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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`EISAI INC.
`Petitioners
`
`v.
`
`CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD.
`Patent Owner
`
`____________________
`
`Patent No. 10,759,779
`____________________
`
`DECLARATION OF WILLIAM MAYO, 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 30
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`EISAI EXHIBIT 1023
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`TABLE OF CONTENTS
`
`INTRODUCTION .......................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................ 1
`II.
`III. MATERIALS REVIEWED ........................................................................... 6
`IV. TECHNICAL BACKGROUND .................................................................... 7
`A.
`Crystalline Forms of Compounds ........................................................ 7
`1.
`Crystalline Solids ....................................................................... 7
`2.
`Amorphous Solids ...................................................................... 8
`3.
`Polymorphic Solids .................................................................... 9
`X-Ray Powder Diffraction Testing (XRPD) ...................................... 10
`B.
`Interpreting XRPD Results ................................................................. 14
`C.
`CRYSTALLINE FORM OF LEMBOREXANT PREPARED USING
`PROCEDURES IN EXAMPLE G OF THE ’109 PATENT ....................... 16
`A. XRPD Patterns Disclosed in the ’779 Patent ..................................... 17
`B.
`XRPD Patterns of Samples Dr. Bihovsky Prepared by
`Following the Procedures in Example G of the ’109 Patent .............. 18
`XRPD Patterns of Eisai’s Prior Lemborexant Lots ........................... 23
`C.
`VI. CONCLUSION ............................................................................................. 27
`
`V.
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`i
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`I, William Mayo, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`1.
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`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 I have been asked to determine whether (1) the lemborexant samples I
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`obtained from Dr. Ron Bihovsky, and (2) certain batches of lemborexant that Eisai
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`prepared, contain the features recited in Claims 1-3 of the ’779 patent.
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`2.
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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
`3.
`I presently serve as a Professor Emeritus at Rutgers University and am
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`the Co-Founder and former Chief Scientist at H&M Analytical Services, which I
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`sold in 2015. All of my opinions stated in this Declaration are based on my own
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`1
`Where appropriate, I refer to exhibits that I understand are to be attached to
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`the petition for Post-Grant Review of the ’779 patent.
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`1
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`personal knowledge and professional judgment. In forming my opinions, I have
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`relied on my knowledge and more than 50 years of experience in X-Ray Powder
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`Diffraction (“XRPD”).
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`4.
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`I am over 18 years of age and, if I am called upon to do so, I would be
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`competent to testify as to the matters set forth herein. I understand that a copy of
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`my current curriculum vitae, which details my education and professional and
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`academic experience, is being submitted by Petitioner as Exhibit 1024. The
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`following provides an overview of some of my experience that is relevant to the
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`matters set forth in this Declaration.
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`5.
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`I taught material sciences and engineering at Rutgers for the period
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`1982 to 2008. I joined the faculty in the Department of Mechanics and Material
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`Science in 1982 as an Assistant Professor and then progressed to Associate
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`Professor in 1988, Full Professor in 1995, and Emeritus Professor in 2008.
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`6.
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`I received a Bachelor of Science Degree in Physics from Carnegie
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`Mellon University in 1971. I received a Master’s Degree in Metallurgy and
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`Materials Science from Carnegie Mellon University in 1974. In 1978, I began
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`graduate studies at Rutgers, where I received a Ph.D. in Mechanics and Materials
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`Science in 1982. I also served as a Post-doctoral fellow at Bell Laboratories in
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`1982.
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`7.
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`I have co-founded five companies (H&M Analytical Services, Nano
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`Pac, XStream Systems/Veracity Networks, XRD Associates, and XID LLC) in the
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`private sector that were closely linked to my Rutgers research and experiences.
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`XStream (later reconstituted as Veracity) focused on the detection of counterfeit
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`pharmaceuticals utilizing a novel XRPD method that I developed with Federal
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`Aviation Administration (“FAA”) funding for rapid detection of explosives hidden
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`inside checked baggage. The XRPD method developed in that early work was
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`later used by XID to develop an instrument to detect opioids being smuggled
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`through the international postal system and was funded by the US Postal Service
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`(“USPS”) and the Department of Homeland Security (“DHS”). Nano Pac
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`commercialized work that I had done with National Science Foundation (“NSF”)
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`and Department of Defense (“DOD”) funding to develop nanoscale materials via a
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`controlled transformation of metastable starting materials. H&M Analytical
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`Services was founded as a consulting and testing company to take advantage of my
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`nearly 50 years of experience in XRPD methods. Finally, I founded XRD
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`Associates as a consulting company focusing mostly on XRPD analysis of
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`pharmaceutical materials. I have been involved with these companies on a
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`part-time (1997-2008) or full time (2008-present) basis for more than 20 years.
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`8.
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`As part of my academic duties at Rutgers, I taught nineteen different
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`courses in various aspects of material characterization and general aspects of
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`Material Science, all of which are itemized in Exhibit 1024. Of those courses, I
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`taught three undergraduate courses and five graduate courses dealing with various
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`aspects of basic and advanced principles of XRPD. I have also provided training
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`in XRPD at the post-graduate level. Finally, I supervised three different XRPD
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`laboratories where I was responsible for purchasing, maintaining, instructing, and
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`supervising all aspects of the laboratories. In total, I have utilized more than 40
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`different X-ray diffractometers and personally analyzed well in excess of 100,000
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`diffraction patterns during my career.
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`9.
`
`In addition to my teaching duties related to XRPD, I have been very
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`active in providing services to the XRPD community. In recognition of this fact,
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`in 2006, I was awarded the title of Fellow by the International Center for
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`Diffraction Data (“ICDD”), which is the world’s foremost source of X-ray powder
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`diffraction data. This honor was bestowed on me in recognition of my 18 years as
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`an editor for the Powder Diffraction File (“PDF”), 8 years as an Editor for New
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`Data for the journal Powder Diffraction and 35+ years of effort in advancing the
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`development of XRPD techniques.
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`10. My experiences with the ICDD include an important role in the
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`editorial review of the PDF patterns submitted by scientists from around the world,
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`as well as contribution of new patterns. As a member and Chair of Technical
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`Committees within the ICDD, I am also experienced in the interactions of the
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`ICDD and its predecessor organizations and have interacted with government
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`agencies such as the National Institute of Standards (NIST) with regard to the
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`development and publication of powder diffraction data.
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`11.
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`I have numerous publications, including 8 books written, 25
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`monographs edited, 4 book chapters, 3 instructional texts, 138 refereed articles, 83
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`archival abstracts, and 100 conference presentations. Most of these publications
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`focus on the use or development of XRPD methods.
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`12.
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`In addition to teaching, research, publications, and editorial work
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`related to XRPD, I have designed and constructed numerous XRPD instruments
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`for the FAA, Department of Homeland Security, XStream, Veracity, L-3
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`Communications, XID, and Rutgers. Much of this work revolved around the
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`design of advanced algorithms and neural networks for phase identification of
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`various crystalline materials, including their polymorphs. My research has resulted
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`in the filing of eight patent applications, three of which issued as patents.
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`13. Based on my education, practical training, teaching, research,
`
`equipment design, editorial work, patents, consulting, and industrial experience, I
`
`consider myself to be an expert in the area of X-ray diffraction, material
`
`characterization, use of XRPD databases for general phase identification and
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`quantification, with a special emphasis on detection of polymorph phases.
`
`14. My qualifications are further detailed in my curriculum vitae, a copy
`
`of which is attached hereto as Exhibit 1024.
`
`III. MATERIALS REVIEWED
`15. The opinions contained in this Declaration are based on the
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`documents I reviewed, XRPD testing of lemborexant samples prepared by Dr. Ron
`
`Bihovsky, and my professional judgment, as well as my education, experience, and
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`knowledge regarding XRPD.
`
`16.
`
`In forming my opinions expressed in this Declaration, I reviewed:
`
` U.S. Patent No. 10,759,779 (“the ’779 patent”) (Ex. 1001)
`
` U.S. Patent No. 9,416,109 (“the ’109 patent”) (Ex. 1006)
`
` X-Ray Powder Diffraction Pattern of Lemborexant Lot 169R2601
`(Ex. 1012)
`
` X-Ray Diffraction Pattern of Lemborexant Lots AZW-673a and
`GAM-388-2 in Eisai’s Internal Monthly Report re HAND Project
`for December 2010 (Ex. 1016)
`
` Any other materials I refer to in this Declaration in support of my
`opinions
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`6
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`17. Based on my experience and expertise, it is my opinion that the
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`lemborexant samples I received from Dr. Bihovsky exhibit the characteristic
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`XRPD pattern peaks recited in Claims 1-3 of the ’779 patent. The lemborexant
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`samples from testing lots produced by Eisai also exhibit the characteristic peaks
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`recited in Claims 1-3 of the ’779 patent.
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`IV. TECHNICAL BACKGROUND
`18.
`In this section, I present a brief overview of certain fundamental
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`aspects of crystalline forms and XRPD at the time of the alleged invention of the
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`’779 patent.
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`A. Crystalline Forms of Compounds
`19. Solid materials generally can exist in either a “crystalline” form or an
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`“amorphous”/“non-crystalline” form.
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`1.
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`Crystalline Solids
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`20.
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`“Crystalline” materials have atoms that are arranged in a periodic and
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`predictable way, forming a three-dimensional atomic lattice structure. For
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`example, a crystalline structure of MgB2 is shown in Figure 1 below:
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`U.S. Patent No. 10,759,779
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`Figure 1: Crystalline Mg B2
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`2
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`21. Most inorganic solid materials have a crystalline form and consist of
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`“grains,” within which the same crystal structure and orientation exists.
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`2.
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`Amorphous Solids
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`22. When the atoms in a solid are disordered and non-repeating, the
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`material is amorphous, as exemplified in the figures below:
`
`
`2
`Xun Xu et al., Superconducting Properties of Graphene Doped Magnesium
`
`Diboride, in APPLICATIONS OF HIGH-TC SUPERCONDUCTIVITY (Adir Moysés Luiz
`
`ed., 2011), available at https://www.intechopen.com/books/applications-of-high-tc-
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`superconductivity/superconducting-properties-of-graphene-doped-magnesium-
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`diboride.
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`Crystalline SiO2
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`Non-crystalline SiO2
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`Figure 2: Crystalline (left) and amorphous (right) SiO2
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`3
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`23. Amorphous forms may be obtained, for example, when the solids are
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`formed rapidly – either through a rapid precipitation from solution or through rapid
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`cooling (as is the case for amorphous metallic glass). The rapid solidification may
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`not allow the atoms time to space themselves in the most energy efficient or
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`thermodynamically stable manner, and instead they are randomly interspersed in
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`the material. Accordingly, when working to obtain a crystalline material, one
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`typically would ensure the transition occurs relatively slowly.
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`3.
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`Polymorphic Solids
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`24. Some crystalline materials can exhibit multiple crystal forms, which
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`are called polymorphs when they occur in multi-element compounds or allotropes
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`
`3
`W.D. Callister, “Material Science and Engineering”, 5th Ed., Wiley, 2000,
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`p. 58.
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`U.S. Patent No. 10,759,779
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`for elements. For example, carbon atoms form a variety of crystal structures,
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`ranging from diamonds to graphite.
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`25. Not all crystalline materials are known to have polymorphs; some
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`solids only have one crystal form. For example, under normal atmospheric
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`conditions, salt (NaCl) has only one known crystal form.
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`B. X-Ray Powder Diffraction Testing (XRPD)
`26. XRPD is the principal method for characterizing the crystalline
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`structure of solid materials and has been in use for almost a century. Because
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`XRPD is also used in the ’779 patent to characterize the crystalline structure of
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`lemborexant, a review of the basic principles of XRPD is provided below.
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`27. X-rays are high-energy electromagnetic radiation having a wavelength
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`in the range of 0.01 to 10 nanometers, which is comparable to the atomic spacing
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`in crystalline solid materials. As a result, crystalline materials scatter X-rays at
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`certain angles, in a manner called diffraction. This diffraction, when properly
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`observed, provides useful information about the crystalline structure of the material
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`being analyzed, as different materials will diffract the X-rays in different ways.
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`The result is that the diffraction pattern for any given crystal form is unique, i.e., a
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`fingerprint for that crystal form. The process of diffraction is shown schematically
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`in the figures below.
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`Figure 3: X-rays diffracting off molecules4
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`28. The waves of the X-ray beam interact (Figure 3 above) with parallel
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`planes of atoms separated by a distance d and are diffracted at a particular angle
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`(i.e., 2θ), which is defined as the angle between the incident and diffracted beams.
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`The incident X-ray beam (i.e., the beam emanating from the X-ray tube) is
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`comprised of nearly parallel waves and appears on the left side of Figure 4 below.
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`X-rays are typically generated for XRPD by directing a beam of electrons at a
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`copper (CU) anode, though a different anode material will generate X-rays with
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`different characteristics. X-rays thus generated with a Cu anode are termed CuKα
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`radiation.
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`4
`Microscopy Australia, Diffraction, https://myscope.training/legacy/xrd/
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`background/concepts/diffraction/ (last updated Jun. 18, 2014).
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`U.S. Patent No. 10,759,779
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`29. A device called a diffractometer is used to obtain a diffraction pattern.
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`In this device, the X-ray source (X-ray tube) and the detector are located on
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`opposite sides of the sample to be tested. In the most common diffractometer
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`design, the tube and detector rotate around a common axis to collect the spectrum.
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`The detected X-ray intensity will be recorded as a function of the angle 2θ.
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`
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`Figure 4: An X-ray beam in a diffractometer5
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`30. The recorded values are then plotted on a “diffractogram” with
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`relative intensity on the Y axis and 2θ on the X axis. Typically, a diffraction
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`pattern consists of several sharp peaks separated by regions of relatively low
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`5
`Scott A. Speakman, Basics of X-Ray Diffraction, slide 21, available at
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`https://www.slideserve.com/jarvis/basics-of-x-ray-powder-diffraction-training-to-
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`become-an-independent-user-of-the-x-ray-sef-at-the-center-for-material.
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`background intensity as shown in the exemplary diffractogram below (Figure 5)
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`analyzing a simple crystalline material.
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`
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`Figure 5: Sample diffraction pattern6
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`31.
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`In Figure 5 above, at 2θ values of approximately 20.5°, 29.2°, 36.1°,
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`42.0°, and 47.1°, a number of the crystals in the sample are in the proper
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`orientation to produce a diffraction peak. Between these peak values, however, the
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`intensities are very low. The diffraction pattern is collected over a wide range of
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`2θ values to capture a sufficient number of peaks to properly characterize a
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`crystalline material.
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`6
`Scott A. Speakman, Basics of X-Ray Diffraction, slide 21, available at
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`https://www.slideserve.com/jarvis/basics-of-x-ray-powder-diffraction-training-to-
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`become-an-independent-user-of-the-x-ray-sef-at-the-center-for-material.
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`32. The Y axis in an XRPD diffractogram (representing intensity) is
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`typically on a relative scale of 0 to 100%, with the strongest peak set at 100%.
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`Any peak below 1% intensity will likely be buried in background noise and will
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`therefore be difficult to measure accurately. Peaks whose intensity are less than
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`three times the background noise (known as the three sigma (3σ) rule) usually
`
`cannot be reliably differentiated from the background signal. Therefore, these very
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`weak peaks are usually ignored.
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`33. The diffraction peaks are usually sharp, permitting accurate
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`determination of peak position. A typical report of diffraction data contains
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`diffraction angle 2θ, the d value, and the relative intensity for each sufficiently
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`intense peak observed in the diffraction pattern.
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`34. To prepare crystal samples for XRPD analysis, the samples are lightly
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`ground, which randomizes the crystal orientations and results in a diffraction
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`pattern with few artifacts. Well ground samples will typically have more, well
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`defined peaks with reproducible intensities while poorly ground samples frequently
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`show one or two very strong peaks and numerous very weak peaks.
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`C.
`Interpreting XRPD Results
`35. Once a diffraction pattern has been collected, certain information must
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`be extracted from the pattern to compare the crystalline form of the sample with a
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`known crystalline form. The most common set of features used to identify a
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`crystalline form are the position, 2θ (in degrees), and relative intensity, I, of each
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`peak of sufficient intensity that can be reliably located. For archival purposes, the
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`peak position, 2θ, is then converted into the corresponding crystal interplanar
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`spacing, d, using the well-known Bragg’s Law (λ(cid:3404)2d(cid:4666)sinθ(cid:4667), where λ=
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`wavelength of the x-ray). Thus, a peak list may consist of either (2θ vs. I) or (d vs.
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`I), with the latter form being preferred.
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`36. The position of a peak on the X axis may vary depending on the
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`source of X-ray radiation used. Thus, in order to compare two diffraction patterns
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`and identify a crystalline form, the two diffraction patterns must use X-ray
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`radiation from the same type of anode. As mentioned above, CuKα radiation is the
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`type of radiation most commonly used in XRPD. I note that this problem can be
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`avoided if the peak listing uses the calculated d spacings, which are independent of
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`the X-ray wavelength.
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`37. The recommended method for identifying a crystalline form has been
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`in place for more than 75 years and is described in numerous XRPD texts, which
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`utilizes the position of several of the strongest diffraction lines, typically 8-10.
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`38. When establishing a match between two XRPD patterns, the locations
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`of the peaks for the test sample should agree to within ± 0.2° with the peaks of the
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`reference material, as specified in USP <941>.7 This margin of error takes into
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`account differences in diffractometers used by different labs, but more importantly,
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`the peak agreement error takes into account typical lot-to-lot variations and degree
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`of hydration. Since the ’779 patent lists its characteristic peaks at 2θ values with a
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`margin of error of ± 0.2° (Ex. 1001, 2:31-53), which is consistent with USP<941>,
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`the method used in the ’779 patent will be used here to analyze the samples
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`synthesized by Dr. Bihovsky and Eisai’s internal samples.
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`V. CRYSTALLINE FORM OF LEMBOREXANT PREPARED
`USING PROCEDURES IN EXAMPLE G OF THE ’109 PATENT
`39.
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`I was asked to use XRPD to analyze samples of lemborexant that Dr.
`
`Bihovsky prepared and securely provided to me. I compared the XRPD patterns
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`resulting from my analysis of these samples to the peak positions recited in Claims
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`1-3 of the ’779 patent and the XRPD patterns in the various Figures of the ’779
`
`
`7
`United States Pharmacopeia General Chapter <941>; Characterization of
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`Crystalline and Partially Crystalline Solids by X-ray Powder Diffraction (XRPD)
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`(2012), available at https://www.drugfuture.com/Pharmacopoeia/usp35/PDF/0427-
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`0433%20%5b941%5d%20CHARACTERIZATION%20OF%20CRYSTALLINE
`
`%20AND%20PARTIALLY%20CRYSTALLINE%20SOLIDS%20BY%20X-
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`RAY%20POWDER%20DIFFRACTION%20(XRPD).pdf (Ex. 1010).
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`patent for the CS2 crystal form. I also compared the XRPD patterns of
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`lemborexant, which I understand Eisai had previously manufactured and
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`characterized, to the peak positions recited in Claims 1-3 of the ’779 patent and the
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`XRPD patterns in the various Figures of the ’779 patent for the CS2 crystal form.
`
`A. XRPD Patterns Disclosed in the ’779 Patent
`40. The ’779 patent states that the CS2 crystal form of lemborexant has an
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`XRPD pattern with 2θ values for characteristic peaks at 7.8°, 15.6°, 11.4°
`
`(for Claim 1); 12.5°, 21.3°, 27.3° (for Claim 2); and 24.0°, 19.4°, 22.3° (for Claim
`
`3), each with a tolerance of ±0.2°. (Ex. 1001, 14:7-18.)
`
`41. The ’779 patent provides the following corresponding images of the
`
`XRPD patterns of the CS2 form:
`
`Figure 6: XRPD Pattern of Form CS2 in Example 1 of the ’779 patent
`(Ex. 1001, Fig. 1)
`
`
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`17
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`Page 19 of 30
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
`
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`Figure 7: XRPD Pattern of Form CS2 in Example 2 of the ’779 patent
`(Ex. 1001, Fig. 5)
`
`42. From these patterns, the ’779 patentees extracted partial lists of 2θ
`
`peak positions and rounded them to one tenth of a degree in Claims 1-3. Because
`
`the peak positions are rounded to one tenth of degree, I also rounded peak positions
`
`for the XRPD patterns used in my analysis to the same tenth of a degree for
`
`purposes of comparison with Claims 1-3 of the ’779 patent.
`
`B. XRPD Patterns of Samples Dr. Bihovsky Prepared by
`Following the Procedures in Example G of the ’109 Patent
`
`43.
`
`I was asked to analyze, using XRPD, two sets of lemborexant samples
`
`that Dr. Ron Bihovsky prepared, and which were supplied to me. One set was
`
`identified as having been produced in accordance with the first procedure in
`
`Example G of the ’109 patent, and the other set was identified as having been
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`produced in accordance with the alternate procedure in Example G of the ’109
`
`patent. (Ex. 1006, 46:15‒50:6.)
`
`44. To analyze these lemborexant samples, I followed the standard
`
`protocols and methods for XRPD analysis, as described above. Additionally, the
`
`’779 patent stated that its diffraction patterns were obtained using CuKα radiation
`
`(see, e.g., Ex. 1001, 14:7‒18), so I also used CuKα radiation when obtaining
`
`XRPD patterns for the lemborexant samples.
`
`45. To conduct this analysis, each sample was back-loaded into a standard
`
`holder and placed into a Panalytical X’pert X-ray Diffractometer equipped with a
`
`Pixcel detector and using CuKα Radiation at 45KV/40mA. I then ran X-ray
`
`diffraction scans over the range of 3°-40° with a step size of 0.0131°, a counting
`
`time of 100 seconds per step, a Ni filter, ¼° divergence slit, and ½° anti-scatter slit.
`
`During data collection, the sample was spun in-plane at a speed of
`
`4 seconds/revolution to help eliminate preferred orientation of the grains in the
`
`sample, which might otherwise lead to anomalous peak intensities. The ’779
`
`patent indicates that the patentee obtained the X-ray diffraction patterns on a
`
`Bruker D2 PHASER X-ray Powder Diffractometer using CuKα Radiation at
`
`30kV/10mA with a scan range from 3.0°-40.0°. (Ex. 1001, 6:28‒46.) The ’779
`
`patent does not specify a step size or counting time or other such details regarding
`
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`19
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`the specific equipment or test parameters. The use of different instruments or test
`
`conditions, however, would not change the location of any of the peaks observed in
`
`the diffraction patterns relative to those in the ’779 patent.
`
`46. Figures 8 and 9 below show the resultant X-ray diffraction pattern of
`
`the samples prepared by Dr. Bihovsky, which I display at full scale. On these
`
`X-ray diffraction patterns, I have also overlaid “sticks” for the three sets of
`
`characteristic peaks for the CS2 crystal form of lemborexant that are recited in
`
`Claims 1-3 of the ’779 patent, respectively. The sticks overlaid on the XRPD
`
`patterns do not show the relative intensities of the peaks, as the ’779 patent does
`
`not indicate the intensities of any of the characteristic peaks in Claims 1-3.
`
`47. Tables 1 and 2 below correspond to Figures 8 and 9, and also set forth
`
`the 2θ values claimed by the ’779 patent in Claims 1-3 along with the 2θ values of
`
`the peak positions of the XRPD patterns which I obtained by testing Dr.
`
`Bihovsky’s samples. At the bottom of each table in parentheses is the difference
`
`between the reference peak from the ’779 patent and the corresponding peak from
`
`the experimental scan of Dr. Bihovsky’s sample.
`
`48. First, I ran XRPD on the sample received from Dr. Bihovsky that was
`
`identified as having been prepared according to the first procedure of Example G
`
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`20
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`Page 22 of 30
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`of the ’109 patent. The XRPD pattern of this sample, with sticks overlaid for the
`
`peak positions in Claims 1-3 of the ’779 patent, is shown below:
`
`
`
`Figure 8: XRPD Pattern for Dr. Bihovsky’s Sample (13-113-2x) Prepared
`According to the First Method of Example G of the ’109 Patent
`
`Claim 1 Peak Positions
`7.8°
`15.6°
`11.4°
`
`Claim 2 Peak Positions
`12.5°
`21.3°
`27.3°
`
`Claim 3 Peak Positions
`24.0°
`19.4°
`22.3°
`
`’109 Patent
`First Method
`
`8.0°
`(+0.2°)
`
`15.6°
`(0.0°)
`
`11.6°
`(+0.2°)
`
`12.7°
`(+0.2°)
`
`21.5°
`(+0.2°)
`
`27.4°
`(+0.1°)
`
`23.9°
`(-0.1°)
`
`19.5°
`(+0.1°)
`
`22.3°
`(0.0°)
`
`
`Table 1: Comparison of Peak Positions in Figure 8 and the ’779 patent
`
`49. Next, I ran XRPD on the sample received from Dr. Bihovsky that was
`
`identified as having been prepared according to the alternate procedure of Example
`
`G of the ’109 patent. The XPRD pattern of this sample, with sticks overlaid for the
`
`peak positions in Claims 1-3 of the ’779 patent, is shown below:
`
`
`
`21
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`Page 23 of 30
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`Figure 9: XRPD Pattern for Dr. Bihovsky’s Sample (13-115-1x) Prepared
`According to the Alternate Method of Example G of the ’109 Patent
`
`Claim 1 Peak Positions
`7.8°
`15.6°
`11.4°
`
`Claim 2 Peak Positions
`12.5°
`21.3°
`27.3°
`
`Claim 3 Peak Positions
`24.0°
`19.4°
`22.3°
`
`
`
`8.0°
`(+0.2°)
`
`15.7°
`(+0.1°)
`
`11.6°
`(+0.2°)
`
`12.7°
`(+0.2°)
`
`21.5°
`(+0.2°)
`
`27.4°
`(+0.1°)
`
`’109 Patent
`Alternate Method
`
`Table 2: Comparison of Peak Positions in Figure 9 and the ’779 patent
`
`24.0°
`(0.0°)
`
`19.6°
`(+0.2°)
`
`22.3°
`(0.0°)
`
`50.
`
`In my opinion, the XRPD patterns of both of the samples that were
`
`provided to me by Dr. Bihovsky are consistent with the characteristic peaks
`
`claimed in the ’779 patent. Moreover, any observed slight differences in peak
`
`locations are within the acceptable error range of ±0.2° as specified in Claims 1-3
`
`of the ’779 patent.
`
`51. Based upon my comparison of the XRPD patterns of the samples Dr.
`
`Bihovsky prepared and the peak values recited in Claims 1-3 of the ’779 patent, it
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`Page 24 of 30
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`is my opinion that each of the samples that Dr. Bihovsky prepared has the same
`
`CS2 crystal form of lemborexant described and claimed in the ’779 patent.
`
`C. XRPD Patterns of Eisai’s Prior Lemborexant Lots
`52.
`In addition to analyzing the lemborexant samples prepared by Dr.
`
`Bihovsky by XRPD, I was also asked to analyze the XRPD pattern of lemborexant
`
`from Lot 169R2601, which I understand Eisai obtained by analyzing lemborexant
`
`prepared consistent with the first procedure of Example G of the ’109 patent.
`
`53. As with the XRPD patterns for the samples that Dr. Bihovsky
`
`provided and as described above in paragraphs 46 to 49 of my Declaration, I
`
`overlaid sticks showing the characteristic peaks of the Form CS2 in Claims 1-3 of
`
`the ’779 patent on the XRPD pattern that Eisai obtained for Lot 169R2601, which
`
`is shown in Figure 10. Additionally, I determined the numerical values for the
`
`locations of the peaks in the XRPD pattern of Lot 169R2601, which are shown in
`
`Table 3. The XRPD patterns from those batches are copied below:
`
`
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`23
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`Page 25 of 30
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`Figure 10: XRPD Pattern for Eisai’s Lot 169R2601 (Ex. 1012)
`
`Claim 1 Peak Positions
`7.8°
`15.6°
`11.4°
`
`Claim 2 Peak Positions
`12.5°
`21.3°
`27.3°
`
`Claim 3 Peak Positions
`24.0°
`19.4°
`22.3°
`
`Lot 169R2601
`
`8.0°
`(+0.2°)
`
`15.7°
`(+0.1°)
`
`11.6°
`(+0.2°)
`
`12.7°
`(+0.2°)
`
`21.2°
`(-0.1°)
`
`27.5°
`(+0.2°)
`
`24.0°
`(0.0°)
`
`19.2°
`(-0.2°)
`
`22.3°
`(0.0°)
`
`
`Table 3: Comparison of Peak Positions in Figure 10 and the ’779 patent
`
`54.
`
`I understand that Eisai also produced batches of lemborexant
`
`designated as Lots AZW-673a and GAM-388-2 using a method that was consistent
`
`with the alternate procedure of Example G of the ’109 patent. I was also provided
`
`XRPD patterns that Eisai obtained from those lots to analyze. Again, I overlaid the
`
`sticks representing the characteristic peaks recited in Claims 1-3 of the ’779 patent
`
`over the XRPD patterns of Lots AZW-673a and GAM-388-2, which is shown in
`24
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`Declaration of William Mayo, Ph.D.
`U.S. Patent No. 10,759,779
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`Figures 11 and 12. I also estimated the peak positions of the XRPDs for these
`
`Eisai lots for purposes of comparing them to the claimed peak positions in the ’779
`
`patent, which is shown in Tables 4 and 5. The XRPD patterns are produced below:
`
`
`
`Figure 11: XRPD P
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