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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`EISAI INC.
`Petitioner
`
`v.
`
`CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD.
`Patent Owner
`
`____________________
`
`Patent No. 10,759,779
`____________________
`
`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 56
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`EISAI EXHIBIT 1002
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`
`
`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`TABLE OF CONTENTS
`
`I.
`INTRODUCTION .......................................................................................... 1
`BACKGROUND AND QUALIFICATIONS ................................................ 2
`II.
`SUMMARY OF OPINIONS .......................................................................... 3
`III.
`IV. PERSON OF ORDINARY SKILL IN THE ART ......................................... 6
`V. OVERVIEW OF THE ’779 PATENT ........................................................... 7
`A.
`The Disclosures of the ’779 Patent ...................................................... 9
`B.
`Claims of the ’779 Patent ................................................................... 12
`VI. THE TWO PROCEDURES OF THE ’109 PATENT FOR
`PREPARING THE CRYSTALLINE FORM OF LEMBOREXANT ......... 13
`A. Overview of the Two Procedures ....................................................... 13
`B.
`Lemborexant Prepared Using the
`Procedures in Example G of the ’109 Patent ..................................... 18
`1.
`The First Procedure of Example G .......................................... 20
`2.
`The Alternate Procedure .......................................................... 26
`VII. EISAI’S PREPARATION OF LEMBOREXANT ...................................... 32
`A.
`Eisai’s Preparation Consistent with the
`First Procedure of ’109 Patent Example G ........................................ 32
`Eisai’s Preparations Consistent with the
`Alternate Procedure of ’109 Patent Example G ................................. 35
`1.
`Eisai’s Preparation of Lot AZW-673a ..................................... 35
`2.
`Eisai’s Preparation of Lot GAM-388-2 ................................... 37
`VIII. THE ’109 PATENT DISCLOSED ALL OF THE
`LIMITATIONS OF CLAIMS 1-4 OF THE ’779 PATENT ........................ 39
`A.
`The ’109 Patent Disclosed the Limitations of Claims 1-3 ................. 39
`B.
`The ’109 Patent Disclosed the Limitations of Claim 4 ...................... 43
`IX. THE ’109 PATENT RENDERS OBVIOUS
`CLAIMS 1-4 OF THE ’779 PATENT ......................................................... 44
`
`B.
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`X.
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`THE ’109 PATENT IN COMBINATION WITH
`THE ’995 PUBLICATION RENDERS OBVIOUS
`CLAIMS 7 AND 8 OF THE ’779 PATENT ................................................ 46
`A.
`Claim 7 Is Unpatentable for Obviousness .......................................... 47
`1.
`The ’995 Publication Disclosed a
`Pharmaceutical Composition with a
`Therapeutically Effective Dose of Lemborexant ..................... 48
`A POSA Would Have Been Motivated to Combine the
`Teachings of the ’109 Patent with the ’995 Publication
`with a Reasonable Expectation of Success .............................. 49
`Claim 8 Is Unpatentable for Obviousness .......................................... 51
`B.
`XI. CONCLUSION ............................................................................................. 52
`
`2.
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`ii
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`I, Ron Bihovsky, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`I have been retained by Eisai Inc. (“Petitioner”) as an independent
`1.
`
`expert consultant in this proceeding before the United States Patent and Trademark
`
`Office (“PTO”) regarding U.S. Patent No. 10,759,779 (“the ’779 patent”)
`
`(Ex. 1001) to Crystal Pharmaceutical (Suzhou) Co., Ltd. (“Patent Owner”).1 I
`
`have been asked to consider whether: (1) U.S. Patent No. 9,416,109 (“Eisai’s ’109
`
`patent” or “the ’109 patent”) (Ex. 1006) inherently disclosed the features recited in
`
`claims 1-4 of the ’779 patent; (2) the ’109 patent renders claims 1-4 obvious; and
`
`(3) claims 7-8 of the ’779 patent are rendered obvious by the ’109 patent in view of
`
`International Patent Publication No. WO 2016/063995 (“the ’995 publication”)
`
`(Ex. 1007).
`
`2.
`
`I am being compensated at my normal consulting rate for the time I
`
`spend on this matter. My compensation is in no way contingent on the nature of
`
`my findings, the presentation of my findings in testimony, or the outcome of this or
`
`any other proceeding. I have no other interest in this proceeding.
`
`
`1
`Where appropriate, I refer to exhibits that I understand will be attached to
`
`the petition for post-grant review of the ’779 patent.
`
`
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`1
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`II. BACKGROUND AND QUALIFICATIONS
`I am an organic chemistry and medicinal chemistry expert. In my
`3.
`
`laboratory, I synthesize organic compounds for the pharmaceutical, biotechnology,
`
`and agrochemical industries. I have more than 35 years of academic and industrial
`
`chemistry experience. My research has resulted in 50 publications in refereed
`
`journals, 15 granted U.S. Patents, and numerous foreign patents
`
`4.
`
`I obtained a Bachelor of Science degree in chemistry from the State
`
`University of New York, Stony Brook in 1970. I earned a Ph.D. in organic
`
`chemistry from the University of California, Berkeley in 1978, and was a National
`
`Institute of Health postdoctoral fellow at the University of Wisconsin, Madison
`
`from 1978 to 1980. My research included synthesis and structure elucidation of
`
`biologically-active molecules.
`
`5.
`
`From 1980 to 1987, I was an assistant professor of organic chemistry
`
`at the State University of New York, Stony Brook, where I performed organic
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`chemistry research, synthesized natural products, supervised undergraduates,
`
`graduate students, and postdoctoral fellows, and taught classes including graduate
`
`level synthetic organic chemistry and undergraduate organic chemistry courses.
`
`6.
`
`From 1987, I worked in the pharmaceutical industry as a medicinal
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`chemist in roles of increasing responsibility at Berlex Laboratories and Cephalon
`
`
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`2
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`Inc., where I synthesized numerous classes of small molecules ranging from
`
`heterocycles to peptide mimetics as potential pharmaceuticals.
`
`7.
`
`From 2001 to 2003, I was an adjunct professor of chemistry at
`
`Villanova University, where I created and taught a graduate medicinal chemistry
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`course.
`
`8.
`
`In 2001, I founded Key Synthesis LLC, an organic chemistry
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`laboratory located in the Philadelphia, Pennsylvania metropolitan area. Key
`
`Synthesis is fully equipped to conduct custom organic synthesis, contract
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`medicinal chemistry research, and process research for the pharmaceutical and
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`biotechnology industries. I have worked continuously at Key Synthesis since
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`2001.
`
`9.
`
`I have served on the steering committee of Chemical Consultants
`
`Network, a topical group of the American Chemical Society, from 2007 to present,
`
`and served as its chairman from 2009 to 2012.
`
`10. My qualifications are further detailed in my curriculum vitae, a copy
`
`of which is attached hereto as Exhibit 1003.
`
`III. SUMMARY OF OPINIONS
`11. The opinions contained in this Declaration are based on the
`
`documents I reviewed, my preparation of lemborexant samples according to the
`
`
`
`3
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`
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`procedures of the ’109 patent, and my professional judgment, as well as my
`
`education, experience, and knowledge regarding organic chemistry and medicinal
`
`chemistry.
`
`12.
`
`In forming my opinions expressed in this Declaration, I reviewed the
`
`following documents and materials:
`
`• U.S. Patent No. 10,759,779 (“the ’779 patent”) (Ex. 1001)
`
`• U.S. Patent No. 8,268,848 (“the ’848 patent”) (Ex. 1005)
`
`• U.S. Patent No. 9,416,109 (“the ’109 patent”) (Ex. 1006)
`
`• International Patent Publication No. WO 2016/063995
`(“the ’995 publication”) (Ex. 1007)
`
`• Yuzo Wantanabe, EISAI LEMBOREXANT STUDY REPORT NO.
`W-20170092 (2017) (Ex. 1011)
`
`• X-Ray Powder Diffraction Pattern of Lemborexant Lot 169R2601
`(Ex. 1012)
`
`• GAM-388-2 – Eisai Lab Notebook of George Moniz (Ex 1015)
`
`• Eisai Internal Report re HAND Project – December 2010 (Ex. 1016)
`
`• AZW-673a – Eisai Lab Notebook of Annie Wearing (Ex. 1017)
`
`• Y. Yoshida et al., Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-
`yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-
`yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral
`Orexin Receptor Antagonist, 58 J. MEDICINAL CHEMISTRY 4648
`(2015) (Ex. 1020)
`
`• M. Moline et al., Dual Orexin Receptor Antagonist E2006 Shows
`Efficacy on Sleep Initiation and Maintenance on Sleep Diary
`4
`
`
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`
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`Measures in Phase 2 Study, J. OF SLEEP AND SLEEP DISORDERS
`RESEARCH, Vol. 38, 2015 Abstract Supplement, Abstract 0636
`(Ex. 1030)
`
`• X-ray powder diffractograms (“XRPDs”) of the lemborexant samples
`I prepared
`
`• Any other materials to which I refer in this Declaration in support of
`my opinions
`
`13. My opinions have also been guided by my appreciation of how a
`
`person of ordinary skill in the art would have understood the claims at issue and
`
`the specification of the ’779 patent at the time of the alleged invention, which I
`
`understand was no earlier than August 1, 2017 (i.e., the filing date of Chinese
`
`Patent Application No. 201710648135.2, which I understand is the earliest possible
`
`priority date for the ’779 patent).2 My opinions reflect how one of ordinary skill in
`
`the art would have understood the ’779 patent, the prior art to the patent, and the
`
`state of the art at the time of the alleged invention.
`
`14. Based on my experience and expertise, and my review of the
`
`documents and materials set forth above, the following are my opinions:
`
`
`2
`I understand from counsel that the earliest possible priority date of a patent
`
`is the filing date of the first member in a family of patent applications.
`
`
`
`5
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`• The natural result of following either one of the two procedures for
`preparing lemborexant3 in Example G of the ’109 patent is the
`crystalline form of lemborexant recited in claims 1-4 and 7-8 of the
`’779 patent;
`
`• The ’109 patent disclosed, either expressly or inherently, all of the
`limitations recited in claims 1-4 of the ’779 patent;
`
`• The ’109 patent would also render obvious claims 1-4 of the ’779
`patent; and
`
`• The ’109 patent in combination with the ’995 publication renders
`obvious claims 7 and 8 of the ’779 patent.
`IV. PERSON OF ORDINARY SKILL IN THE ART
`I am familiar with the level of ordinary skill in the art with respect to
`15.
`
`the alleged inventions of the ’779 patent as of August 1, 2017, which is the filing
`
`date of Chinese Patent Application No. 201710648135.2 to which the ’779 patent
`
`claims priority. Based on my review of the ’779 patent, the technology underlying
`
`the ’779 patent, the educational level and experience of active workers in the field,
`
`the types of problems faced by workers in the field, the solutions found to those
`
`problems, the sophistication of the technology in the field, and drawing on my own
`
`experience, a person of ordinary skill in the art (“POSA”) would have had a
`
`3
`The chemical name for lemborexant is (1R,2S)-2-(((2,4-dimethylpyrimidin-
`
`5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-
`
`yl)cyclopropanecarboxamide.
`
`
`
`6
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`master’s degree in biochemistry, medicinal chemistry, organic chemistry, or the
`
`equivalent degree relevant to small molecule drug development, and at least two to
`
`three years of experience with crystallization techniques. More education can
`
`supplement practical experience and vice versa. My opinions expressed in this
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`declaration would not be different in the POSA had slightly more or less education
`
`and/or experience.
`
`16. All of my opinions in this Declaration are from the perspective of one
`
`of ordinary skill in the art, as I have defined it here, during the relevant timeframe
`
`of 2017.
`
`V. OVERVIEW OF THE ’779 PATENT
`17. The ’779 patent generally relates to the crystalline form of
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`lemborexant and processes that result in that crystalline form. The ’779 patent
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`recognizes that Eisai developed the compound lemborexant and, based on clinical
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`trials that Eisai conducted, Eisai was able to show that lemborexant “can
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`significantly improve sleep efficiency in patients with insomnia.” (Ex. 1001, 1:25-
`
`33.)
`
`18. The ’779 patent alleges that (1) before the ’779 patent was filed, “no
`
`crystalline forms of [lemborexant] was [sic] disclosed,” and (2) when the named
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`’779 inventors performed the process for preparing lemborexant disclosed in
`
`
`
`7
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`
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`CN103153963B, “an amorphous solid was obtained.”4 (Ex. 1001, 1:61-66.) The
`
`’779 inventors do not provide any detailed information relating to how they
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`allegedly performed the method disclosed in CN103153963B.
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`19. The ’779 patent discloses a single crystalline form, which the
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`inventors identify as “Form CS2.” According to Figure 1 of the ’779 patent, Form
`
`CS2 has the following XRPD pattern:
`
`20. The ’779 patent discloses the following proposed formulation for a
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`tablet with lemborexant as its active pharmaceutical ingredient:
`
`
`
`
`4
`I understand from counsel that CN103153963B is a Chinese patent that
`
`claims priority to the same U.S. provisional application as the ’848 patent
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`(Ex. 1005). I understand from counsel that Eisai owns both the Chinese patent and
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`the ’848 patent.
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`
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`8
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`(Ex. 1001, 12:30-44.) The ’779 patent, however, does not disclose or otherwise
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`purport to have conducted any in vitro or in vivo experiments to develop this
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`formulation or identify a therapeutically effective dose of “E-2006” (i.e.,
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`lemborexant).
`
`A. The Disclosures of the ’779 Patent
`21. The ’779 patent does not assert or identify the existence of multiple
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`crystalline forms of lemborexant. Rather, in its examples, the ’779 patent discloses
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`several methods, all of which are asserted to result in the same crystalline form of
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`lemborexant:
`
`• Example 1 – “Approximately 199.6 mg of [lemborexant] was
`weighted [sic] and dissolved in 3.0 mL of acetone, followed by
`filtration and slowly evaporation [sic] to obtain a solid at room
`temperature. The obtained solid was confirmed to be Form CS2.”
`(Ex. 1001, 7:46-51.)
`
`
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`9
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`• Example 2 – “Approximately 1026.0 mg of [lemborexant] was
`weighted [sic] and dissolved in 10.0 mL of methanol. The solution
`was filtered and stirred while adding about 10.0 mL of water as an
`anti-solvent. After stirred [sic] for about 4 hours, a large amount
`of solid precipitated out. The precipitation [was] collected by
`suction filtration and dried under vacuum at 40° C. for about 18
`hours to obtain solids. The obtained solid was confirmed to be
`Form CS2.” (Ex. 1001, 8:29-36.)
`
`• Examples 3 to 5 – “Approximately 31.5 mg of [lemborexant] was
`dissolved in 1.0 mL of acetonitrile and filtered. A small amount of
`ionic liquid as shown in Table 3 was added, and the solution was
`slowly evaporated at room temperature to obtain solid. The solid
`obtained in example 3-5 were [sic] labeled as samples 3-5 and
`confirmed to be Form CS2.”
`
`(Ex. 1001, 9:23-36.)
`
`
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`22. Each of these methods starts with a sample of lemborexant that has
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`already been synthesized, which is then dissolved in a particular solvent
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`(i.e., acetone, methanol, or acetonitrile) and then allowed to precipitate by addition
`
`
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`10
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`of an anti-solvent or evaporation of the solvent. These methods do not specify the
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`form of the starting lemborexant before it is dissolved. The suggestion of these
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`methods, consistent with the understanding of a POSA, is that the initial form of
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`lemborexant before dissolution is immaterial to obtaining the crystal form of
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`lemborexant through precipitation after dissolution. Furthermore, as a POSA
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`would know, a compound dissolved in a solvent has no crystalline form, such that
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`lemborexant dissolved in a solvent would have no crystal form prior to it being
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`precipitated out of the solution.
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`23. Regarding the amorphous material that the inventors allegedly created
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`by performing the process for preparing lemborexant disclosed in CN103153963B,
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`the ’779 patent states: “The preparation of amorphous [sic] is usually a rapid
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`precipitation process to produce kinetically stable solid, which easily leads to
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`excessive residual solvent.” (Ex. 1001, 2:5-8.) In contrast, crystalline solids can
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`frequently be obtained by dissolving a compound in a solvent and then
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`precipitating it by slowly adding an anti-solvent.
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`B. Claims of the ’779 Patent
`24. At the request of counsel, I have analyzed the following claims of the
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`’779 patent:
`
`
`
`
`
`(Ex. 1001, 14:7-29, 40-47.)
`In Section VIII of my Declaration, I provide my opinions regarding
`25.
`
`whether the ’109 patent discloses, either expressly or inherently, all of the
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`limitations of claims 1-4 of the ’779 patent. In Section IX of my Declaration, I
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`provide my opinions regarding whether the ’109 patent renders obvious claims 1-4
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`of the ’779 patent. In Section X of my Declaration, I provide my opinions
`
`regarding whether the ’109 patent in combination with the ’995 publication renders
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`obvious claims 7 and 8 of the ’779 patent.
`
`VI. THE TWO PROCEDURES OF THE ’109 PATENT FOR
`PREPARING THE CRYSTALLINE FORM OF LEMBOREXANT
`A. Overview of the Two Procedures
`26. Before Patent Owner filed the ’779 patent, Eisai had already
`
`discovered lemborexant and its potential use as a pharmaceutical compound. For
`
`example, the ’109 patent disclosed, inter alia, lemborexant for treatment of sleep
`
`disorders, such as insomnia. (Ex. 1006, ’109 patent, 20:16-24.)
`
`27. Example G of the ’109 patent disclosed two procedures for preparing
`
`lemborexant. The first procedure is set forth in columns 46 to 47, as shown below:
`
`
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`13
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`(Ex. 1006, 46:52-47:20.)
`28. Example G also sets forth the following “alternate procedure” in
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`
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`column 49, as shown below:
`
`
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`14
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`(Ex. 1006, 49:6-56.)
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`29. The two procedures disclosed in Example G for preparing
`
`lemborexant (identified as compound 14 in the schematic below) both utilized the
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`coupling of a carboxylic acid (identified as compound 13 in the green box)5 with
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`an amine (which is shown in the blue box)6:
`
`(Ex. 1006, 46:15-45.)
`
`
`
`
`5
`The chemical name of the carboxylic acid is (1R,2S)-2-(((2,4-
`
`dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic
`
`acid.
`
`6
`
`
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`The chemical name of the amine is 2-amino-5-fluoropyridine.
`
`16
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`30. Under Example G’s first procedure, lemborexant is synthesized by
`
`coupling (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-
`
`fluorophenyl)cyclopropanecarboxylic acid (i.e., “the carboxylic acid”) with 2-
`
`amino-5-fluoropyridine (i.e., “the amine”) using N,N-diisopropylethylamine
`
`(“DIPEA”) and n-propylphosphonic anhydride (“T3P”) in ethyl acetate solvent to
`
`accomplish the reaction.
`
`31. Under Example G’s alternate procedure, lemborexant is synthesized
`
`by coupling (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-
`
`fluorophenyl)cyclopropanecarboxylic acid (i.e., “the carboxylic acid”) with 2-
`
`amino-5-fluoropyridine (i.e., “the amine”) using N,N,N’,N’-tetramethyl-O-(7-
`
`azabenzotriazol-1-yl)uronium hexafluorophosphate (“HATU”) and N,N-
`
`diisopropylethylamine in dimethylformamide (“DMF”) solvent to accomplish the
`
`reaction.
`
`32. The ’109 patent provides other examples setting forth methods for
`
`preparing precursor compounds that may ultimately be used to prepare
`
`lemborexant (e.g., preparing the carboxylic acid that is used in the Example G
`
`procedures). The processes disclosed in the Example G procedures, however,
`
`determine whether and which crystalline form of lemborexant will be present in
`
`the final product. For instance, during Example G’s coupling reactions, the
`
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
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`starting materials (i.e., the carboxylic acid and amine) are dissolved in a solvent
`
`(i.e., ethyl acetate or DMF). Similarly, during Example G’s purification process,
`
`the lemborexant from the prior work-up is dissolved in ethyl acetate.7 Thus, any
`
`pre-existing form of a precursor compound would be lost when it is dissolved in
`
`solution, and the crystal is then formed as a result of the Example G procedure.
`
`B.
`
`33.
`
`Lemborexant Prepared Using the
`Procedures in Example G of the ’109 Patent
`I was asked by counsel to prepare lemborexant according to both
`
`procedures disclosed in Example G of the ’109 patent.
`
`34. To prepare lemborexant for use in either procedure, I used starting
`
`materials (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)
`
`cyclopropanecarboxylic acid (Lot # 13XP0234) and 2-amino-5-fluoropyridine
`
`(Lot # D0179-23-DC19001), which I received from Eisai. Both samples were
`
`shipped on excess dry ice (-78°C) and stored at -20°C prior to use. As shown in
`
`the tables below, I confirmed the identity of the carboxylic acid by comparison to
`
`7
`“Work-up” is an informal term used by a POSA to describe steps that are
`
`undertaken to isolate the product following the completion of the reaction and
`
`before any purification. During a work-up, the product of the reaction is isolated
`
`and impurities such as un-reacted starting materials are removed.
`
`
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`18
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`the H-NMR, C-NMR, and mass spectrometry values for this starting material set
`
`forth in the ’109 patent:
`
`CNMR (DMSO)
`HNMR (DMSO)
`’109 patent,
`Carboxylic Acid
`’109 patent,
`Carboxylic Acid
`45:35-40
`(Eisai)
`45:31-35
`(Eisai)
`172.65
`172.25
`12.47 (s, 1H)
`12.51 (s, 1H)
`162.48 (d)
`162.04 (d)
`8.17 (s, 1H)
`8.17 (s, 1H)
`159.08
`158.63
`7.39 (td, 1H)
`7.39 (td, 1H)
`156.24
`155.79
`7.29 (d, 1H)
`7.29 (dt, 1H)
`149.45
`148.99
`7.27-7.22 (m, 1H) 7.25 (dt, 1H)
`145.15 (d)
`144.71 (d)
`7.10 (td, 1H)
`7.09 (td, 1H)
`139.60
`139.11
`4.63 (d, 1H)
`4.63 (d, 1H)
`130.71 (d)
`130.28 (d)
`4.30 (d, 1H)
`4.29 (d, 1H)
`124.79 (d)
`124.34 (d)
`2.46 (s, 3H)
`2.45 (s, 3H)
`115.60 (d)
`115.15 (d)
`2.26 (s, 3H)
`2.26 (s, 3H)
`114.32 (d)
`113.88 (d)
`2.13 (dd, 1H)
`2.13 (dd, 1H)
`1.63-1.54 (m, 2H); 1.60-1.57 (m, 2H) 71.15
`70.68
`
`
`33.92 (d)
`33.45
`
`
`26.46
`26.01
`
`
`24.96
`24.48
`
`
`19.72
`19.28
`
`
`18.70
`18.23
`
`
`
`
`
`
`’109 patent, 45:41-42
`HRMS [M+H]+
`317.1298
`
`Mass Spectra
`Carboxylic Acid from Eisai
`[M+H]+
`317.1
`
`
`(Ex. 1014, 1-4, 16-18, 25.) As shown in the table below, I also confirmed the
`
`identity of the amine that I received from Eisai through the measurement of its
`
`melting point (96-100°C) and H-NMR spectrum:
`
`
`
`19
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`
`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`HNMR (DMSO)
`7.84 (d)
`7.30 (td, 1H)
`6.44 (dd, 1H)
`5.82 (s, 2H)
`
`
`
` (Ex. 1014, 5-7.)
`
`The First Procedure of Example G
`1.
`I faithfully followed the steps of the first procedure disclosed in
`
`35.
`
`Example G of the ’109 patent to prepare lemborexant. (Ex. 1013, 112-113.) The
`
`synthesis was conducted on one-tenth the scale reported in the ’109 patent. As a
`
`POSA would recognize, this reduction in scale would not affect the crystalline
`
`form.
`
`36. For the “coupling” reaction of the first procedure, I dissolved 1.280 g
`
`(i.e., 4.05 mmol) of the carboxylic acid and 476 mg (i.e., 4.25 mmol) of the amine
`
`in 10.2 mL of ethyl acetate, under nitrogen. (Ex. 1013, 112.) The solution was
`
`then cooled to an internal temperature of 5°C, and 1.410 mL (i.e., 8.084 mmol) of
`
`N,N-diisopropylethylamine was added to the reaction mixture while maintaining
`
`an internal temperature of 5°C. (Id.) I stirred the mixture at a temperature of 5°C
`
`for 20 min. (Id.) A 50% by weight solution of n-propylphosphonic anhydride
`
`(“T3P”) in ethyl acetate (3.61 g or 5.67 mmol) was added while maintaining an
`
`
`
`20
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`internal temperature of 10°C. (Id.) I then stirred the reaction 20-25°C for 21 hours
`
`and monitored the reaction by HPLC and TLC, which indicated that the reaction
`
`was complete and no starting carboxylic acid or amine remained. (Id.) The
`
`resulting product of the coupling reaction was an organic solution containing
`
`lemborexant.
`
`37. After the coupling reaction was completed, I proceeded to work-up
`
`the lemborexant from the coupling reaction. I isolated the lemborexant by cooling
`
`the mixture to an internal temperature of 5°C and quenching the reaction with
`
`6.4 mL water at an internal temperature below 15°C. (Id.) Upon quenching the
`
`ethyl acetate solution from the coupling reaction with water, a two phase system
`
`resulted, with a clear separation between the organic layer (i.e., ethyl acetate) and
`
`the aqueous layer (i.e., water). I separated the layers using a separatory funnel and
`
`set aside the ethyl acetate layer.
`
`38.
`
`I added MTBE (7.68 mL) to the aqueous solution to create another
`
`two phase system. (Id.) In this system, the lemborexant in the aqueous layer was
`
`extracted into the organic, MTBE phase, which allowed me to recover any
`
`lemborexant that potentially entered the aqueous layer during quenching. I
`
`separated the MTBE and aqueous phases using a separatory funnel.
`
`
`
`21
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`I then combined the ethyl acetate and MTBE phases and washed them
`
`39.
`
`once with 3.84 mL saturated aqueous sodium bicarbonate solution and once with
`
`3.84 mL water. (Id.) I filtered the combined organic MTBE and ethyl acetate
`
`layer and rinsed the filter with 1.28 mL of MTBE. (Id. at 113.) I then
`
`concentrated the organic layer under reduced pressure to give 1.70 g of crude
`
`lemborexant as a light amber oil. (Id.)
`
`40. Example G of the ’109 patent also provided detailed instructions
`
`regarding purification of the lemborexant from the work-up process. (Ex. 1006,
`
`47:8-20.) I followed these instructions and obtained a crystalline solid of
`
`lemborexant.
`
`41. For the purification process, I added 6.08 mL of ethyl acetate to the
`
`crude lemborexant and heated the mixture to 50°C to achieve a clear solution.
`
`(Ex. 1013, 113.) I slowly added 8.63 mL of n-heptane to the mixture with a pipette
`
`(adding the n-heptane over the course of about one minute), using a magnetic
`
`stirring bar and stir plate to agitate the solution. (Id.) This would be a routine way
`
`for a POSA at the relevant time to slowly add an anti-solvent (i.e., n-heptane) in
`
`these types of purifications.
`
`42.
`
`I observed that white crystals formed in about 1 minute. I cooled the
`
`mixture to 24°C and stirred for an hour at 24°C and then for 2 hours at 5°C,
`
`
`
`22
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`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`cooling with a crushed ice bath. (Id.) I stirred at a rate of about 2 to 3 revolutions
`
`per second using a magnetic stir bar and stir plate, which is a routine way for a
`
`POSA at the relevant time to have stirred the mixture to precipitate out the
`
`lemborexant from solution. I filtered the suspension and washed the cake twice
`
`with 1.28 mL of 5:1 heptane/ethyl acetate. (Id.) I dried the cake to a constant
`
`weight under vacuum to obtain 877 mg of lemborexant. It would have been
`
`routine for a POSA to dry the final solid product under vacuum until a constant
`
`weight was achieved since that would suggest that the product was sufficiently dry.
`
`I observed that the resulting lemborexant was a white crystalline solid, consistent
`
`with the description of the color in the ’109 patent.
`
`43. As shown in the table below, I confirmed that the resulting compound
`
`was the same as the lemborexant prepared in Example G of the ’109 patent based
`
`on H-NMR, C-NMR, and mass spectra:
`
`
`
`23
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`Page 26 of 56
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`

`
`
`HNMR (DMSO)
`’109 patent,
`Bihovsky
`47:23-29
`Sample
`11.19 (s, [sic]
`11.21 (s, 1H)
`8.31 (d, 1H)
`8.32 (d, 1H)
`8.12 (s, 1H)
`8.12 (s, 1H)
`7.94-7.85 (m, 1H) 7.90 (dd, 1H)
`7.62 (tt, 1H)
`7.63 (dt, 1H)
`7.44 (dd, 1H)
`7.44 (m, 1H)
`7.41-7.40 (m, 1H) 7.40 (m, 2H)
`7.39 (s, 1H)
`
`7.14-7.06 (m, 1H) 7.10 (m, 1H)
`4.67 (d, 1H)
`4.67 (d, 1H)
`4.29 (t, 1H)
`4.29 (d, 1H)
`2.63 (t, 1H)
`2.63 (t, 1H)
`2.38 (s, 3H)
`2.38 (s, 3H)
`2.03 (s, 3H)
`2.03 (s, 3H)
`1.76-1.64 (m, 1H) 1.71 (t, 1H)
`1.49 (dd, 1H)
`1.49 (dd, 1H)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`CNMR (DMSO)
`’109 patent,
`Bihovsky
`47:29-35
`Sample
`168.68
`168.72
`161.98 (d)
`162.01 (d)
`158.46
`158.49
`155.15
`155.53
`155.38 (d)
`155.41 (d)
`148.90
`148.93
`148.51
`148.55
`145.00 (d)
`145.03 (d)
`139.37
`139.37
`135.15 (d)
`135.20 (d)
`130.06 (d)
`130.11 (d)
`125.05 (d)
`125.10 (d)
`124.70 (d)
`124.74
`115.71 (d)
`115.75 (d)
`114.20 (d)
`114.23
`113.70 (d)
`113.75 (d)
`70.80
`70.81
`34.09 (d)
`34.11
`26.90
`26.92
`24.38
`24.40
`18.37
`18.40
`17.78
`17.80
`
`Mass Spectra
`’109 patent, 47:36-37
`HRMS [M+H]+
`411.1632
`
`433.1
`
`Bihovsky Sample
`[M+Na]+
`
`
`
` (Ex. 1014, 8-11, 19-21, 27.)
`
`
`
`24
`
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`Page 27 of 56
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`
`
`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`44. After preparing the lemborexant using the first procedure in Example
`
`G, I sent my samples to Dr. Mayo for XRPD analysis.8 I understand from counsel
`
`that Dr. Mayo obtained the following XRPD pattern for the lemborexant that I
`
`prepared using Example G’s first procedure:
`
`
`
`
`8
`I stored the samples at -20°C to avoid any potential degradation and also
`
`shipped the samples via FedEx overnight to Dr. Mayo in an insulated container
`
`with an ice pack that started at -20°C.
`
`
`
`25
`
`
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`Page 28 of 56
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`
`
`Declaration of Ron Bihovsky, Ph.D.
`U.S. Patent No. 10,759,779
`
`
`
`45. As shown by the presence of distinguishable peaks in a pattern, Dr.
`
`Mayo’s diffractogram confirms that the lemborexant prepared based on Example
`
`G’s first procedure results in a crystalline form.9
`
`The Alternate Procedure
`2.
`46. As noted above, Example G of the ’109 patent also disclosed an
`
`“alternate procedure” for preparing lemborexant from the carboxylic acid and
`
`amine. In addition to preparing lemborexant according to the first procedure of
`
`Example G, I also prepared lemborexant by faithfully following the alternate
`
`procedure of Example G. (Ex. 1013, 114-115.) This procedure was also
`
`conducted on one-tenth the scale reported in the ’109 patent.
`
`47. For the coupling reaction, I dissolved 1.28 g (i.e., 4.05 mmol) of the
`
`carboxy