the drug.
`-48-
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`
`
`Dry powder inhaler has no water or other carrier solution. It is simply particles of
`drug that have been formulated such that the particles would contain a specified
`amount of drug and would be deliverable through a device directly to the lungs
`without requiring it to be put in any kind of solution whatsoever.
`
`Ex. 50 (Rubin 2021 Dep. Tr.) at 97:13-98:12 (emphasis added). I agree with Dr. Rubin that
`
`formulation of dry powder formulations is completely different than formulation of nebulized
`
`solutions, and that devices for delivery of solutions are unsuitable for delivery of dry powder
`
`formulations and that devices for delivery of dry powders are unsuitable for delivery of solutions.
`
`139. Second, because treprostinil is a highly potent drug, I understand that the dry
`
`powder formulation needs to be such that a precise amount of treprostinil is delivered to a patient
`
`in each dose using a dry powder inhaler. Ex. 50 (Rubin 2021 Dep. Tr.) at 93:25-95:3 (testifying
`
`“unlike asthma drugs where you give a little more, you give a little less, it’s not a big deal. These
`
`are were potent compounds and so the delivery has to be precise.”); see also Ex. 1038 at 1310
`
`(“The small dose size required for many of these potent drugs is a confounding factor in developing
`
`optimal DPIs.”); Ex. 55 (Gonda 1991) at 109 (“[T]he drug has to be delivered in a precise amount
`
`into the dosage form during the manufacture, and out of it into the patient during inhalation.”).
`
`Dosing a drug like treprostinil with relatively narrow margins of differences between the required
`
`dose for efficacy and a dose that causes adverse reactions such as treprostinil is more challenging
`
`than for drugs which were routinely delivered by inhalation pre-2006 in the form of dry powder
`
`inhalers such as asthma drugs, as noted also by Dr. Rubin. Ex. 50 (Rubin 2021 Dep. Tr.) at 93:9-
`
`95:3; see also Ex. 17 (Ventavis® Label); Ex. 38 (Voswinckel JESC). Such drugs require precise
`
`dosing, which, as described further below, would have been a challenge for delivery of treprostinil
`
`to PH patients using a dry powder inhaler.
`
`140. To precisely dose a potent drug like treprostinil, it is necessary to mix the API with
`
`a carrier material to provide adequate bulk, so that the drug can be precisely metered. Ex. 25
`
`
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`-49-
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`(Telko & Hickey 2005) at 1221 (“Usually, no more than a few milligrams of drug need to be
`
`delivered, and [carriers] provide bulk, which improves handling, dispensing, and metering of the
`
`drug.”).
`
`141. For nebulized solutions of treprostinil, like those discussed in Examples 1 and 2 of
`
`the ’793 Patent, the carrier is water—a material of indisputable safety, particularly in the absence
`
`of additives like metacresol. In addition to water, the qualitative and quantitative composition of
`
`excipients to make such solutions for inhalation safe and well tolerated was well understood. See
`
`generally Ex. 1070. Often sodium chloride and buffers well-known to be safe and tolerable are
`
`used. The methods for testing the performance of nebulizers with solutions were well-understood
`
`and routine for a POSA to use. See Ex. 56 (O’Callaghan & Barry 1997) at S35-S39; see also
`
`Ex. 73 (Cipolla 1994) at 51-61. The methods of achieving precise dosing with nebulizers,
`
`including pulsed nebulization, were also described. Ex. 72 (Denyer 2004).
`
`142. For dry powders, however, there were very few carriers available with proven
`
`tolerability and safety by inhalation as of May 2006. Ex. 25 (Telko & Hickey 2005) at 1221
`
`(“Currently, lactose is the only excipient used in DPIs marketed in the United States.”). As of
`
`September 2005, lactose was the only FDA-approved carrier used in dry powder formulations in
`
`the United States. Id. Nonetheless, selection of the correct carrier remains of crucial importance
`
`to effective drug administration via dry powder inhaler. Id. (“Despite the apparent lack of choices,
`
`the [carrier] must be carefully selected; physicochemical properties such as size and morphology
`
`profoundly affect the performance of the formulation.”). And even after a non-toxic and tolerable
`
`carrier is identified, a POSA must ensure that the carrier does not react chemically with the API
`
`(i.e., treprostinil). It is noteworthy that only two treprostinil dry powder inhaler products have
`
`
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`-50-
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`been developed and submitted to the FDA: MannKind and Liquidia. See Ex. 50 (Rubin 2021 Dep.
`
`Tr.) at 167:7-22; see also ¶¶ 127-128 above.
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`143. Third, a POSA must ensure that delivery of the treprostinil powder formulation via
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`a dry powder inhaler is reproducible. Ex. 25 (Telko & Hickey 2005) at 1210 (“Dose uniformity is
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`a challenge in the performance of DPIs. This is a greater concern with powders than with liquids
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`because of the size and discrete nature of the particulates.”); see also Ex. 24 (Atkins) at 1311
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`(“[C]ommon to the development of all systems is an appreciation that one of the most important
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`factors in pulmonary delivery from a DPI is the requirement for a good-quality aerosol (in terms
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`of the aerodynamic particle size of the cloud generated) and its potential to consistently achieve
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`the desired regional deposition in vivo. This has been the goal of many scientists over many years
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`and we are still short of that goal.”). Since at least 2005, it was well-known that powders present
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`unique design challenges compared to liquid formulations because, among other reasons, they are
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`2-phase gas-solid systems. Ex. 25 (Telko & Hickey 2005) at 1211-1212 (“The character of
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`particulate systems is central to the performance of DPIs. Powders present unique design
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`challenges.”); Ex. 7 (Clark) at 382 (“[I]n contrast to nebulizer formulations, or indeed to some
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`extent pMDI formulations, the formulation of dry powders for use in DPIs is critically important
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`for their effective performance.”). When static, powders behave as solids; when flowing, powders
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`behave as liquids; and when dispersed in the air, powders behave as their carrier gas. Ex. 25 (Telko
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`& Hickey 2005) at 1212 (“As a consequence, equations describing the behavior of solids are less
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`predictive than their fluid counterparts.”).
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`144. A significant challenge to reproducibility of drug delivery is that dry powder
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`inhalers, unlike nebulizers, soft mist inhalers and pressurized-MDIs, use the patient’s breathing
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`effort to elicit the powder from the inhaler and disperse the powder in the device into respirable
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`particles of the correct size. Id. at 211 (“When a patient activates the DPI and inhales, airflow
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`through the device creates shear and turbulence; air is introduced into the powder bed and the static
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`powder blend is fluidized and enters the patient’s airways.”). Most common form of dry powder
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`inhalation formulations, especially for potent drugs like treprostinil, was in the form of large carrier
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`particles (at that time in USA only lactose carrier was in the approved products) onto which the
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`small drug particles were adhered. When the dry powder is dispersed in the device and carried via
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`the patient’s mouth to enter the lungs, carrier particles must separate from the drug particles with
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`the former impacting in the oropharynx while the drug particles are carried deeper into the lungs.
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`Id. Variabilities in patient breath can cause inadequate and variable drug-carrier separations during
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`inhalation. Id. at 1211 (“[D]eposition into the lungs is determined by the patient’s variable
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`inspiratory airflow.”); Ex. 24 (Atkins) at 1307-1308 (“[L]ung delivery depends on patient factors,
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`such as inspiratory flow, patient inhalation technique, and device resistance.”); Ex. 7 (Clark) at
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`384-85 (“[D]elivery and dispersion performance, and hence the dose which [DPIs] deliver to the
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`lung, is affected by a patient’s ability to inhale a suitable high flow rate.”). In contrast, nebulized
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`inhaled solutions contain the drug dissolved uniformly in all droplets in a mist whose generation
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`is afforded by the external energy (from electrical supply to a compressor or a compressed gas
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`from a gas cylinder). The mist already includes droplets of the size suitable for deposition in the
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`lung. Further, in the case of dry powder inhaler the drug enters as a “bolus” at the beginning of
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`the inspiration. Therefore, the volume of air that the subject inhales during the inspiration is also
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`important for reproducible dose delivery to ascertain efficacy. Consequently, the development of
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`a dry powder inhaler product requires matching the compatibility of the device and the formulation
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`also with the ability of the PH patients to inhale the formulation such that a reproducible precise
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`dosing is possible. Different powder inhalers have different flow resistance. Ex. 54 (Clark &
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`Hollingworth 1993); Ex. 24 (Atkins) at 1307. These require different inspiratory efforts by
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`patients, achieve differe