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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`_____________________________
`
`Case No. IPR2020-00770 –
`Patent No. 9,604,901
`_____________________________
`
`DECLARATION OF RODOLFO PINAL, PH.D.
`SUPPORTING UNITED THERAPEUTIC CORPORATION’S
`PATENT OWNER RESPONSE
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`TABLE OF CONTENTS
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` Page
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`I. 
`II. 
`III. 
`IV. 
`V. 
`
`QUALIFICATIONS ............................................................................................ 1 
`SCOPE OF WORK ............................................................................................. 4 
`SUMMARY OF OPINIONS .................................................................................. 5 
`LEGAL PRINCIPLES.......................................................................................... 7 
`OVERVIEW OF THE ’901 PATENT ..................................................................... 8 
`Claims of the ’901 Patent .................................................................. 9 
` 
`Prosecution Histories ...................................................................... 10 
` 
`1.  The Examiner Already Considered All of Liquidia’s Prior Art
`During Prosecution .......................................................................... 10 
`2.  Examiner Valenrod Considered the Full Record of the ’393
`IPR During Prosecution .................................................................. 15 
`3.  The ’393 IPR Final Written Decision is Not Material to the
`Patentability of the Challenged Patent Claims ................................ 17 
`THE LEVEL OF ORDINARY SKILL IN THE ART ............................................... 24 
`VI. 
`VII.  CLAIM TERMS ............................................................................................... 34 
`“Pharmaceutical Product” ............................................................... 35 
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`“Pharmaceutical Batch” .................................................................. 37 
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`“A Salt Treprostinil” ....................................................................... 40 
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`“Storing” and “Storage” .................................................................. 40 
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`VIII.  DR. WINKLER’S GROUNDS LACK CREDIBLE BASES, IGNORE CLAIM
`LIMITATIONS, AND MISCONSTRUE THE ASSERTED ART ............................................ 42 
`  Misguided Focus on General Syntheses of Treprostinil ................. 42 
`Lack of Support for Conclusions .................................................... 52 
` 
`1.  Phares Does Not Render Obvious Claims 1-9 of the ’901
`Patent. .............................................................................................. 53 
`2.  Moriarty and Phares Do Not Render Obvious Claims 1-9 of the
`’901 Patent. ....................................................................................108 
`Further Considerations of Process Impurities ...............................132 
` 
`CONCLUDING STATEMENTS ........................................................................ 138 
`APPENDIX – LIST OF EXHIBITS ................................................................... 139 
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`IX. 
`X. 
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`I, Rodolfo Pinal, declare as follows:
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`
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`I am the same Rodolfo Pinal that submitted the declaration marked as
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`Exhibit 2002 in this proceeding.
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`I. QUALIFICATIONS
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`
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`I am currently Associate Professor in the Department of Industrial and
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`Physical Pharmacy at Purdue University, in West Lafayette, Indiana, where I have
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`been teaching since 2003. I also serve as Director of the NSF-I/UCRC Purdue
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`Dane O. Kildsig Center for Pharmaceutical Processing Research (CPPR), a
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`position I have held since 2005. Since 2016, I have served as Director of Graduate
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`Studies in the Department of Industrial and Physical Pharmacy at Purdue. I am also
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`a member of the Faculty Senate at Purdue.
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`I received my Ph.D. from the University of Arizona in Pharmaceutical
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`Sciences with a concentration in Physical Chemistry and have over 30 years of
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`experience studying formulation science, specifically on aspects pertaining to
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`formulations for pharmaceutical composition and pharmaceutical product
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`development.
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`Prior to joining academia, I gained over thirteen years of industry
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`experience in pharmaceutical research and development as a scientist with
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`Hoffman-La Roche. From 1990-1993, I served as a Research Associate and then as
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`a Senior Scientist in the pre-formulation group. During this time, my work focused
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`on the physiochemical characterization of new chemical entities (i.e., drug
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`candidates), including developing stability-indicating methods, stability screening
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`of drug candidates, photodegradation and drug-excipient compatibility studies, and
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`solubility/solubilization and partitioning studies.
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`
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`From 1993-1997, I served as a Principal Scientist in the Sterile
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`Dosage Forms group at Roche. In this role, I developed injectable formulations for
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`new and investigational drug products. I was responsible for developing
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`formulations for use in clinical trials, development of HPLC methods for assaying
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`potency and stability of the active compound as well as pharmaceutical
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`compositions intended for injection. I was also responsible for writing the
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`directions for manufacturing clinical batches in the cGMP suite and for supervising
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`the sterile suite operators during the manufacture of the resulting pharmaceutical
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`products.
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`From 1997-2003, I served as Principal Scientist and then a Research
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`Leader in the Solid-State Pharmaceutics group at Roche, which was part of the oral
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`dosage forms development group. In this role, I was responsible for identifying and
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`devising methods for the measurement and monitoring of physical
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`properties/parameters critical for the development of a given specific
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`pharmaceutical product or process. I also worked extensively with process
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`chemists from the Chemical Synthesis Department “Kilo Lab” at the company’s
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`site in New Jersey, as well as with process chemists from the industrial production
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`site located in South Carolina.
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`I have first-hand industrial experience in the scale-up process for
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`making APIs (active pharmaceutical ingredients). The laboratory under my
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`supervision was responsible for the solid-state characterization of every batch of
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`API generated at the New Jersey facility during the scale up of the synthesis. This
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`responsibility extended to API batches produced at other sites but utilized during
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`research and development at the New Jersey plant. The solid-state characterization
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`work performed in my laboratory included crystal form and polymorphism,
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`covering thermodynamic vs. kinetic stability, hygroscopicity, crystal morphology,
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`particle size, solvates, hydrates, etc. A quick description of part of my
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`responsibilities is as follows. As process (Kilo Lab) chemists began to work on
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`replacing the synthetic process of APIs originally used by (drug discovery)
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`medicinal chemists, toward one suitable for large scale production, they sent
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`samples of their produced batches to me. My laboratory performed the solid-state
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`characterization work required and convey the information to the Kilo Lab.
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`Through an iterative process, the two groups would find the different polymorphs
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`of the API, establish the stability relationship among them, and also establish the
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`specifications for crystal morphology, particle size among the relevant attributes
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`necessary for downstream processing. I was responsible for writing the sections
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`pertaining to crystal polymorphism and particle morphology included in NDA and
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`IND submissions to the FDA.
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`A listing of my credentials and publications was previously provided
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`as Exhibit 2003. See also EX2002, ¶¶1-12.
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`II. SCOPE OF WORK
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`I understand that the Board has instituted a petition for Inter Partes
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`Review of U.S. Patent No. 9,604,901 (IPR2020-00770). I understand the petition
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`was filed on behalf of Liquidia Technologies, Inc. (“Liquidia”). I understand the
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`challenged patent is currently assigned to United Therapeutics Corporation (“UT”).
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` UT retained me as a technical expert in both proceedings to provide
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`various opinions regarding the ’901 patent. I have not previously served as an
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`expert witness for UT other than in the preparation of the declaration I previously
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`submitted in this proceeding. I do not have any current or past affiliation with
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`Liquidia.
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`I have been specifically asked to review the Institution Decision
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`rendered by the Board in this proceeding, and, in light of the determinations made
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`by the Board, provide additional expert opinions on the validity of claims 1-9 of
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`the ’901 patent. In connection with my analysis, in addition to reviewing the
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`Institution Decision and materials I considered in connection with my first
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`declaration (EX2002), I have reviewed the deposition testimony of Dr. Winkler. I
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`have also reviewed and considered various other documents in arriving at my
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`opinions and may cite to them in this declaration. For convenience, I list additional
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`documents considered in arriving at my opinions in Section X.
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` UT is compensating me $480 per hour for my services. No part of my
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`compensation depends opinions or on the outcome of this proceeding.
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`III. SUMMARY OF OPINIONS
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` As noted in my first declaration, Dr. Winkler asserts “three strong
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`reasons” that purportedly support a finding of unpatentability. See Declaration of
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`Dr. Jeffery D. Winkler (“Winkler,” EX1002), ¶36. Each of these reasons lacks
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`merit. In my opinion, neither Dr. Winkler’s testimony nor his references
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`demonstrates a reasonable likelihood that any of the challenged claims is rendered
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`obvious by Phares alone, or is rendered obvious by Moriarty in view of Phares.
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`In my opinion, the Board’s provisional determination that “the
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`combination of Moriarty and Phares teaches the same process steps as challenged
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`claim 1 [such that] the product from these steps would include the same resulting
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`impurities” was based on flawed and unsupported testimony. See Institution
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`Decision, 27. Rather, as even Dr. Winkler acknowledges, the same general
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`synthetic steps – in terms of main starting materials and products – does not
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`guarantee sameness in the final product or impurity profile. Indeed, Dr. Winkler
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`testified that:
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`[V]ariations could be [due to] different experimentalists. They could
`involve things like the rate of addition being not exactly the same in
`the two cases. The method of st[ir]ring being not exactly the same in
`the two cases. The solvents, even though they’re said to be exactly the
`same, maybe they’re not exactly the same. And maybe one introduces
`an impurity that the other one doesn’t, or a contaminant. So it’s the
`kind of thing where I think we really have to do the experiment to be
`certain[.]
`Winkler Deposition Transcript, December 14, 2020 (“Winkler Depo.,” EX2026),
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`122:19-123:9. I agree that even the seemingly smallest change – in the process
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`chemist or engineer, or even in the stirring, as Dr. Winkler suggests, can have an
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`effect on the outcome of a reaction.
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`I note, however, when asked if “manufacturing pharmaceutical
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`products” was “a problem facing those skilled in the art,” Dr. Winkler responded
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`“It could be, but I don’t really know. I don’t know what that is or would be.”
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`EX2026 (Winkler Depo.), 72:23-73:9. When asked if any of the exhibits he cited
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`“discuss the preparation of pharmaceutical batches,” Dr. Winkler testified: “I’m
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`afraid that I don’t understand your question.” Id., 94:23-95:2. When asked if “one
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`engaged in pharmaceutical manufacturing use batch the same way” he did, he
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`responded he “d[id]n’t know exactly how that person would be using the term
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`batch.” Id., 97:6-19. These lines of testimony underscore the misguided focus of
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`Dr. Winkler’s analyses in this case, and lack of understanding of the field pertinent
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`to the claims of the ’901 patent. I note for example that in the pharmaceutical field,
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`terms such as “batch” have a clear regulatory definition.
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` As I discuss in more detail below, I continue to hold the opinion that
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`the challenged claims of the ’901 patent recite inventive subject matter that is
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`patentably distinct from the disclosures asserted by Dr. Winkler.
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` Because my first declaration addressed both the ’066 and the ’901
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`patents, many of my opinions were expressed first with regard to the ’066 patent,
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`and then echoed more succinctly for the ’901 patent, by making reference to my
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`analysis of the ’066 patent claims. Yet the ’901 patent is now the only patent
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`undergoing inter partes review. Thus, I have chosen to reiterate much of my
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`testimony from my first declaration, more specifically framing my opinions to the
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`’901 patent claims. In addition, I have added additional analysis in view of the
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`Institution Decision as well as the additional testimony of Dr. Winkler from his
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`December 14, 2020 deposition.
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`IV. LEGAL PRINCIPLES
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` The legal principles applied in my first declaration are again applied
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`here.
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`In addition, I understand that the patent law concept of inherency may
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`supply a missing claim limitation in an obviousness analysis; however, the use of
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`inherency must be carefully circumscribed in the context of obviousness. For
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`example, I understand that the inherency of an advantage and its obviousness are
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`entirely different questions because obviousness cannot be predicated on what was
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`unknown.
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`I further understand that inherency cannot be established by
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`probabilities or possibilities; the putative inherent feature must necessarily be
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`present. The mere fact that a certain thing might result from a given set of
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`circumstances is not sufficient. The concept of inherency must be limited when
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`applied to obviousness and is present only when the limitation at issue is the
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`“natural result” of the combination of prior art elements.
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`I also understand that product-by-process claims are defined at least in
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`part in terms of the method or process by which it is made. I understand that, in
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`determining patentability of a product-by-process claim, the focus is on the product
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`and not the process of making it. I further understand that when the process by
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`which a product is made imparts structural and functional differences
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`distinguishing the claimed product from the prior art, then those differences are
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`relevant as evidence of patentability even though they are not explicitly part of the
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`claim.
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`V. OVERVIEW OF THE ’901 PATENT
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` The ’901 patent is entitled “Process to Prepare Treprostinil, the Active
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`Ingredient in Remodulin®.” EX1001, Title. I understand the ’901 patent has a
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`priority date of December 17, 2007. Id., [60].
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` Claims of the ’901 Patent
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` The ’901 patent has 9 claims. Claim 1, the only independent claim,
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`recites:
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`1. A pharmaceutical batch consisting of treprostinil or a salt thereof
`and impurities resulting from
`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution
`comprising treprostinil,
`(c) contacting the solution comprising treprostinil from step (b)
`with a base to form a salt of treprostinil, (d) isolating the
`salt of treprostinil, and (e) optionally reacting the salt of
`treprostinil with an acid to form treprostinil, and
`wherein the pharmaceutical batch contains at least 2.9 g of
`treprostinil or its salt.
`EX1001 (the ’901 patent), 17:24-18:2; see also EX2007 (Complete ’901
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`Prosecution History (“’901 PH”)), 3-6 (correcting claim 1, which issued reciting
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`“(c) containing the,” to “(c) contacting the”).
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` Claims 2-5 recite limitations associated with the pharmaceutical batch
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`of claim 1. EX1001 (the ’901 patent), 18:3-11.
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` Claims 6-9 are method claims. Claim 6 recites a method of preparing
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`a pharmaceutical product from the pharmaceutical batch of claim 1, comprising
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`storing a pharmaceutical batch of a treprostinil salt at ambient temperature and
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`preparing a pharmaceutical product from the pharmaceutical batch after storage.
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`EX1001 (the ’901 patent), 18:12-17. Claim 8 recites a method of preparing a
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`pharmaceutical batch as recited in claim 1, including forming and isolating a
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`treprostinil salt. Id., 18:20-27. Claims 7 and 9 depend from claims 6 and 8,
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`respectively, and recite that the treprostinil salt is treprostinil diethanolamine. Id.,
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`18:18-19, 28-29.
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`
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`Prosecution Histories
`1.
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`The Examiner Already Considered All of Liquidia’s Prior
`Art During Prosecution
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`
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`I understand Liquidia acknowledges that Examiner Valenrod, who
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`examined the applications that issued as the ’901 patent, “considered both Moriarty
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`(Ex. 1009) and Phares (Ex. 1008) and relied upon these two prior art references in
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`issuing a rejection of all claims” of each of the ’901 patent. Pet., 4. This is true.
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` Liquidia also asserts that “the Examiner did not have an accurate and
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`complete picture of the prior art” when allowing the challenged claims. Pet., 4.
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`This is not true.
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` Examiner Valenrod considered every single prior art reference cited in
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`each petition, and every single prior art reference that Dr. Winkler cites in each of
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`his declarations, during prosecution. More specifically, each of the following
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`documents was expressly marked as considered by Examiner Valenrod. In fact, the
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`’901 patent prosecution history also includes copies of many of these documents,
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`as noted below.
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` EX1007 - U.S. Patent No. 6,765,117 to Moriarty et al.
`o See, e.g., EX2007 (’901 PH):
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` 7270, listing the ’177 patent as considered
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` EX1008 - PCT Patent Application No. WO 2005/007081 to Phares
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`et al.
`o See, e.g., EX2007 (’901 PH):
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` 6928, using Phares in a rejection
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` 6933-7054, full text of Phares
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` 7271, listing Phares as considered
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` EX1009 - Moriarty, et al., The Intramolecular Asymmetric Pauson-
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`Khand Cyclization as a Novel and General Stereoselective Route
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`to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil),
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`J. ORG. CHEM., 69(6) 1890-1902 (2004);
`o See, e.g., EX2007 (’901 PH):
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` 6925-28, 7255, using Moriarty in a rejection
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` 7272, listing Moriarty as considered
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` EX1010 - Wiberg, K., Laboratory Technique in Organic Chemistry,
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`(1960) p. 112;
`o See, e.g., EX2007 (’901 PH):
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` 7056, listing Wiberg as considered
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` 3313-18, 7204-09, same excerpt of Wiberg as
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`submitted in EX1010
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` EX1011 - Schoffstall, A. M., et al., Microscale and Miniscale
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`Organic Chemistry Laboratory Experiments, 2nd ed. (2004) pp.
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`200-02
`o See, e.g., EX2007 (’901 PH):
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` 7056, listing Schoffstall as considered
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` 3302-06, 7210-14, same excerpt of Schoffstall as
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`submitted in EX1011
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` EX1012 - English translation of Japanese Patent Application No. 56-
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`122328A to Kawakami, et al.
`o See, e.g., EX2007 (’901 PH):
` 7271, listing Kawakami as considered
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` EX1013 - Eğe, S., Organic Chemistry, 2nd ed. (1989) pp. 541-47
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`o See, e.g., EX2007 (’901 PH):
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` 7056, listing Eğe as considered
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` 7195-7203, same excerpt of Eğe as submitted in
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`EX1013
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` EX1014 - U.S. Patent No. 4,306,075 to Aristoff
`o See, e.g., EX2007 (’901 PH):
` 7270, listing the ’705 patent as considered
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` 4673-4726, full text of the ’705 patent
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`See also EX1001, [56], 1-3.
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` Dr. Winkler cites to the file history just once in his analysis of the
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`challenged claims. See EX1002, ¶26n.1. I note that Dr. Winkler does not
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`acknowledge, however, that the Examiner previously considered each of prior art
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`references that he cites. See also EX2026 (Winkler Depo.), 74:24-75:9 (noting, “I
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`don’t remember” and “I can’t remember” when asked, e.g., if he “consider[ed] the
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`prosecution history for the ’901 patent in forming your opinion on claim
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`construction”).
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` Examiner Valenrod allowed the challenged claims in the ’901 patent
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`after specifically considering Moriarty (EX1009) and Phares (EX1008). See, e.g.,
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`EX2007 (’901 PH), 7255 (anticipation by Moriarty), 6925-28 (anticipation by
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`Moriarty; obviousness over Moriarty and Phares).
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` Dr. Winkler echoes arguments already raised and resolved during
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`prosecution. EX2007, 7255 (Examiner Valenrod asserting: “Moriarty discloses
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`compound 7 which has the same structure as the instantly claimed product”), 6925-
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`26 (“Although the method of Moriarty and the steps recited in the instant claims
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`are not identical, the product obtained is the same”); EX1002, ¶¶62-72. But this
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`assertion, as Examiner Valenrod later acknowledged, was, and still is, incorrect.
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` UT subsequently amended the pending claims and requested
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`reconsideration of the non-final rejection based on Moriarty and Phares. EX2007
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`(’901 PH), 3819-25 . While noting the commercial process context of the pending
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`claims and the pharmaceutical products to which they were drawn, UT also
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`underscored its desire “to bring to the Examiner’s attention documents from
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`IPR2016-0006,” which involved the “parent” of the ’901 patent—U.S. Patent No.
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`8,497,393. EX2007 (’901 PH), 3822 (similar).
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` Though Examiner Valenrod subsequently issued a Final Rejection for
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`double patenting, he withdrew the prior art-based rejection over Moriarty and
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`Phares. EX2007 (’901 PH), 3808-13. The Examiner withdrew the rejection
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`because the combination of Moriarty and Phares does not teach the claimed
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`pharmaceutical batches or pharmaceutical products recited in the ’901 patent
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`claims. The difference between Moriarty’s treprostinil product and that claimed by
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`UT is presented as secondary to this fact. See, e.g., EX2007 (’901 PH), 3810
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`(withdrawing Moriarty and Phares-based rejections for multiple reasons, including,
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`e.g., claim amendments). As noted in my first declaration, Liquidia ignores these
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`missing teachings in the prior art in both its summary of the file history, as well as
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`in the substantively identical challenge it brings in its IPRs.
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` After UT submitted a terminal disclaimer, having considered all of the
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`submitted materials, including those from the ’393 IPR in addition to each and
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`every prior art document now submitted by Liquidia in the present cases, as well as
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`materials from four pending district court cases, Examiner Valenrod issued a
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`Notice of Allowance. EX2007 (’901 PH), 11-15, 3473-76.
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`2.
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`Examiner Valenrod Considered the Full Record of the ’393
`IPR During Prosecution
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`
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`I understand Liquidia asserts the importance and relevance of the ’393
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`IPR (specifically the final written decision of the ’393 IPR) in challenging the ’901
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`patent. But the final written decision of the ’393 IPR is a legal determination on
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`different claims. It does not alter the fact that the Examiner expressly considered
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`the same prior art when assessing the patentability of the distinct claims of either
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`patent here. And while the ’393 final written decision was not cited during
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`prosecution (it came out three days after the ’901 patent issued), every other
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`material document from that case and related litigation was considered during
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`prosecution and is subsequently cited on the face of the ’901 patent. See EX1001,
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`2-3; see also EX2026 (Winkler Depo.), 82:17-83:3 (Dr. Winkler testifying “I don’t
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`remember” when asked if was “aware that the Examiner knew about the ’393
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`patent record and allowed the ’901 claims anyway”).
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`I understand the file history exhibits submitted by Liquidia and cited
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`by Dr. Winkler were heavily excerpted, running just 178 and 252 pages, while the
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`complete file histories are thousands of pages long. See EX1006, see also Pet., 4;
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`EX1002, ¶26n.1; EX2007 (’901 PH). I understand the pages not submitted by
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`Liquidia include notices of related proceedings and associated papers and exhibits
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`(including the entire record of the ’393 IPR up to the final written decision).
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`I understand Liquidia asserts that Examiner Valenrod “erred in
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`discounting the arguments set forth by the petitioner and its expert in the ’393
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`IPR.” Pet., 5. Nothing suggests these arguments were discounted. Rather, quite the
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`opposite is true. The entire record of the petitioner’s arguments (including even its
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`demonstratives for the final oral hearing) in the ’393 IPR were considered by
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`Examiner Valenrod during prosecution. EX2007 (’901 PH), 20-23 (’393
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`Petitioner’s Demonstratives, Patent Owner Response, Patent Owner
`
`Demonstratives, Institution Decision), 3468 (’393 Petitioner’s Reply), 7056 (’393
`
`Petition). Materials and arguments from four pending district court cases were also
`
`considered by the Examiner, but Liquidia also omitted these pages from the file
`
`-16-
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`

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`
`
`history exhibit in this proceeding. See EX2007 (’901 PH), 21-23; see also, e.g., id.,
`
`37-265, 269-303, 2373-3141.
`
`
`
`In my opinion, there is no indication that after reviewing the entire
`
`record up to the FWD of the ’393 IPR, Examiner Valenrod misunderstood the prior
`
`art, the arguments made in the ’393 IPR, or the materiality of arguments made in
`
`the ’393 IPR to the patentability of the claims of the ’901 patent.
`
`3.
`
`The ’393 IPR Final Written Decision is Not Material to the
`Patentability of the Challenged Patent Claims
`
`
`
`I have also reviewed the ’393 final written decision and find that
`
`Liquidia does not accurately represent the Board’s rationale provided in the ’393
`
`IPR. I also find nothing contradictory between the ’393 IPR final written decision
`
`and Examiner Valenrod’s analysis during prosecution of the ’901 patent.
`
`
`
`In his declaration, Dr. Winkler invokes arguments he previously made
`
`in the context of the ’393 IPR. See, e.g., EX1002, ¶¶36-37. For example, Dr.
`
`Winkler asserts: “since the claim limitations of the ’901 patent are substantively
`
`similar to the invalidated ’393 patent, the ’901 patent should be similarly declared
`
`invalid.” EX1002, ¶36; see also id., ¶37 (asserting “Claims 1-9 of the ’901 patent
`
`should be held invalid for similar reasons as the ’393 patent because the claims of
`
`the ’901 patent are substantively similar to those of the ’901 patent in that they
`
`disclose the same treprostinil and the identical treprostinil salt”). I understand,
`
`-17-
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`however, that Dr. Winkler did not consider that the scope of claim 1 of the ’393
`
`patent is drastically larger than that of the ’901 patent, or whether all of the claims
`
`were product-by-process claims. EX2026 (Winkler Depo.), 65:19-67:23.
`
` Rather, all of Dr. Winkler’s analysis is done through the lens of a
`
`“chemist, looking at the structural formula that’s given in claim 1” of the ’393
`
`patent, and all Dr. Winkler considered is that a chemist “would understand that
`
`[’393 claim 1] could include treprostinil, and that it could also include the
`
`treprostinil diethanolamine salt.” Id., 86:22-87:8; see also id., 88:21-89:3 (“I think
`
`the important thing to me in my analysis was that both the ’393 and the ’901
`
`disclose treprostinil and the treprostinil diethanolamine salt”), 90:1-14 (“[T]hey
`
`disclose the same compound. As a chemist, that’s certainly where my focus is, the
`
`structures and the identities of the chemical entities”), 91:24-92:14 (“I recognize
`
`that the wording in the [] claims [of the ’393 and ’901 patents] are not identical,
`
`but [] the compound that they’re looking at, the compound that they’re describing
`
`is identical,” and “I see no differences in the descriptions of treprostinil and
`
`treprostinil diethanolamine salt, as I understand the claims of the two patents”).
`
`Yet whether or not the ’901 patent recites claims that reference treprostinil or
`
`treprostinil diethanolamine is not the end of the analysis. As I set forth in detail in
`
`my first declaration, and in more detail below, the scope of Dr. Winkler’s analysis
`
`is, at the very most, only the beginning.
`
`-18-
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`
` Dr. Winkler’s assertions are incorrect. The claims of the ’901 patent
`
`recite limitations relating to a pharmaceutical batch consisting of a treprostinil API
`
`(active pharmaceutical ingredient) and impurities. See EX1001 (the ’901 patent),
`
`17:24-18:2; see also, e.g., id., 18:5-9 (claims 3-4, reciting therapeutically effective
`
`amounts of treprostinil or its salt), 18:12-19 (claims 6-7, reciting methods of
`
`preparing a pharmaceutical product that involve storing a pharmaceutical batch of
`
`a treprostinil salt). These limitations do not appear in the ’393 patent claims either.
`
`See EX1004 (’393 patent), 17:52-21:16.
`
`
`
`I provide a table comparing the limitations of the independent claims
`
`of the ’393 and ’901 patents below, as well as their dependent claims, aligning
`
`similar or related limitations horizontally where possible, while highlighting
`
`differences in red.
`
`’393 PATENT CLAIM 1
`
`’393 PATENT CLAIM 9
`
`1. A product comprising
`
`9. A product comprising
`
`’901 PATENT CLAIM 1
`1. A pharmaceutical batch
`consisting of
`
`a compound of formula I
`
`a compound having formula
`IV
`
`
`or a pharmaceutically
`acceptable salt thereof,
`
`wherein said product is
`prepared by a process
`comprising
`
`
`or a pharmaceutically
`acceptable salt thereof,
`wherein the product is
`prepared by the process
`comprising
`
`treprostinil or a salt thereof
`
`
`
`
`-19-
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`

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`
`
`’393 PATENT CLAIM 1
`(a) alkylating a compound of
`[a genus including
`benzindene triol] with an
`alkylating agent to produce a
`compound [from a genus
`comprising treprostinil],
` (b) hydrolyzing the product
`[] step (a) with a base,
`
`7. The product of claim 1,
`[that is treprostinil].
`
` (c) contacting the product
`of step (h) with a base B to
`form a salt of formula Is.
`
`’393 PATENT CLAIM 9
`
`’901 PATENT CLAIM 1
`
`(a) alkylating a compound of
`[a genus including
`benzindene triol] with an
`alkylating agent to produce a
`compound of [a genus
`including the cyano-
`treprostinil precursor]
`(b) hydrolyzing the product
`[]of step (a) with a base,
`
`(c) contacting the product
`of step (h) with a base B to
`form a salt of formula IVs,
`and
`
`and impurities resulting
`from (a) alkylating a
`benzindene triol, (b)
`hydrolyzing the product of
`step (a) to form a solution
`comprising treprostinil,
`
`(c) contacting the solution
`comprising treprostinil from
`step (b) with a base to form a
`salt of treprostinil,
`
`
`
`
`
`
`
`
`
`(d) isolating the salt of
`treprostinil,
`
`(d) optionally reacting the
`salt formed in step (c) with
`an acid to form the
`compound of formula I.
`21. The product of claim 1,
`wherein step (d) is
`performed.
`
`(d) optionally reacting the
`salt formed in step (c) with
`an acid to form the
`compound of formula IV.
`
`and (e) optionally reacting
`the salt of treprostinil with
`an acid to form treprostinil,
`
`and wherein the
`pharmaceutical batch
`contains at least 2.9 g of
`treprostinil or its salt.
`
`
`
`
`
`22. The product of claim
`21, wherein the product
`comprises a
`pharmaceutically
`acceptable salt formed
`from the product of step
`(d).
`
`
`
`
`
`-20-
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`
`’393 PATENT CLAIM 1
`
`’393 PATENT CLAIM 9
`
`
`
`’901 PATENT CLAIM 1
`See claim 1.
`
`8. A method of preparing a
`pharmaceutical batch as
`claimed in claim 1,
`comprising (a) alkylating a
`benzindene triol, (b)
`hydrolyzing the product of
`step (a) to form a solution
`comprising treprostinil, (c)
`contacting the solution
`comprising treprostinil from
`step (b) with a base to form a
`salt of treprostinil, (d)
`isolating the salt of
`treprostinil, and (e)
`optionally reacting the salt
`of treprostinil with an acid to
`form treprostinil.
`
`See claim 1.
`
`See claim 9.
`
`See claim 1.
`
`2. The product of claim 1,
`wherein the purity of
`compound of formula I in
`said product is at least
`99.5%.
`3. The product of claim 1,
`wherein the alkylating agent
`is Cl(CH2) wCN,
`Br(CH2)wCN, or I(CH2)
`wCN.
`4. The product of claim 1,
`wherein the base in step (b)
`is KOH or NaOH.
`
`See also claim 19.
`5. The product of claim 1,
`wherein the base B in step
`(c) is selected from the
`group [that includes
`diethanolamine].
`
`10. The product of claim 9,
`wherein the purity of
`product of step (d) is at
`least 99.5%.
`
`11. The product of claim 9,
`wherein the alkylating agent
`is ClCH2CN.
`
`12. The product of claim 9,
`wherein the base in step (b)
`is KOH