Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner
`v.
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner
`
`IPR2020-00770
`U.S. Patent No. 9,604,901
`
`REPLY DECLARATION OF JEFFREY D. WINKLER, PH.D.
`
`Liquidia's Exhibit 1017
`IPR2020-00770
`Page 1
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`TABLE OF CONTENTS
`
`Page
`INTRODUCTION .......................................................................................... 1
`I.
`II. QUALIFICATIONS ....................................................................................... 2
`III. MATERIALS CONSIDERED ....................................................................... 4
`IV. PERSONS OF ORDINARY SKILL IN THE ART ....................................... 6
`V. UNDERSTANDING OF LEGAL CONCEPTS .......................................... 13
`A. Obviousness ........................................................................................ 13
`B.
`Secondary Considerations of Non-Obviousness ................................ 14
`C.
`Product-By-Process Claims ................................................................ 15
`VI. DR. PINAL MISQUOTES AND MISCHARACTERIZES MY
`DEPOSITION TESTIMONY ....................................................................... 15
`VII. DR. PINAL INCORRECTLY FOCUSES ON INDUSTRIAL SCALE
`PROCESSES ................................................................................................ 36
`VIII. THE ’901 PATENT FILE HISTORY HAS ALREADY BEEN
`ACCURATELY CONSIDERED BY THE BOARD .................................. 41
`IX. THE ’393 IPR IS RELEVANT TO THIS PROCEEDING ......................... 47
`A. Motivation To Combine Moriarty and Phares ................................... 47
`B.
`Comparability of the ’393 Claims and ’901 Claims .......................... 49
`CLAIM CONSTRUCTION ......................................................................... 54
`X.
`XI. GROUND 1: PHARES RENDERS OBVIOUS THE CLAIMS OF
`THE ’901 PATENT ...................................................................................... 54
`A.
`Phares Teaches (+)-Treprostinil Synthesis......................................... 54
`B. Dr. Pinal’s Focus on Impurities and Polymorphs is Misplaced ......... 67
`C. A POSA Would Have Been Motivated to Make the
`Diethanolamine Salt of Treprostinil ................................................... 69
`1. Making a Salt of Treprostinil Would Improve
`Bioavailability .......................................................................... 70
`No Safety Problems Relative to FDA-Approved
`Remodulin ................................................................................ 71
`
`2.
`
`
`
`
`
`-i-
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`E.
`
`F.
`
`2.
`
`D. A POSA Would Have Had a Reasonable Expectation of
`Success in Forming Treprostinil Diethanolamine Based on the
`Disclosures in Phares ......................................................................... 71
`Elimination of the Crude Treprostinil Isolation Step in Phares
`Would Have Been Obvious ................................................................ 72
`1.
`A POSA Would Have Been Motivated to Eliminate the
`Crude Treprostinil Isolation Step of Phares to Improve
`Synthetic Efficiency and Reduce Cost ..................................... 72
`A POSA Would Have Had a Reasonable Expectation of
`Success in Eliminating the Crude Treprostinil Isolation
`Step of Phares ........................................................................... 74
`Synthesis of Gram-Scale Product Quantities was Well Known
`and Scaling Up the Product Quantity in Phares Would Have
`Been Obvious ..................................................................................... 78
`G. Dependent Claims 2-5 and 8-9 ........................................................... 79
`XII. GROUND 2: MORIARTY IN COMBINATION WITH PHARES
`RENDERS OBVIOUS THE CLAIMS OF THE ’901 PATENT ................ 82
`A. Dr. Pinal Does Not (and Cannot) Dispute that Moriarty
`Discloses the Claimed Alkylation and Hydrolysis Steps ................... 82
`B. Dr. Pinal’s Lengthy Discussion of “Impurity Profiles” and
`“Batch-to-Batch Variations” is Misplaced ......................................... 85
`C. A POSA Would Be Motivated to Combine Moriarty with
`Phares ................................................................................................. 88
`D. A POSA Would Have Had a Reasonable Expectation of
`Success in Forming Treprostinil Diethanolamine Based on the
`Disclosures in Phares ......................................................................... 92
`Elimination of the Crude Treprostinil Isolation and
`Crystallization Steps of Moriarty Would Have Been Obvious .......... 97
`Dependent Claims 2-5 and 8-9 ........................................................... 99
`F.
`XIII. STORAGE CLAIMS 6 AND 7 ARE OBVIOUS ........................................ 99
`
`-ii-
`
`
`E.
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`
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`TABLE OF CONTENTS
`(continued)
`
`Page
`XIV. SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ........... 105
`XV. CONCLUSION ........................................................................................... 107
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`-iii-
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`I, Jeffrey D. Winkler, hereby declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained by counsel for the Petitioner to offer technical
`
`opinions with respect to U.S. Patent No. 9,604,901 (“the ’901 patent”) and prior art
`
`references cited in inter partes review proceedings for the ’901 patent.
`
`3.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate, which is $850 per hour. My compensation is not dependent
`
`on the outcome of, or the content of my testimony in, the present IPR.
`
`4.
`
`I have reviewed the ’901 patent and, in assessing it, I have considered
`
`the teachings of the scientific literature before December 17, 2007, in light of general
`
`knowledge in the art before that date.
`
`5.
`
`I understand that the Patent Trial and Appeal Board (“the Board”) has
`
`instituted inter partes review of the ’901 patent based on the petition submitted by
`
`Liquidia Technologies, Inc. (“Liquidia”). Since IPR institution, I understand that
`
`United Therapeutics Corporation (“UTC”) has filed a Patent Owner Response as
`
`well as a declaration from Rodolfo Pinal, Ph.D. in support thereof.
`
`6.
`
`This declaration presents my additional expert opinions, considering
`
`the Institution Decision rendered by the Board, as well as UTC’s Patent Owner
`
`1
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`Response and Supporting Declaration of Dr. Pinal, that Claims 1-9 of the ’901 patent
`
`would have been obvious to a person of ordinary skill in the art before December
`
`17, 2007.
`
`II. QUALIFICATIONS
`
`7. My background, qualifications, and experience relevant to the issues
`
`raised in this proceeding are summarized below. A full description of my
`
`background and qualifications is set forth in my curriculum vitae. Ex. 1003.
`
`8.
`
`I am a professor of chemistry with more than 35 years of experience in
`
`academia, as well as experience in drug design. For over three decades, my
`
`laboratory has focused and continues to focus on the development of new
`
`methodology in organic synthesis and the application of this methodology to the
`
`synthesis of naturally occurring compounds and molecules of design (unnatural
`
`products) with important biological activity.
`
`9.
`
`In 1977, I received my Bachelor of Arts, cum laude, in Chemistry from
`
`Harvard College. In 1978, I received my Master of Arts in Chemistry from
`
`Columbia University. In 1981, I received my Ph.D. in Chemistry from Columbia
`
`University. From 1981 to 1983, I was an American Cancer Society post-doctoral
`
`fellow in the laboratory of Professor Ronald Breslow in the Chemistry Department
`
`at Columbia University.
`
`2
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`10. From July 1990 until June 1996, I was an Associate Professor in the
`
`Department of Chemistry at the University of Pennsylvania (the “University”).
`
`From July 1996 until present, I have been a Professor in the University’s Department
`
`of Chemistry. In January 2001, I became the University’s Merriam Professor of
`
`Chemistry, a position I still hold today. In July 2018, I became the Undergraduate
`
`Chair in the University’s Department of Chemistry.
`
`11. During my time at the University, I have taught both undergraduate
`
`organic chemistry as well as several graduate-level courses in the Department of
`
`Chemistry including Organic Reaction Mechanisms, Bioorganic Chemistry, and
`
`Special Topics in Organic Chemistry. Since 2002, I have given over 80 invited
`
`lectures at universities, conferences, and various companies,
`
`typically
`
`pharmaceutical companies, around the world in the areas of the design and synthesis
`
`of organic molecules.
`
`12. Further, as I explained during my cross-examination, I have extensive
`
`experience consulting for process chemistry groups of pharmaceutical companies. I
`
`spent a year working for Bristol Myers Squibb where I advised medicinal and
`
`process chemistry groups. Ex. 2026 at 24:13-25:18. And my laboratory has
`
`developed several new compounds that have anti-cancer properties. Id. In the
`
`context of this work, we have prepared many compounds on greater than 2.9 gram
`
`scale. In fact, I co-founded a company based on one of the compounds my laboratory
`
`3
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`developed. In that role, I was directly involved in the scale-up of drug production
`
`of API for both in vitro testing and animal studies. I anticipate that this compound
`
`will be the basis of an FDA filing later in 2021, the first step in our projected clinical
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`studies.
`
`13.
`
`I have authored or co-authored about 130 peer-reviewed articles
`
`published in scholarly journals, including more than 25 articles since 2011.
`
`14. Accordingly, I am an expert in the field of organic chemistry, and I have
`
`been an expert in this field since prior to December 17, 2007. Further information
`
`regarding my qualifications and credentials are fully set forth in my curriculum vitae.
`
`Ex. 1003.
`
`III. MATERIALS CONSIDERED
`
`15.
`
`In addition to the materials that I considered in connection with my
`
`prior declaration (Ex. 1002, refiled with a final paragraph swearing to the truth of
`
`the statements made therein as Ex. 1039), in forming the opinions in this declaration
`
`I have reviewed the Institution Decision, Patent Owner Response, the supporting
`
`declaration of Dr. Pinal and exhibits, and the deposition testimony of Dr. Pinal. In
`
`arriving at my opinions, I have also reviewed and considered additional documents
`
`that are cited in this declaration. I have listed the additional documents considered
`
`below. To the extent I am provided additional documents or information, including
`
`any additional expert declarations in this proceeding, I may offer further opinions.
`
`4
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`1020
`
`1022
`
`Document
`Ex. No.
`1018 Deposition transcript of Rodolfo Pinal, dated February 10, 2021
`1019 Gao, K., “Synthesis of A-Galceramides, (-)-Treprostinil, and Design
`and Synthesis of Anti-Viral Agents,” Thesis submitted as partial
`fulfillment of the requirements for the degree of Doctor Of
`Philosophy in Chemistry in the Graduate College of the University of
`Illinois at Chicago, 2006
`Parks, B.W., et al., “Convenient Synthesis of 6,6-Bicyclic
`Malonamides: A New Class of Conformationally Preorganized
`Ligands for f-Block Ion Binding,” J. Org. Chem., 71:9622-27 (2006)
`1021 Hanessian, S., et al., “Structure-Based Organic Synthesis of a
`Tricyclic N-Malayamycin Analogue,” J. Org. Chem., 71:9807-17
`(2006)
`Frost, J.M., et al., “Synthesis and Structure – Activity Relationships
`of 3,8-Diazabicyclo[4.2.0]octane Ligands, Potent Nicotinic
`Acetylcholine Receptor Agonists,” J. Med. Chem., 49:7843-53
`(2006)
`1023 Regan, J., et al., “Quinol-4-ones as Steroid A-Ring Mimetics in
`Nonsteroidal Dissociated Glucocorticoid Agonists,” J. Med. Chem.,
`49:7887-96 (2006)
`1025 Mak, K.K.W., et al., “Mannich Reactions in Room Temperature
`Ionic Liquids (RTILs): An Advanced Undergraduate Project of
`Green Chemistry and Structural Elucidation,” J. Chem. Ed.,
`83(6):943-46 (2006)
`Supplemental Materials to Mak, K.K.W., et al., “Mannich Reactions
`in Room Temperature Ionic Liquids (RTILs): An Advanced
`Undergraduate Project of Green Chemistry and Structural
`Elucidation,” J. Chem. Ed., 83(6):943-46 (2006)
`1027 Baar, M.R., et al., “Enantiomeric Resolution of (±)-Mandelic Acid
`by (1R,2S)-(–)-Ephedrine,” J. Chem. Ed., 82(7):1040-42 (2005)
`Supplemental Materials for Baar, M.R., et al., “Enantiomeric
`Resolution of (±)-Mandelic Acid by (1R,2S)-(–)-Ephedrine,” J.
`Chem. Ed., 82(7):1040-42 (2005)
`1029 Brigandi, L.M., et al., “Synthesis and Analysis of Copper Hydroxy
`Double Salts,” J. Chem. Educ., 82(11):1662 (2005)
`Supplemental Material for Online Publication for Brigandi, L.M., et
`al., “Synthesis and Analysis of Copper Hydroxy Double Salts,” J.
`Chem. Educ., 82(11):1662 (2005)
`
`1026
`
`1028
`
`1030
`
`5
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`1033
`
`1035
`
`1037
`1038
`
`Document
`Ex. No.
`1031 Hamilton, “Experiment #5: Resolution of (R,S)-1-Phenylethylamine
`via Diastereoisomer formation with (2R),(3R)-Tartaric Acid,”
`Laboratory Manual for Chemistry 202, Organic Chemistry
`Laboratory I at Mount Holyoke College (2006)
`1032 Yadav, J.S., et al., “A concise and stereoselective synthesis of both
`enantiomers of altholactone and isoaltholactone,” Tetrahedron
`Letters, 44:5831-33 (2003)
`Takadoi, M., et al., “Synthetic studies of himbacine, a potent
`antagonist of the muscarinic M2 subtype receptor 1. Stereoselective
`total synthesis and antagonistic activity of enantiomeric pairs of
`himbacine and (2’S,6’R)-diepihimbacine, 4-epihimbacine, and novel
`himbacine congeners,” Tetrahedron 58 (2002) 9903–23
`1034 Berge, S.M., et al., “Pharmaceutical Salts,” J. Pharm. Scis., 66(1):1-
`19 (1977)
`Excerpts from Loewenthal, H.J.E., et al., A Guide for the Perplexed
`Organic Experimentalist, Chapter 4: Running Small-scale Reactions
`in the Research Laboratory, pp. 87-119, 2d ed. (1990)
`1036 Heidelberger, M., An Advanced Laboratory Manual of Organize
`Chemistry (1928)
`Product Information for Remodulin (2006) (“Remodulin Label”),
`Excerpt from Hawley’s Condensed Chemical Dictionary, 15th ed.
`(2007)
`1039 Refiled Declaration of Jeffery D. Winkler, Ph.D. (Ex. 1002)
`
`
`IV. PERSONS OF ORDINARY SKILL IN THE ART
`
`16.
`
`I understand that “one of ordinary skill in the art” is not a specific, real
`
`individual, but rather a hypothetical individual who is presumed to have known the
`
`relevant art at the time of the invention. In defining “one of ordinary skill in the art,”
`
`I have been advised to consider factors such as the educational level and years of
`
`experience not only of the person or persons who have developed the invention that
`
`is the subject of the case, but also others working in the pertinent art at the time of
`
`6
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
`IPR2020-00770
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`the invention; the types of problems encountered in the art; the teachings of the prior
`
`art; patents and publications or other persons or companies; and the sophistication
`
`of the technology.
`
`17.
`
`I have assessed the level of ordinary skill in the art based upon my
`
`review of the prior art, the patent, and my over thirty years of working in the field of
`
`organic chemistry.
`
`18. Given the high education level of the scientists actually working in this
`
`field, a person of ordinary skill in the art (POSA) of chemistry at the time of the
`
`alleged invention would have a master’s degree or a Ph.D. in medicinal or organic
`
`chemistry, or a closely related field. Alternatively, a POSA would include an
`
`individual with a bachelor’s degree and at least five years of practical experience in
`
`medicinal or organic chemistry.
`
`19. As reflected in my qualifications set forth above and in my curriculum
`
`vitae (Ex. 1003), I qualified as a POSA at the time of the alleged invention (before
`
`December 17, 2007).
`
`20. Dr. Pinal defines a POSA as requiring specialized experience with
`
`“industrial scale” or “large-scale” production of pharmaceutical batches. See, e.g.,
`
`Ex. 2025 at ¶¶ 61-62. I disagree. In particular, Dr. Pinal testified that none of the
`
`challenged claims of the ʼ901 patent include the terms “commercial,” “high-scale,”
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`“industrial scale,” or “large-scale manufacture.” Ex. 1018 at 105:22-106:22.
`
`7
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
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`Additionally, Dr. Pinal testified that claim 1’s requirement that the pharmaceutical
`
`batch contains “at least 2.9 grams” of treprostinil or its salt would not, by itself,
`
`denote to a POSA, commercial scale production. Id. at 116:1-119:2. Dr. Pinal also
`
`testified that the phrase “pharmaceutical product,” which appears in claims 3-6, does
`
`not indicate “commercial,” as a pharmaceutical product would include one that is
`
`not sold, but instead administered in a pre-clinical (in vitro or animal) or clinical
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`(human) trial. Id. at 112:12-115:21. Finally, Dr. Pinal confirmed that the claims of
`
`the ʼ901 patent only require the steps of alkylation of a benzidine triol, hydrolysis of
`
`the resulting product, contacting the resulting treprostinil with a base, and isolating
`
`the resulting treprostinil salt, and do not specify any particular solvent or reagent
`
`besides use of diethanolamine in dependent claims 5, 7, and 9 to form the treprostinil
`
`diethanolamine salt. Id. at 53:1-54:8, 74:14-77:3. As such, while Dr. Pinal asserts
`
`that the ʼ901 patent is directed to “industrial” or “commercial” scale production,
`
`Dr. Pinal’s testimony confirms that the claims of the ʼ901 patent are not so directed.
`
`21. This is consistent with the Board’s findings in the Final Written
`
`Decision for U.S. Patent No. 8,497,393. Ex. 1005. There, the Board rejected the
`
`same arguments made by UTC, stating that “the challenged claims are not directed
`
`to an efficient, cost-effective, or commercial scale synthesis . . . .” Id. at 63
`
`(emphases added).
`
`8
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
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`22. Dr. Pinal is also incorrect to the extent he contends that a POSA need
`
`have experience in salt selection. See, e.g., Ex. 2025 at ¶¶ 56, 62. Claim 1 does not
`
`specify any particular salt, and the only salt claimed explicitly by the ’901 patent is
`
`the diethanolamine salt (see Ex. 1001 at claims 7, 9), which was extensively
`
`described by Phares as possessing favorable properties and having been delivered
`
`safely to patients during clinical trials. See, e.g., Ex. 1008 at 91 (disclosing
`
`treprostinil diethanolamine as a “particularly preferred embodiment”), 82-85
`
`(disclosing two clinical studies of treprostinil diethanolamine that demonstrated
`
`improved bioavailability and a favorable safety profile), 85-90 (characterizing
`
`polymorphic forms of treprostinil diethanolamine by XRPD, DSC, TG, hot stage
`
`microscopy, IR, Raman spectroscopy, and moisture sorption). Medicinal and
`
`organic chemists would readily identify the sole claimed salt of the ’901 patent as
`
`advantageous and would be capable of producing it using the process disclosed in
`
`Phares. Ex. 1008 at 22. Thus, to the extent Dr. Pinal contends that a POSA would
`
`need extensive experience in salt selection, Dr. Pinal is incorrect and overlooks the
`
`claim language and the disclosure of the prior art.
`
`
`1 For Phares (Ex. 1008), the page numbers I cite refer to the numbers at the bottom
`
`center of each page, with the first two pages (coverpage/abstract) unnumbered.
`
`
`
`9
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
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`23. Dr. Pinal’s inflated POSA definition also assumes that the claimed
`
`product-by-process must meet the heightened regulatory requirements of FDA
`
`approval. See, e.g., Ex. 2025 at ¶¶ 59 (arguing that a POSA must have experience
`
`with “development considerations, such as evaluations of purities across batches or
`
`the successful storage of polymorphic salts for eventual pharmaceutical product
`
`development”), 64 (“This individual must have had experience in the production and
`
`manufacture of pharmaceutical compositions and pharmaceutical products,
`
`activities that are also inextricably linked to regulatory requirements.”). However, I
`
`understand from counsel that the requirements for patentability and FDA approval
`
`are two separate and distinct standards. Moreover, neither the FDA nor any FDA
`
`regulation is mentioned in the ʼ901 patent’s specification. And Dr. Pinal testified
`
`that the claims of the ʼ901 patent do not specify any particular polymorphic form of
`
`treprostinil or its salt. Ex. 1018 at 53:1-6. Dr. Pinal’s verbose discussion of FDA
`
`requirements, such as solubility, surface properties, tablet properties, cooling rates,
`
`and stirring rates, should be given no weight because they are nowhere in the claims,
`
`specification, or file history of the ’901 patent.
`
`24. To the extent Dr. Pinal argues that a POSA would need to have
`
`“specialized” training in “[i]mpurity identification” (Ex. 2025 at ¶ 53 (quoting
`
`Ex. 2021)), Dr. Pinal overlooks that no specific impurity is identified by the claims,
`
`specification, or file history of the ’901 patent. Dr. Pinal confirmed as much in his
`
`10
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
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`deposition. Ex. 1018 at 67:4-70:11. Further, no particular means for impurity
`
`identification are disclosed in the specification. Moreover, the Board rejected
`
`similar arguments during the ’393 IPR, observing “that the ’393 patent itself does
`
`not discuss any of the individual impurities, or attribute any clinical relevance to the
`
`purported differences between Moriarty treprostinil and that made according to the
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`’393 patent process.” Ex. 1005 at 42; see also id. at 38 (finding that “individual
`
`commercial batches of Moriarty treprostinil exhibit impurity profiles nearly
`
`identical, if not superior, to those seen in individual commercial batches of ’393
`
`patent treprostinil”). The ʼ393 patent shares the same specification as the ʼ901
`
`patent. Because all chemical reactions result in at least some chemical impurities
`
`and no purification method is 100% effective at removing impurities, an organic or
`
`medicinal chemist would know that the claimed steps would produce a
`
`pharmaceutical batch possessing impurities “resulting from” the claimed steps. See
`
`Sections XI.B and XII.B below; see also Ex. 1018 at 55:20-58:18 (“I agree [with
`
`Dr. Winkler] that there is no -- I don’t know of any exception, any reaction in which
`
`there is not some sort of side-product or impurity or something like that.”), 59:6-
`
`62:16 (“The process of impurity removal, the processes used are not black and white.
`
`They are not 100 percent effective. Some of them are very highly effective. Some
`
`of them are less. But none of them gives you 100 and zero, or zero and 100. That
`
`cannot happen physically.”).
`
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`Reply Declaration of Jeffrey D. Winkler, Ph.D.
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`25. Dr. Pinal implies that a POSA would need to have experience with
`
`“ultra-pure” pharmaceutical batches. See Ex. 2025 at ¶ 63. However, as Dr. Pinal
`
`concedes, “Claim 1 of the ’901 patent recites a pharmaceutical batch consisting of
`
`. . . impurities.” Id. at ¶ 54 (emphasis added). A POSA, moreover, would not need
`
`experience with “ultra-pure” pharmaceutical batches because, Dr. Pinal confirmed
`
`that the claims of the ʼ901 patent do not specify a purity limitation.
`
`26. Dr. Pinal is incorrect that “Moriarty highlights the difficulties in
`
`adjusting a procedure based on general organic chemistry to a larger production scale
`
`for pharmaceutical manufacturing purposes.” Ex. 2025 at ¶ 63 (quoting Ex. 1009 at
`
`3). The quote relied on by Dr. Pinal was merely in reference to an “early route” to
`
`treprostinil and does not refer to the synthesis disclosed in Moriarty. Ex. 1009 at 3.
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`As Gao (Ex. 1019) explains, Moriarty discloses a synthesis of an “optically pure”
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`treprostinil that “can be employed to make substantial amount of final product
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`efficiently . . . .” Ex. 1019 at 199. Additionally, the Board found during the ’393
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`IPR, “the record indicates that batches of Moriarty treprostinil satisfy the 98%
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`minimum purity requirement for treprostinil approved by the FDA, and could be
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`sold to the public.” Ex. 1005 at 41-42 (citation omitted). Moreover, the PTAB found
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`that UTC used the Moriarty process to make commercial batches of treprostinil. Id.
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`at 38. Finally, the claims of the ʼ901 patent only require 2.9 grams of treprostinil or
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`its salt. Moriarty, as depicted in Example 6, “former process” (POPR at 61), results
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`in substantially more than 2.9 grams. See also Ex. 1009 at 13 (Moriarty synthesis
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`of 441 grams treprostinil).
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`27. To be sure, even under Dr. Pinal’s inflated POSA definition, I would
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`still be considered a POSA. As I explained during my deposition and as shown in
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`my CV, I have consulted for process chemistry groups of several pharmaceutical
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`companies, worked for Bristol Myers Squibb advising their medicinal and process
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`chemistry groups, and have overseen the scale-up of drugs developed in my
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`laboratory for commercial use (e.g., as startup company drug candidates), including
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`for the claimed “at least 2.9 gram” quantities. Ex. 2026 at 24:13-25:18, 26:5-16,
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`27:5-21, 29:23-30:21; Ex. 1003.
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`28. For these reasons, I stand by my opinion that a POSA, with respect to
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`the claims of the ʼ901 patent would be an individual with the qualifications recited
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`in Paragraph 18.
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`V. UNDERSTANDING OF LEGAL CONCEPTS
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`A. Obviousness
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`29.
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`I understand from counsel that the law recognizes a concept called
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`“obviousness.” I understand that a patent claim is invalid for obviousness if the
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`differences between the subject matter sought to be patented and the prior art are
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`such that the subject matter as a whole would have been obvious to a person of
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`ordinary skill in the art at the time of the invention. I understand that for a single
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`reference or a combination of references to render the claimed invention obvious, a
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`person of ordinary skill in the art must have been able to arrive at the claims by
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`modifying or combining the applied references.
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`30.
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`It is my further understanding that, in order to render an invention
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`obvious, there must be a motivation to combine or modify the applied references.
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`31.
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`It is my further understanding that a person of ordinary skill in the art
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`must have a reasonable expectation of success that making the combination will
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`make the invention work.
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`B.
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`32.
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`Secondary Considerations of Non-Obviousness
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`I have been advised by counsel that certain other factors, known as
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`“secondary considerations,” may be utilized as indicia of nonobviousness. These
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`considerations include commercial success, unexpected results, long felt but
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`unresolved need, industry acclaim, simultaneous invention, copying by others,
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`skepticism by experts in the field, and failure of others. I understand that secondary
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`considerations must be connected, or have a “nexus,” with the claimed invention. I
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`further understand that it is the patent owner’s obligation (here, UTC) to identify
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`objective evidence of non-obviousness.
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`C.
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`Product-By-Process Claims
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`33.
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`I understand that the challenged claims are “product by process” claims.
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`I understand that this means that the claims cover a recited product made by a process
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`that includes the recited process steps.
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`34.
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`I further understand that as a result of the claims being classified as
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`“product-by-process” claims, both the claimed product and also the claimed
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`processes should be analyzed. If the processes in the claims are in the prior art, then
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`the claims are invalid. As noted below, I further understand the process in a product-
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`by-process claim merits weight in comparing it to the prior art only if it imparts some
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`unique and novel property or structure in the resulting product.
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`VI. DR. PINAL MISQUOTES AND MISCHARACTERIZES MY
`DEPOSITION TESTIMONY
`
`35.
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`In his Declaration supporting UTC’s Patent Owner Response, Dr. Pinal
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`repeatedly misquotes and mischaracterizes my deposition testimony. I have counted
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`at least fifteen instances where Dr. Pinal adulterates my testimony by omitting or
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`replacing critical words and phrases, or presenting my words out of context. These
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`adulterations are made in a manner that is either meant to disparage my opinions and
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`expertise, or to support Dr. Pinal’s and UTC’s positions. Below, I identify these
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`mischaracterizations and then provide the true and accurate statement from my
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`deposition testimony.
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`36.
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`In paragraph 14 of his Declaration, Dr. Pinal opines on “the Board’s
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`provisional determination that ‘the combination of Moriarty and Phares teaches the
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`same process steps as challenged claim 1 [such that] the product from these steps
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`would include the same resulting impurities . . . .’” Ex. 2025 at ¶ 14. He suggests
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`the determination was based on “flawed and unsupported testimony.” Id. In support
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`of his opinion, Dr. Pinal claims that I “acknowledge[], the same general synthetic
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`steps — in terms of main starting materials and products — does not guarantee
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`sameness in the final product or impurity profile,” and further states I 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), 122:19-123:9.2
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`2 Dr. Pinal similarly misconstrues my testimony in paragraphs 125, 246, and 249.
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`Ex. 2025 at ¶¶ 125, 246, 249 (stating “[i]ndeed, Dr. Winkler testified that:
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`[V]ariations could be [due to] different experimentalists. They could involve things
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`like the rate of addition being not exactly the same in the two cases. The method of
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`Id. But Dr. Pinal has both omitted the question posed to me, critical language from
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`my testimony and taken my words out of context. I did not say the same general
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`synthetic steps do not guarantee sameness. In fact, when questioned immediately
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`before on whether, without doing the experiment, one would not know whether the
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`impurity profile is necessarily and always the same, I replied:
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`I don’t think that's exactly what I said. I think what I said wa