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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________
`
`EISAI INC.
`Petitioners
`
`v.
`
`CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD.
`Patent Owner
`
`____________________
`
`Case PGR2021-00047
`Patent 10,759,779
`____________________
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`SECOND DECLARATION OF RON BIHOVSKY, PH.D.
`IN SUPPORT OF PETITION FOR POST-GRANT REVIEW
`OF U.S. PATENT NO. 10,759,779
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`Page 1 of 55
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`EISAI EXHIBIT 1049
`Eisai v. Crystal Pharm.
`PGR2021-00047
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`PGR2021-00047
`U.S. Patent No. 10,759,779
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`TABLE OF CONTENTS
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`
`Introduction ..................................................................................................... 1
`I.
`Background and Qualifications ...................................................................... 2
`II.
`Summary of Opinions ..................................................................................... 2
`III.
`IV. My Experiments Uniformly Demonstrate That CS2 is the Natural
`Result of Following Example G of the ’109 Patent ....................................... 6
`A. My Disagreement with Dr. Rogers’ Criticisms of My First Set
`of Experiments ..................................................................................... 7
`1. My First Set of Experiments Followed the Procedures of
`Example G .................................................................................. 7
`Conducting a “Dry Run” Is My Normal Practice .................... 18
`2.
`3. My Laboratory Notebook Properly Included Details of
`My Experiments ....................................................................... 19
`B. My Repetition of Dr. Rogers’ Work Precipitated a Solid That
`Was Form CS2 ................................................................................... 20
`1.
`Dr. Rogers’ Failure to Obtain a Solid Product ........................ 20
`2. My Additional Experiments Confirm That Following
`Example G of the ’109 Patent Naturally Results in CS2 ......... 25
`V. My Additional Experiments Further Demonstrate that the ’109 Patent
`Discloses Each and Every Limitation of Claims 1-3 of the ’779 Patent ...... 48
`VI. My Additional Experiments Further Demonstrate That Claims 1-3 of
`the ’779 Patent Are Obvious ........................................................................ 49
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`I, Ron Bihovsky, Ph.D., declare as follows:
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`PGR2021-00047
`U.S. Patent No. 10,759,779
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`
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`I.
`
`Introduction
`1.
`I have been retained by Eisai Inc. (“Petitioner”) as an independent
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`expert consultant in this proceeding before the United States Patent and Trademark
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`Office (“PTO”) regarding U.S. Patent No. 10,759,779 (“the ’779 patent”)
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`(Ex. 1001).1
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`2.
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`I am the same Ron Bihovsky, Ph.D. who submitted a declaration in
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`this proceeding titled “Declaration of Ron Bihovsky, Ph.D. in Support of Petition
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`for Post-Grant Review of U.S. Patent No. 10,759,779.” (Ex. 1002.)
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`3.
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`I prepared this declaration (“Second Declaration”) in response to
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`certain opinions and experiments offered by Patent Owner’s expert, Dr. Robin
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`Rogers, in the Declaration of Professor Robin D. Rogers in Support of Patent
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`Owner’s Preliminary Response (“Dr. Rogers’ First Declaration”), which was
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`submitted in this proceeding on May 10, 2021, and the Second Declaration of
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`Professor Robin D. Rogers in Support of Patent Owner’s Response (“Dr. Rogers’
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`1
`Where appropriate, I refer to exhibits as they are identified in Petitioner’s
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`List of Exhibits, submitted at the same time as this Declaration, and Patent
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`Owner’s Fifth Updated Exhibit List (Paper 38).
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`PGR2021-00047
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`Second Declaration”), which was submitted in this proceeding on October 29,
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`2021, as well as the deposition of Robin Don Rogers, Ph.D., which was taken on
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`January 6, 2022 (“Rogers Deposition”).
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`4.
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`I am being compensated at my normal consulting rate for my time
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`working on this proceeding. My compensation is not contingent on the nature of
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`my findings, the presentation of my findings in testimony, or the outcome of this or
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`any other proceeding. I have no other interest in this proceeding.
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`II. Background and Qualifications
`5.
`I provided my background and qualifications in my First Declaration.
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`(Ex. 1002, ¶¶ 3-10.)
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`6.
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`I also provided a copy of my curriculum vitae as Exhibit 1003.
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`III. Summary of Opinions
`7. My opinions that I am offering in my Second Declaration can be
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`summarized as follows:
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`
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`I disagree with Dr. Rogers’ criticisms of my first set of experiments;
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`Dr. Rogers’ attempt to repeat Example G of the ’109 patent is not
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`informative as he simply did not successfully perform the experiment
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`of his protocol;
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`My second set of experiments, which were conducted in response to
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`Dr. Rogers’ failure to obtain a solid lemborexant precipitate and his
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`criticisms of my first set of experiments, further confirm that the
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`crystalline form of lemborexant (“CS2”) is the natural result of
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`following Example G as a POSA would;
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`
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`My additional experiments further demonstrate that the ’109 patent
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`discloses, either expressly or inherently, all of the limitations recited
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`in Claims 1-3 of the ’779 patent; and
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`My additional experiments further demonstrate that the ’109 patent
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`would render obvious Claims 1-3 of the ’779 patent.
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`8.
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`The opinions contained in my Second Declaration are based on
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`documents I reviewed in connection with this proceeding, the experiments I have
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`conducted in connection with this proceeding, and my education, experience, and
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`knowledge regarding organic chemistry and medicinal chemistry.
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`9.
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`In connection with forming my opinions expressed in my Second
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`Declaration, I reviewed the following documents:
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`
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`U.S. Patent No. 10,759,779 (“the ’779 patent”) (Ex. 1001)
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`U.S. Patent No. 9,416,109 (“the ’109 patent”) (Ex. 1006)
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`X-ray powder diffractograms (“XRPDs”) prepared by Dr. Mayo for
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`the samples which resulted from my experiments (Ex. 1057)
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`Declaration of Professor Robin D. Rogers in Support of Patent
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`Owner’s Preliminary Response (Ex. 2006)
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`Second Declaration of Professor Robin D. Rogers in Support of Patent
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`Owner’s Response (Ex. 2044)
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`“Rogers Experimental Report” (Ex. 2045)
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`Dr. Rogers’ Laboratory Notebook (Ex. 2046)
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`Produced HPLC/MS and NMR data associated with Dr. Rogers’
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`experiments (Ex. 2046, 21-22, Ex. 2053)
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`January 6, 2022 deposition transcript of Dr. Rogers (Ex. 1048)
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`Annotated excerpts from Ex. 2053, NMR data associated with Dr.
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`Rogers’ experiments (Ex. 1047)
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`HANDBOOK OF INDUSTRIAL CRYSTALLIZATION (Allan S. Myerson,
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`Deniz Erdemir & Alfred Y. Lee eds., 3rd ed. 2019) (Ex. 2024)
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`J. Dunitz & J. Bernstein, Disappearing Polymorphs, 28 ACC. CHEM.
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`RES. 193 (1995) (Ex. 2019)
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`TECHNIQUES AND EXPERIMENTS FOR ORGANIC CHEMISTRY (Addison
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`Ault, 4th ed. 1983) (Ex. 1058)
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`INTRODUCTION TO ORGANIC LABORATORY TECHNIQUES, A
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`CONTEMPORARY APPROACH (Donald L. Pavia, Gary M. Lampman,
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`George S. Kriz, Jr., 2nd ed. 1982) (Ex. 1059)
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`Any other materials I refer to in this Second Declaration, or my First
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`Declaration, in support of my opinions
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`10. As I stated in my First Declaration, my opinions have been guided by
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`my understanding of how a person of ordinary skill in the art (“POSA”) would
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`have understood the claims and specification of the ’779 patent at the time of the
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`alleged invention, which I understand was no earlier than August 1, 2017.2 My
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`opinions also reflect how a POSA would have understood the prior art to the ’779
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`patent, and the state of the art at the time of the alleged invention of the ’779
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`patent. My opinions would not be different if Dr. Rogers’ asserted definition of a
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`POSA had been applied.
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`2
`I understand that August 1, 2017 is the filing date of Chinese Patent
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`Application No. the 201710648135.2 (“related Chinese Application”) and is the
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`earliest possible priority date for the ’779 patent.
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`11. Nothing in Dr. Rogers’ declarations, nor his deposition testimony,
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`changes any of the opinions that I expressed in my First Declaration or during my
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`October 8, 2021 deposition in this matter.
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`IV. My Experiments Uniformly Demonstrate That CS2 is the Natural
`Result of Following Example G of the ’109 Patent
`12.
`In my First Declaration, I described my first set of two experiments,
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`which followed the first and the alternate procedures of Example G in the ’109
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`patent. (Ex. 1002, ¶¶ 33-57.) In his declarations, Dr. Rogers criticized various
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`aspects of my first set of experiments (Ex. 2006, ¶¶ 97-162; Ex. 2044, ¶¶ 9-32),
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`and I respond to those criticisms below.
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`13.
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`In addition, I also performed a second set of four experiments in
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`response to Dr. Rogers’ efforts to perform his protocol and his criticisms of my
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`work. As discussed in further detail below, two of my additional experiments
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`repeated Dr. Rogers’ experimental protocols, one for the first procedure of
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`Example G and one for the alternate procedure of Example G. My other two
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`additional experiments repeated Dr. Rogers’ experimental protocols, with slight
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`modifications to experimental technique identified below, again one for the first
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`procedure of Example G and one for the alternate procedure of Example G.
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`14. All of my experiments naturally resulted in crystalline form CS2 of
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`lemborexant.
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`A. My Disagreement with Dr. Rogers’ Criticisms of My First Set of
`Experiments
`1. My First Set of Experiments Followed the Procedures of
`Example G
`a.
`Reaction Scale
`15. Dr. Rogers opines that I did not follow “the procedure faithfully” and
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`that I “biased the experiment toward crystallization” on the basis that my first set
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`of experiments were conducted at one-tenth the scale of Example G of the ’109
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`patent. (Ex. 2006, ¶ 99.) Dr. Rogers further opines that the process of
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`crystallization is scale dependent, and that “[s]maller scale systems are easier to
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`purify and easier to crystallize” due “to the ease of mixing and ability to readily
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`obtain a homogeneous solution.” (Ex. 2006, ¶ 98.) He also states that it is “easier
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`to control concentration and heat transfer with smaller volumes and smaller
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`vessels,” and “[s]maller reactions are also more susceptible to unintentional
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`seeding.” (Ex. 2006, ¶ 98; Ex. 2044, ¶ 13.)
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`16.
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`I disagree with these opinions. A reduction to one-tenth scale in my
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`first set of experiments would not have any impact on my experimental results or
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`affect the crystalline form of lemborexant. (See, e.g., Ex. 1002, ¶ 35.) Dr. Rogers
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`cites a chemical engineering textbook (“Myerson 2019”) (Ex. 2044, ¶ 13), but
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`Myerson 2019 was directed to industrial scale crystallizers and how to scale up
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`from laboratory (or bench) scale. (Ex. 2024, at 253-254, 300.) Myerson 2019 also
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`explained the additional challenges in achieving homogeneity at a “large scale”
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`compared to a “bench scale.” (Ex. 2024, at 300.) In my opinion, “bench scale”
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`would encompass both my one-tenth scale reaction (14.71 mL crystallization
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`volume) and the ’109 patent scale (147.1 mL crystallization volume). A POSA
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`would not expect my modest scale reduction from one bench scale to another
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`bench scale to affect the solid form of lemborexant.
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`b.
`Speculations of Seeding
`17. Dr. Rogers opines that “unintentional seeding” from previous
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`experiments could have contaminated my subsequent experiments,3 and that “any
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`production of the crystal form from these [subsequent] experiments was unrelated
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`to the procedure followed.” (Ex. 2006, ¶¶ 161-162.)
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`18.
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`I disagree with Dr. Rogers’ opinion. Consistent with the literature
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`that Dr. Rogers cites, instances of unintentional seeding generally apply in rare
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`3
`In his First Declaration, Dr. Rogers speculates that I may have carried out
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`earlier nondisclosed experiments on lemborexant that generated crystalline form
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`CS2. (Ex. 2006, ¶ 161, n. 9.) As I testified in my deposition, I did not carry out
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`any experiments on lemborexant prior to the “dry run” discussed below.
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`(Ex. 2049, 39:7-41:1.)
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`circumstances to compounds with more than one known polymorph. (Ex. 2019,
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`194 (“[u]nintentional seeding is often invoked as an explanation of phenomena
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`which otherwise are difficult to interpret.”).) The precipitation of lemborexant
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`does not involve any such unexplained phenomena.
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`19. As explained in my deposition (Ex. 2049, 187:4-189:5), unintentional
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`seeding is extremely unlikely to have occurred here. Regardless, unintentional
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`seeding would not have had any effect on the solid formation of my experiments
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`even if it had occurred (and I have no reason to believe it did). In my opinion,
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`even if any seed crystals were present, they would dissolve in solvents that were
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`used in my experiments (e.g., ethyl acetate and DMF) and lose their crystalline
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`structure. (Ex. 2049, 203:10-22.) After crystalline structure is lost, it could not
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`impact any solid that was subsequently formed. (Ex. 2049, 203:10-22.)
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`c.
`Evaporation of Solvent in the Alternate Procedure
`20. Dr. Rogers criticizes my first experiment following the alternate
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`procedure of Example G because I attempted to “remove every bit of solvent from
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`[my] crude product mixture” and did not obtain a “minimal stirrable volume.” (Ex.
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`2044, ¶ 19; Ex. 2006, ¶ 151.) Dr. Rogers also opines that removing too much
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`solvent “could have a major effect on solid formation and potential crystallization”
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`and “has potentially changed the resulting solid form in an unpredictable way.”
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`(Ex. 2006, ¶ 152.)
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`21.
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`I disagree with Dr. Rogers’ opinion. As I explained during my
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`deposition, my first experiment following the alternate procedure of Example G
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`resulted in a beige semisolid at this step, which a POSA would consider a
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`“minimal stirrable volume.” (Ex. 2049, 161:9-13, 164:6-13.) As I also stated
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`during my deposition, “semisolid” means “that it’s partially solid, partially liquid,”
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`and “you can stir it.” (Ex. 2049, 161:9-13.)4
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`4
`At deposition, I was pressed to engage in hypotheticals about what
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`“minimum stirrable volume” might mean, despite my having explained I obtained
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`a semisolid which was stirrable. (Ex. 2049, 161:4-13, 161:15-164:13.) I was not
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`suggesting, as Dr. Rogers claims, that my opinion depends on “stirrable” referring
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`“to any collection of matter short of a single, solid, undifferentiated mass.” (Ex.
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`2044, ¶ 19.) Simply put, a material does not need to be a pure liquid to be
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`“stirrable,” and my semisolid was stirrable. In any event, none of this matters to
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`the point of Example G in context, which is obtaining the work-up product for use
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`in dissolving and precipitating in the following purification steps.
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`22.
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`In my opinion, the steps I took to remove solvent in the alternate
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`procedure of Example G followed the procedure of the ’109 patent. As Example G
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`states, the “organic layer was polish filtered and the filter was rinsed with MTBE
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`. . . [i]t was then concentrated under reduced pressure to a minimum stirrable
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`volume.” (Ex. 1006, 49:41-44.) A POSA would understand this statement to
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`instruct that as much solvent as practicable should be removed under vacuum, a
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`process which is commonly accomplished with a rotary evaporator (“rotovap”).
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`Example G then states that “[t]he residual toluene in the residue was ≤10%.” (Ex.
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`1006, 49:44-45.) A POSA would understand that the use of “<” in these
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`parameters would allow for even the complete removal of toluene from the filtrate
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`solution.
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`d.
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`Addition of Extra Reagents Prior to the Work-Up
`Portion of the Alternate Procedure
`23. Dr. Rogers criticizes my first experiment prior to the work-up portion
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`of the alternate procedure of Example G on the basis that I added “an additional
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`amount of the aminopyridine” during the coupling reaction. (Ex. 2006, ¶ 148; Ex.
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`2044, ¶ 18.) Dr. Rogers opines that “the combination of unreacted reagents from
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`an incomplete reaction and the addition of extra, uncalled-for reagents would add
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`impurities” and that the “impurity profile of a reaction is a significant factor that
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`can influence precipitation behavior of a solution.” (Ex. 2044, ¶ 18.) Dr. Rogers
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`then concludes that my use of this “additional amount of the aminopyridine”
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`means that I did not follow the alternate procedure of Example G. (See, e.g., Ex.
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`2006, ¶¶ 150, 153.)
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`24.
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`I disagree with Dr. Rogers’ opinion. As I stated in my First
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`Declaration, I added the additional 2-amino-5-fluoropyridine starting material to
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`continue to drive the synthesis reaction to completion. (Ex. 2049, at
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`130:18-131:19.) A POSA would understand that this is a routine and common
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`method to drive a reaction to further completion.
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`25. As I also stated during my deposition, the addition of extra reagents at
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`this stage of the reaction – prior to numerous extractions meant to purify the
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`reaction solution – is an “immaterial change” to the procedure that would not affect
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`the quality of synthesis of the lemborexant product. (Ex. 2049, 132:6-15, 135:1-
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`136:2.) As this addition of 2-amino-5-fluoropyridine was followed by the aqueous
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`extraction work-up steps, a POSA would also understand that any “extra,
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`uncalled-for reagents” would be removed prior to, and thus have no material
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`impact on, the purification step. Even if, as Dr. Rogers argues, my procedure
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`resulted in the presence of a small amount of 2-amino-5-fluoropyridine as
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`compared to the ’109 patent, such an impurity (if anything) could impede
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`(rather than facilitate) crystallization, which is inconsistent with his assertion of
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`bias toward crystallization. For lemborexant, however, we can see that it
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`crystallizes as form CS2 under numerous varying conditions, unaffected by the
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`factors Dr. Rogers discusses.
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`e.
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`Coupling Reaction Prior to the Work-Up Portion of
`Alternate Procedure
`26. Dr. Rogers criticizes my first experiment following the alternate
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`procedure of Example G on the basis that I “failed to run the reaction to
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`completion.” (Ex. 2006, ¶ 149; Ex. 2044, ¶ 20.) Dr. Rogers opines that the
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`reaction mixture contained 5% carboxylic acid and would have “progressed
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`significantly further had [I] allowed it to continue reacting.” (Ex. 2044, ¶¶ 21-22;
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`Ex. 2006, ¶ 149.) Dr. Rogers then concludes that “failure to take the reaction to
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`completion” means that I did not follow the alternate procedure of Example G.
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`(See, e.g., Ex. 2006, ¶¶ 150, 153.)
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`27.
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`I disagree with Dr. Rogers’ opinion. As I explain above, I was simply
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`driving the reaction to completion using routine methods that a POSA would use
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`(e.g., adding additional starting material). While the reaction did not go to
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`completion (≥97% conversion to the product), the 95% conversion that I obtained
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`still provided sufficient lemborexant to move to the next step in which a solid is
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`precipitated from solution, and I ultimately obtained a solid product. In my
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`opinion, the slightly lower amount of conversion (2%) was an immaterial change
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`which did not affect whether a solid product was formed or what the solid form of
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`lemborexant would be.
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`f.
`Heating During the Precipitation Step
`28. Dr. Rogers criticizes my first experiments on the basis that, during the
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`precipitation step of Example G, I heated to a temperature of 50°C and did not
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`indicate whether “a clear solution was actually obtained or whether it was or could
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`have been obtained at temperature below 50°C.” (Ex. 2006, ¶ 139.) Dr. Rogers
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`opines that “there is no indication if the temperature may have gone above 50°C, or
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`how Dr. Bihovsky insured it did not.” (Ex. 2006, ¶ 139.) Dr. Rogers then
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`concludes that my heating the solution to a temperature of 50°C must have been a
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`choice that was “tainted by hindsight.” (Ex. 2006, ¶ 115.)
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`29.
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`I disagree with Dr. Rogers’ opinion. As I reported in my laboratory
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`notebook, and also explained during my deposition, I monitored the temperature by
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`measuring the temperature of the oil bath used for heating the mixture. (Ex. 1013,
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`at 113 (“Dissolve in EtOAc (6.08 mL) at 50° (b).”); Ex. 2049, 70:6-71:9.) The
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`designation “(b)” refers to the oil bath temperature. The internal temperature of
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`the reaction solution would actually be lower that the temperature of the oil bath,
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`which confirms that the temperature of the solution did not go above 50°C. The
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`use of “dissolve” means that I obtained a clear solution.
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`30. Furthermore, as Dr. Rogers agreed at deposition, Example G allows
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`for heating the solution up to 50°C at this step. (Ex. 1048, 203:21-204:25.)
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`Example G specifies that the temperature of this solution should be “no more than
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`50°C,” which a POSA would understand to include 50°C. (Ex. 1006, 47:8-10,
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`49:45-47.)
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`g.
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`Specific n-Heptane Addition Rate, Stirring Rate, and
`Cooling Rate
`31. Dr. Rogers criticizes my first set of experiments as using an
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`“extremely slow addition of heptane” during the antisolvent addition step. (Ex.
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`2044, ¶ 14; Ex. 2006, ¶ 117.) Dr. Rogers opines that “[a] choice at this extreme
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`end of ‘slowly’ adding the antisolvent is one that appears an effort to bias the
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`results towards possible crystal formation.” (Ex. 2006, ¶ 117.) Dr. Rogers
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`similarly opines that I selected “an extremely slow choice for stirring rate” (Ex.
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`2006, ¶ 119) and “very slowly cool[ed] the solution” (Ex. 2006, ¶ 122).
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`32.
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`I disagree with Dr. Rogers’ opinion of inappropriate bias. Example G
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`of the ’109 patent instructs that “n-Heptane (86.3 mL) was added slowly with
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`agitation.” (Ex. 1006, 47:10-11.) As I testified during my deposition, I consider
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`“slow” to be a qualitative term that does not have a precise meaning, instructing a
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`POSA to use a slow rate for the purpose of the disclosed precipitation steps.
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`(Ex. 2049, 95:1-16.) A POSA would understand that a “slow” addition of an
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`antisolvent at the laboratory scale encompasses about one minute. (Ex. 2049,
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`93:12-94:19.) The exact rate of addition, as long as it was “slow” and precipitates
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`the solid as explained in the example, is immaterial to the creation of a particular
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`crystal form of lemborexant. (Ex. 2049, 95:7-96:10.) Likewise, while the
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`particular stirring and cooling rates are not specified by Example G, both were
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`carried out by ordinary and routine methods that a POSA would have used – i.e.,
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`stirring with a magnetic stir bar and stir plate, and cooling with a crushed ice bath.
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`(Ex. 1002, ¶ 42.)
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`h.
`Visual Appearance of the Final Lemborexant Product
`33. Dr. Rogers criticizes my first experiment of the alternate procedure of
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`Example G as “over-purify[ing] the lemborexant relative to what is done in
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`Example G.” (Ex. 2006, ¶ 155.) Dr. Rogers opines that my “over-purification” led
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`to a low yield of solid product that enhanced the likelihood of crystallization. Dr.
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`Rogers also criticizes the final product I obtained as a different color than the final
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`product reported in the ’109 patent. (Ex. 2006, ¶ 155.)
`
`34.
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`I disagree with Dr. Rogers’ opinion. If anything, a POSA would
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`understand that, in general, a lower concentration of compound in solution could
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`make it more difficult for crystallization to occur, so his incorrect assertions of bias
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`make no sense. A POSA would also understand that the final purification steps of
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`a synthetic procedure have the goal of obtaining pure material, especially in this
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`case where the final product is a drug compound. Moreover, the color of the final
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`lemborexant product that I obtained was white, which is within the “white to off
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`white” color for the final product described in Example G. (Ex. 1013, 115; Ex.
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`1006, 49:53-56.)
`
`35. Dr. Rogers similarly criticizes my description of the visual appearance
`
`of the final product of my experiments (a flocculent white solid) as different from
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`the description that Dr. Mayo provided for the same material (i.e., “fine white
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`powder solid”). (Ex. 2044, ¶ 31.) Dr. Rogers opines that “seeing such a change in
`
`the visual appearance of the solid would simply imply that some change had taken
`
`place in its solid form, and that the solids Dr. Mayo analyzed may not have been in
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`the same solid form as what resulted from [my] experiments.” (Ex. 2044, ¶ 31.)
`
`36.
`
`I disagree with Dr. Rogers’ opinion. These descriptions merely
`
`represent reasonable descriptions of the texture of the same color solid by two
`
`different people. As described during my deposition, I collected about 100 mg of
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`my final products in vials and stored them at -20°C for one day prior to shipping
`
`them to Dr. Mayo for XRPD analysis. I did not process the samples prior to
`
`shipping. (Ex. 2049, 230:20-232:15.) My shipment was sent on October 20, 2020,
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`via Federal Express priority overnight shipping (shipping label 771853694236), on
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`ice packs initially at -20°C in an insulated foam container. (Ex. 2049, 229:11-
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`230:19, 226:6-18.)
`
`2.
`Conducting a “Dry Run” Is My Normal Practice
`37. Dr. Rogers criticizes my experiments because I “ran a procedure
`
`directed toward the first synthetic route in Example G twice,” but my “only
`
`experimental run where the product was analyzed to determine crystalline form,
`
`experiment number 2, is inadequately documented.” (Ex. 2006, ¶¶ 101, 105-107;
`
`Ex. 2044, ¶¶ 28-29.) He opines that, because the final product of my prior
`
`experimental run was not analyzed, “[a] POSA would not know whether Dr.
`
`Bihovsky’s [prior] experimental run generated Form CS2.” (Ex. 2006, ¶ 105.)
`
`38.
`
`I disagree with Dr. Rogers’ opinion. As explained during my
`
`deposition, this experiment was a “dry run or a practice run” conducted to
`
`familiarize myself with the procedure and to confirm that I could obtain a solid
`
`product, as specified by Example G. (Ex. 2049, 43:18-44:11.) I commonly
`
`perform these dry runs. I had no reason to analyze the solid product by XRPD, as
`
`obtaining a solid product was the ultimate goal of the dry run, and it is my common
`
`practice not to conduct XRPD on dry runs. Nonetheless, I have no reason not to
`
`believe that the solid product of the “dry run” experiment was CS2, as all of the
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`parameters measured for the “dry run” and first experiment were “identical.” (See,
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`e.g., Ex. 2049, 48:22-49:8, 51:11-24, 234:17-235:3.) Dr. Rogers also points to no
`
`evidence that that my “dry run” resulted in anything other than crystalline form
`
`CS2.
`
`3. My Laboratory Notebook Properly Included Details of My
`Experiments
`39. Dr. Rogers also criticizes the manner in which I documented my first
`
`set of experiments in my laboratory notebook. (Ex. 2006, ¶¶ 100-107, 130-141;
`
`Ex. 2044, ¶ 30.) He opines that my laboratory notebook lacks “experimental detail
`
`throughout” and that it “was not up to industry standards.” (Ex. 2006, ¶ 104;
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`Ex. 2044, ¶ 30.) He then concludes that “[b]ased on the lack of experimental detail
`
`throughout, a POSA could not be confident that [my] second experiment faithfully
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`followed the Example G procedure even at reduced scale.” (Ex. 2006, ¶ 104.)
`
`40.
`
`I disagree with Dr. Rogers’ opinion. My full experiment for the first
`
`procedure of Example G repeated the procedure that I previously documented for
`
`my “dry run,” and I noted this with the word “Repeat” and the notation “Follow by
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`TLC and HPLC.” (Ex. 1013, 113.) I took the same steps already documented in
`
`my laboratory notebook regarding the first procedure, “completely, literally, and
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`exactly, except for the modifications which are noted.” (Ex. 2049, 37:3-13.)
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`These steps include the information that Dr. Rogers alleges is missing – e.g., the
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`volumes, masses, solvents, temperatures, and times. (Ex. 2006, ¶ 102.)
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`41. Dr. Rogers also criticizes my experimental work on the basis that I
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`added details to my First Declaration that are not in my laboratory notebook. (Ex.
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`2044, ¶ 30.) I disagree. Any additional information present in my First
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`Declaration relates to minor details (e.g., particular equipment in my lab that I
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`used) that were not necessary to record in real-time. (Ex. 2049, 89:3-17, 90:9-
`
`91:6.)
`
`B. My Repetition of Dr. Rogers’ Work Precipitated a Solid That
`Was Form CS2
`1.
`Dr. Rogers’ Failure to Obtain a Solid Product
`42. Example G expressly discloses that the final product of both its first
`
`and alternate procedures is white to off-white solid lemborexant. (Ex. 1006, at
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`47:17-20, see also 49:53-56.) Dr. Rogers, however, offers an experiment where he
`
`did not obtain any solid lemborexant. (Ex. 2044, ¶¶ 6-7.)
`
`43.
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`In my opinion, a POSA would have understood this failure to obtain a
`
`solid product as failed experimental runs, and would have attempted to investigate
`
`the failure and conduct this experiment again in an effort to understand what had
`
`gone wrong, especially after failing twice. A POSA would not, as Dr. Rogers did
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`in his declaration, use this failed experimental run to investigate the question of
`
`what form the solid of Example G naturally takes.
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`44.
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`I understand that Dr. Rogers’ technician performed all the
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`experimentation. In my opinion, and based upon my own experience, the
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`technician may have made experimental errors that Dr. Rogers perhaps did not
`
`observe – e.g., failing to correctly measure one or more of the reagents used in the
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`experiment as prescribed by Example G. In my opinion, warning signs also
`
`occurred in Dr. Rogers’ experiments, which would not have been ignored by a
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`POSA seeking to follow Example G.
`
`45. For example, the acid that Dr. Rogers used as starting material in his
`
`experimental runs could have contributed to his failure to obtain solid product in
`
`accordance with Example G.5 According to Dr. Rogers, the acid that he used was
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`“light orange” in color. (Ex. 2046, 2; Ex. 1048, 145:22-25, 148:8-19.) The ’109
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`patent, however, describes the starting material as “off-white” in color. (Ex. 1006,
`
`45:25-28.) Such a difference in color could suggest some unknown problem with
`
`the starting material, creating difficulties in using it to synthesize lemborexant. At
`
`least this would be something a POSA might consider by, for example, checking
`
`
`5
`The chemical name for this acid starting material is (1R,2S)-2-(((2,4-
`
`dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic
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`acid.
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`on the amount of lemborexant that was being created during the experiment. Dr.
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`Rogers did not do that.
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`46.
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`In my opinion, the 1H NMR of the acid starting material that was
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`taken by Dr. Rogers further indicates that the acid contained unidentifie
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