UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`DECLARATION OF ALLAN S. MYERSON, PH.D.
`
`
`
`
`
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`
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
`
`TABLE OF CONTENTS
`I.
`Introduction ...................................................................................................... 4
`Qualifications and Experience ......................................................................... 4
`II.
`III. Legal Standards ............................................................................................... 8
`IV. The ’708 Patent .............................................................................................. 11
`V.
`The Person of Ordinary Skill in the Art ........................................................ 15
`VI. Background .................................................................................................... 17
`A.
`Stereochemistry ................................................................................... 17
`B.
`Salts ..................................................................................................... 19
`C.
`Crystals and Polymorphism ................................................................ 20
`D.
`Crystallization ..................................................................................... 33
`VII. Obviousness ................................................................................................... 50
`A. Asserted References ............................................................................ 53
`1. WO ’498 (EX1004) ................................................................... 54
`2.
`Bastin (EX1006) ....................................................................... 56
`3.
`Brittain (EX1005) ..................................................................... 57
`B. Motivation ........................................................................................... 58
`1.
`Selecting Sitagliptin or Sitagliptin HCl as a Lead
`Compound. ................................................................................ 60
`Selecting 1:1 Sitagliptin Dihydrogenphosphate. ...................... 63
`Selecting Crystalline Sitagliptin Dihydrogenphosphate. .......... 66
`Selecting a Crystalline Hydrate of Sitagliptin
`Dihydrogenphosphate ............................................................... 69
`Selecting a Crystalline Monohydrate of Sitagliptin
`Dihydrogenphosphate ............................................................... 78
`Reasonable Expectation of Success .................................................... 80
`C.
`D. Obvious to Try ................................................................................... 103
`E.
`Enablement ........................................................................................ 104
`F.
`Unexpected Properties of the Crystalline Monohydrate ................... 106
`
`2.
`3.
`4.
`
`5.
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`2
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`1.
`
`2.
`
`3.
`
`The Monohydrate Form of Sitagliptin
`Dihydrogenphosphate is Stable at High Temperatures. ......... 107
`The Monohydrate Form of Sitagliptin
`Dihydrogenphosphate Does Not Undergo Form
`Conversion. ............................................................................. 115
`The Monohydrate Form Exhibits Superior Formulation-
`Related Properties. .................................................................. 120
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
`
`I.
`
`I, Allan S. Myerson, Ph.D., declare as follows:
`INTRODUCTION
`I have been asked to opine on the obviousness of claim 4 of U.S.
`1.
`
`Patent No. 7,326,708 (“the ’708 patent”), including to address certain opinions
`
`provided by Dr. Mukund Chorghade. See EX1002 (Chorghade Dec.).
`
`2.
`
`In reaching the opinions I express herein, I have considered the ’708
`
`patent and its prosecution history, the materials cited in this declaration, as well as
`
`my training, general knowledge, basic principles, and experience in the relevant
`
`scientific disciplines.
`
`II. QUALIFICATIONS AND EXPERIENCE
`I am the Professor of the Practice in the Department of Chemical
`3.
`
`Engineering at the Massachusetts Institute of Technology (“MIT”) in Cambridge,
`
`Massachusetts. The following is a brief summary of my background, experience,
`
`publications, and achievements, which are more fully set out in my curriculum
`
`vitae. EX2102.
`
`4.
`
`I am a chemical engineer by training. I have a particular interest in
`
`industrial crystallization and have conducted research in this area for over 40 years.
`
`5.
`
`I began my training at Columbia University in New York, where I
`
`obtained my Bachelor of Science in Chemical Engineering in May 1973.
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`Thereafter, I obtained Masters and Ph.D. degrees in Chemical Engineering from
`
`the University of Virginia in January 1975 and January 1977, respectively. I am a
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`registered Professional Engineer in New York and Ohio.
`
`6.
`
`In January 1977, I began my academic career as an Assistant
`
`Professor of Chemical Engineering at the University of Dayton, where I worked
`
`until August 1979.
`
`7.
`
`From September 1979 to December 1984, I was a faculty member at
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`the Georgia Institute of Technology in Atlanta, serving first as an Assistant
`
`Professor of Chemical Engineering and subsequently as an Associate Professor.
`
`8.
`
`In January 1985, I joined the faculty of the Polytechnic University in
`
`Brooklyn, New York. While there, I served in various positions including as
`
`Joseph and Violet J. Jacobs Professor of Chemical Engineering, Head of the
`
`Department of Chemical Engineering, Dean of the School of Chemical and
`
`Materials Science and as Vice Provost for Research and Graduate Studies.
`
`9.
`
`In January 2000, I moved to the Illinois Institute of Technology in
`
`Chicago (“IIT”). I began as Professor of Chemical Engineering and Dean of the
`
`Armour College of Engineering and Science. I remained in that position until
`
`January 2003, when I became the Philip Danforth Armour Professor of
`
`Engineering. Between 2003 and 2008, I was also Provost and Senior Vice
`
`President at IIT. In August 2010, I moved to my current position as Professor of
`
`the Practice in the Department of Chemical Engineering at MIT.
`
`10. My current research focuses on crystallization from solution with an
`
`5
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`emphasis on nucleation, solid forms of pharmaceuticals, impurity-crystal
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`interactions, and industrial applications of crystallization, as well as on the
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`manufacturing of pharmaceutical products, including novel pharmaceutical dosage
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`forms.
`
`11.
`
`I served as a co-principal investigator in the Novartis-MIT Center for
`
`Continuous Manufacturing (2019-2018) and a co-principal investigator in the
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`DARPA funded project, “Pharmacy on Demand” (2012-2018). In both of these
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`projects, my work has focused on pharmaceutical manufacturing methods for both
`
`the active pharmaceutical ingredient and final dosage form, and has included work
`
`on both solid and liquid based formulations.
`
`12. Over the course of my career, I have supervised the Ph.D.
`
`dissertations of approximately 50 students and have supervised the research of
`
`approximately 30 post-doctoral research associates. I currently supervise a
`
`research group consisting of four post-doctoral research associates. In the last two
`
`years, I have taught graduate level elective courses entitled “Crystallization
`
`Science and Technology” and “Pharmaceutical Engineering.”
`
`13.
`
`I have presented the results of my research, including in the area of
`
`crystallization, at numerous national and international meetings. I have also
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`published approximately 280 papers in refereed scientific journals. Many of those
`
`papers pertain to crystallization and related subjects.
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`14.
`
`I have taught short courses in crystallization (sponsored by the Center
`
`of Professional Advancement, the American Chemical Society, and MIT
`
`Continuing Education) in the United States, Europe, and Singapore and have
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`taught special crystallization courses at pharmaceutical and chemical companies in
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`the United States, Europe, India and Japan. I have also consulted for major
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`chemical and pharmaceutical companies in those same regions.
`
`15.
`
`In addition, I have edited six books in the area of crystallization,
`
`including the Handbook of Industrial Crystallization (1st edition 1991, 2nd edition
`
`2001, 3rd edition 2019).
`
`16.
`
`I have received several awards and honors for my research
`
`accomplishments. These include the American Institute of Chemical Engineers
`
`(“AICHE”) Separations Division, Clarence G. Gerhold Award in 2015, AICHE
`
`Process Development Division, Excellence in Process Development Research
`
`Award in 2015 and the American Chemical Society Award in Separation Science
`
`and Technology in 2008.
`
`17.
`
`I have extensive experience over my career in using the various
`
`analytical techniques relevant to crystalline solid forms, including, among others,
`
`methods of X-ray diffraction, Differential Scanning Calorimetry (DSC), and
`
`Thermogravimetric Analysis (TGA).
`
`18. Based on my experience and qualifications, I consider myself to be an
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`expert in the field of solid forms (e.g., salts, crystals, polymorphs), including
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`related crystallization techniques and methods for characterizing crystals and other
`
`solid forms.
`
`19.
`
`I am being compensated at my customary rate of $825 per hour for
`
`my consultation in connection with this proceeding. My compensation is in no
`
`way dependent on the outcome of my analysis or opinions rendered in this
`
`proceeding.
`
`III. LEGAL STANDARDS
`I understand from counsel for Merck that the obviousness of a patent
`20.
`
`claim is evaluated from the perspective of a person of ordinary skill in the art
`
`(“POSA”) as of the effective filing date of the patent application. The provisional
`
`filing date of the ’708 patent is June 24, 2003, which I understand to be the
`
`effective filing date (or, priority date) of claim 4 of the ’708 patent. I further
`
`understand that the filing date of the non-provisional patent application that
`
`resulted in the ’708 patent is June 23, 2004. My opinions below would not change
`
`if that later date was applied.
`
`21.
`
`I understand from counsel that a patent claim would have been
`
`“obvious,” and thus invalid, if the differences between the subject matter sought to
`
`be patented and the prior art are such that the subject matter as a whole would have
`
`been obvious at the time the invention was made to the POSA to which said
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`subject matter pertains. I understand from counsel that analysis of whether a claim
`
`would have been obvious depends on (a) the scope and content of the prior art, (b)
`
`the differences between the claimed invention and the prior art, (c) the level of
`
`ordinary skill in the art, and (d) any objective indicia of non-obviousness. I
`
`understand from counsel that the use of hindsight must be avoided because the
`
`obviousness of an invention is evaluated from the perspective of the POSA at the
`
`time the invention was made. Thus, in conducting an obviousness inquiry, one
`
`must be aware of the distortion caused by hindsight bias and must be cautious to
`
`avoid reading into the prior art the teachings of the claimed invention at issue.
`
`22.
`
`I understand from counsel that, to show that a patent would have been
`
`obvious, the party challenging the patent must demonstrate that a skilled artisan
`
`would have been motivated to combine the teachings of the prior art to achieve the
`
`claimed invention. As such, the challenger must prove not only that the prior art
`
`taught or suggested the invention, but also that the POSA would have had a reason
`
`to combine the teachings of the prior art references to achieve the claimed
`
`invention. In other words, there needs to be a reason to combine the known
`
`elements in the way claimed by the patent at issue.
`
`23.
`
`I further understand from counsel that, in order to demonstrate that a
`
`chemical compound would have been obvious, the challenger must prove (1) that
`
`the skilled artisan would have selected the asserted prior art compounds as lead
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`compounds, or starting points, for further development, and (2) that the skilled
`
`artisan would have been motivated to modify the lead compound to make the
`
`claimed compound.
`
`24.
`
`I also understand from counsel that references that “teach away” from
`
`the invention—in other words, references that would lead the POSA in a different
`
`direction from that taken by the patentee and that would lead the POSA to believe
`
`that the direction taken by the patentee was unsuitable—must be considered. In
`
`determining whether the invention would have been obvious, one must consider
`
`the prior art as a whole.
`
`25.
`
`I understand from counsel that, in addition to having a motivation to
`
`achieve the claimed invention, the POSA must have had a reasonable expectation
`
`of success. I understand from counsel that to have a reasonable expectation of
`
`success, one must be motivated to do more than merely vary all parameters or try
`
`each of numerous possible choices until one possibly arrived at a successful result,
`
`where the prior art gave either no indication of which parameters were critical or
`
`no direction as to which of many possible choices is likely to be successful.
`
`26.
`
`I understand from counsel that, in certain circumstances, a
`
`combination of elements may have been “obvious to try.” Accordingly, when
`
`there is a design need or market pressure to solve a problem and there are a finite
`
`number of identified, predictable solutions, the POSA has good reason to pursue
`
`10
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`the known options within her or his technical grasp. If this leads to the anticipated
`
`success, it is likely the product not of innovation but of ordinary skill and common
`
`sense. Conversely, where the prior art at best gives only general guidance as to the
`
`particular form of the claimed invention or how to achieve it, the combination
`
`would not have been obvious to try. I further understand from counsel that where
`
`the options do not behave predictably, this principle of obvious to try does not
`
`apply.
`
`27.
`
`I understand from counsel that, in order to render a claim
`
`unpatentable, the prior art must enable one skilled in the art to make and use the
`
`claimed invention without undue experimentation.
`
`28.
`
`I understand from counsel that the obviousness analysis involves an
`
`evaluation of any objective indicia of non-obviousness. I understand from counsel
`
`that commonly recognized objective indicia include evidence of unexpected
`
`results, among others. I further understand that any objective indicia must have
`
`sufficient nexus to the claimed invention. I further understand from counsel that,
`
`to be probative of non-obviousness, unexpected results must be demonstrated
`
`relative to the closest prior art.
`
`IV. THE ’708 PATENT
`29. The ’708 patent is titled “Phosphoric Acid Salt of a Dipeptidyl
`
`Peptidase-IV Inhibitor” and is assigned to Merck & Co., Inc. The patent explains
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`that a previous publication, WO 03/004498 (“WO ’498”), disclosed a class of
`
`compounds useful for inhibiting an enzyme called dipeptidyl peptidase-IV (“DP-
`
`IV”). See EX1001 (“’708 Patent”), 1:32–55. One of the compounds disclosed by
`
`WO ’498 was 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
`
`a]pyrazin-7(8H)-yl]-l-(2,4,5 trifluorophenyl)butan-2-amine. Id.
`
`30.
`
` The ’708 patent describes a particular salt form of the
`
`aforementioned compound—specifically, a “monobasic dihydrogenphosphate salt
`
`of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-
`
`yl]-l-(2,4,5 trifluorophenyl)butan-2-amine of the following structural formula I”:
`
`
`
`Id., 2:44–63. As the single “H3PO4” indicates, this structural formula depicts a salt
`
`having a 1:1 ratio of dihydrogenphosphate to sitagliptin. When I refer in this
`
`declaration to “1:1 sitagliptin dihydrogenphosphate,” I mean a
`
`dihydrogenphosphate salt of sitagliptin with this ratio.
`
`31. The asterisk in the illustration above indicates a “center of asymmetry
`
`at the stereogenic carbon atom,” and that illustration does not include any
`
`information about the stereochemistry of the compound. EX1001 (’708 patent),
`
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`2:66-67. The ’708 patent discloses that the compound can “occur as a racemate,
`
`racemic mixture, and single enantiomers.” Id., 3:1-3. The patent discloses
`
`dihydrogenphosphate salt forms of both the (R)- and (S)-enantiomers, which are
`
`Formulas II and III in the patent, respectively. See id., 3:7-45. I understand that
`
`the (R)-configuration is known as sitagliptin. For ease of reference, I may refer to
`
`the (R)-configuration as “sitagliptin” throughout this declaration.
`
`32. The ’708 patent also discloses polymorphic information for the
`
`disclosed salts. In particular, the patent discloses and characterizes a crystalline
`
`monohydrate form of the 1:1 dihydrogenphosphate salt of sitagliptin. As its name
`
`implies, the monohydrate form of this 1:1 sitagliptin dihydrogenphosphate salt has
`
`a 1:1 ratio of water to sitagliptin dihydrogenphosphate in the crystalline unit cell.
`
`See, for example, the graphical representation of the monohydrate in column 8 of
`
`the patent:
`
`
`
`33. The patent provides detailed instructions for synthesizing the
`
`disclosed crystalline monohydrate form. EX1001 (’708 patent), 8:1-13:21. In
`
`particular, it describes a process for crystallizing the crystalline monohydrate via a
`
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`cooling crystallization procedure using sitagliptin free base, aqueous phosphoric
`
`acid, isopropanol, and water. See id., 12:61-13:21. The patent then provides
`
`characterization data for that the crystalline form, including with x-ray powder
`
`diffraction (“XRPD”), solid-state carbon and fluorine nuclear magnetic resonance
`
`(“NMR”) spectroscopy, thermogravimetric analysis (“TGA”), and differential
`
`scanning calorimetry (“DSC”). Id., 13:33-14:47. Those data are illustrated in
`
`Figures 1-5 of the patent.
`
`34. The ’708 patent discloses that the crystalline monohydrate form of
`
`this sitagliptin salt exhibits “enhanced chemical and physical stability” as
`
`compared to sitagliptin free base and the hydrochloride salt of sitagliptin. ’708
`
`patent, 4:19-28. The patent also discloses that the crystalline monohydrate form
`
`has a solubility of about 72 mg/mL. Id., 6:26-28.
`
`35. The claims of the ’708 patent cover, inter alia, the 1:1
`
`dihydrogenphosphate salt as well as the crystalline monohydrate form described
`
`above. Specifically, claim 1 recites:
`
`A dihydrogenphosphate salt of 4-oxo-4-[3-
`(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
`a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-
`amine of structural formula I:
`
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`or a hydrate thereof.
`36. Claim 2, in turn, recites:
`
`
`
`The salt of claim 1 of structural formula II having the (R)-
`configuration at the chiral center marked with an *
`
`
`37. Claim 4 recites the “salt of claim 2 characterized in being a crystalline
`
`
`
`monohydrate.”
`
`38. The ’708 patent also includes additional claims directed at the
`
`crystalline monohydrate form of sitagliptin, characterized via particular techniques,
`
`as well as claims directed at the process for making the claimed compounds. I
`
`understand that those claims, however, are not at issue in this proceeding.
`
`V. THE PERSON OF ORDINARY SKILL IN THE ART
`I have been asked to provide my opinion as to the qualifications of the
`39.
`
`hypothetical person of ordinary skill in the art to whom the inventions disclosed
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`and claimed in the ’708 patent were directed. I have been informed that factors for
`
`determining ordinary skill in the art may include one or more of the following: (1)
`
`the educational level of the inventors; (2) the type of problems encountered in the
`
`art; (3) prior art solutions to those problems; (4) the rapidity with which
`
`innovations are made; (5) the sophistication of the relevant technology; and (6) the
`
`educational level of workers active in the field. I have considered these factors in
`
`my analysis.
`
`40.
`
`In my opinion, the person of ordinary skill in the art for the ’708
`
`patent would have had a doctoral degree in chemistry, chemical engineering or a
`
`related field, with at least two years of laboratory experience working with
`
`pharmaceutical solids, including polymorphic forms, or would have had a master’s
`
`or bachelor’s degree in a similar field of study, with a commensurate increase in
`
`their years of post-graduate experience. Such a person also would have been
`
`familiar with a variety of issues relevant to developing pharmaceutical solids,
`
`including, among other things, analytical characterization techniques and
`
`pharmaceutical formulations.
`
`41.
`
`I understand that Dr. Chorghade has likewise offered an opinion about
`
`the qualifications of the POSA for the ’708 patent. See EX1002 (Chorghade Dec.)
`
`¶¶ 44-48. My opinions would not change if I applied his POSA definition instead
`
`of my own.
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`VI. BACKGROUND
`Stereochemistry
`A.
`42. Despite their depictions on paper, molecules exist in three dimensions
`
`and are almost never flat.
`
`43. When a carbon atom (“C”) bonds to four atoms or groups of atoms
`
`(“substituents”) through single bonds (“—”), those four substituents arrange
`
`themselves around the carbon in a three-dimensional tetrahedron (a pyramid) to
`
`minimize crowding, as shown below:
`
`
`
`44. When a carbon atom bonds to four different substituents, it has two
`
`possible orientations in three dimensions. Each orientation is a non-
`
`superimposable mirror image of the other, called an enantiomer:
`
`45. The three-dimensional arrangement of atoms around a central atom is
`
`
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`referred to as the configuration, absolute configuration, stereochemistry, or
`
`chirality. This central atom is called a “stereocenter” or a “chiral center.” Chiral
`
`molecules are important in the pharmaceutical industry because biological activity
`
`can differ significantly from one enantiomer to the other.
`
`46. Enantiomers are three-dimensional but often must be drawn on flat
`
`surfaces. To depict a molecule in three dimensions, chemists use special bond
`
`depictions:
`
`
`
`
`
`47.
`
`In the above drawings, which correspond to the structures in
`
`Paragraph 44, the central carbon atom, “C,” and the substituents labeled “A” and
`
`“B” exist in the plane of the paper, as indicated by their straight-line bonds. The
`
`solid wedge (
`
`) extends toward the viewer (above the paper), and the hashed
`
`wedge (
`
`) recedes away from the viewer (below the paper).1 Depicting bonds
`
`
`1 Rectangles can be used instead of wedges in certain circumstances. Rarely are
`
`bold or dashed lines employed, and usually when the drafter lacks the technology
`
`to draw formal wedged bonds easily.
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`with wavy lines (
`
`) indicates that the chirality is unknown or not limited.
`
`Straight-line bonds cannot, by themselves, indicate chirality.
`
`48. Conveying the exact three-dimensional structure of a chiral center can
`
`also be accomplished by accepted naming conventions and/or contextual
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`information. Chemists normally designate each of the two possible absolute
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`configurations at a chiral center as either “(R)” or “(S)” according to the Cahn-
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`Ingold-Prelog priority rules. These rules label each chiral center in a molecule as
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`either (R) or (S).
`
`49. A composition containing substantially equal amounts of both the
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`“(R)” and “(S)” enantiomers is referred to as “racemic” or a “racemate” and can be
`
`indicated as “(R,S).” Without a chiral designator, such as (R,S), straight line bonds
`
`indicate no particular spatial orientation, and therefore do not restrict a compound
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`to being racemic, an (R) or (S) enantiomer, or any other specific chirality.
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`Salts
`B.
`50. Salts are electrically neutral compounds that consist of atoms or
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`molecules held together via bonds that include some degree of ionic transfer
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`between the acid and the base. When salts are dissolved, they generally dissociate
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`into their constituent ions. The positive ion is known as the cation, and the
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`negative ion is known as the anion. For example, table salt is comprised of sodium
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`and chloride. As a solid, the ions bond together to form NaCl. When the salt is
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`dissolved, it dissociates into the positively charged sodium ions (Na+) and
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`negatively charged chlorine ions (Cl-).
`
`51. Salts of pharmaceutically active compounds are formed by reacting
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`the parent or “free” form of the compound with either an acid or base, depending
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`on the properties of the parent. If the parent form of the compound is basic, it is
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`reacted with an acid; if acidic, it is reacted with a base. A pharmaceutical salt can
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`exist in many crystalline arrangements or polymorphs, as described further below.
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`C. Crystals and Polymorphism
`52. Crystals are solids in which the constituent atoms or molecules are
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`arranged in a periodic repeating pattern that extends in three dimensions. Solids
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`that are not crystalline and have no long-range order (meaning that their
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`constituent molecules are similarly oriented for no more than a few molecules)—
`
`for instance, glass—are said to be amorphous. See EX2172 (Guillory 19992) at
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`208.
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`53. The internal structure of a crystal is determined by the position of the
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`atoms (or molecules) relative to each other and extending in three dimensions.
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`Depicted below for illustration purposes, is an example of a crystal structure of
`
`
`2 Guillory, Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,
`
`in POLYMORPHISM IN PHARMACEUTICAL SOLIDS (H.G. Brittain ed., 1st ed. 1999).
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`itraconazole (Sporanox®), an antifungal agent. On the left is the chemical structure
`
`of the itraconazole molecule and on the right is the corresponding crystal structure
`
`of itraconazole:
`
`1
`
`2
`
`3
`
`4
`
`
`
`The crystal structure shown is just a small portion of the entire crystal called the
`
`unit cell. The unit cell of a crystal structure is the smallest repeating group in a
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`crystal structure. As shown in this example of itraconazole, the unit cell contains
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`four itraconazole molecules within it.
`
`54. The crystal structure of a compound gives a picture of the
`
`arrangement of the atoms (or molecules) of the chemical species in the crystalline
`
`state. For some compounds, it may be possible to crystallize the compound into
`
`more than one distinct crystal structure. This is called polymorphism, and the
`
`different crystal structures are called polymorphs.
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`55. Certain compounds may also crystallize in such a way that their
`
`structure contains a solvent as part of the crystalline lattice. These crystals are
`
`known as “solvates,” and are sometimes referred to as “pseudopolymorphs.”
`
`56.
`
`“Hydrates” are solvates where the solvent in the crystalline lattice is
`
`water. Hydrates present several potential challenges for use in a pharmaceutical
`
`product. First, hydrates typically have lower solubilities and slower dissolution
`
`rates in water than anhydrous compounds, which can potentially affect the
`
`bioavailability of the active ingredient. See EX2160 (Rocco 19953) at 22
`
`(reporting lower solubility in hydrated versus anhydrous forms and commenting
`
`that “[l]ower solubility and dissolution rate values for the hydrated form of a
`
`compound are common,” citing literature examples); EX2161 (Poole 19684) at
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`1946 (reporting high solubility and faster dissolution rate for anhydrous form of
`
`ampicillin versus trihydrate); see also EX2051 (Chorghade Dep.) 217:1-3
`
`(agreeing that Brittain “notes problems with lower solubility of hydrates”). As a
`
`result, hydrated crystalline forms can exhibit lower bioavailability than anhydrate
`
`
`3 Rocco et al., Solid-State Characterization of Zanoterone, 122 INT’L J.
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`PHARMACEUTICS 17 (1995).
`
`4 Poole et al., Dissolution Behavior and Solubility of Anhydrous and Trihydrate
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`Forms of Ampicillin, 57 J. PHARM. SCI. 1945 (1968).
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`DECLARATION OF ALLAN S. MYERSON, PH.D.
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`forms, e.g., EX2162 (Kobayashi 20005) at 144-45 (reporting lower solubility and
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`dissolution rate for hydrate versus anhydrous forms, which produced a
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`bioavailability difference at high dose); EX2161 (Poole 1968) at 1948 (reporting
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`lower bioavailability for ampicillin trihydrate versus anhydrate), which can be a
`
`disadvantage.
`
`57. Second, hydrates can potentially undergo dehydration or other
`
`changes in hydration state, which can have negative consequences for the physical
`
`properties of the dosage form. See, e.g., EX1005 (Brittain) at 126-27 (“Some
`
`hydrated compounds may convert to an amorphous form upon dehydration. . . .
`
`Other compounds may convert from a lower to a higher state of hydration yielding
`
`forms with lower solubility.”); EX2046 (Vippagunta 20016) at 17 (“Various types
`
`of phase changes are possible in solid-state hydrated or solvated systems in
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`response to changes in environmental conditions, such as relative humidity,
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`temperature and pressure.”); see also EX2051 (Chorghade Dep.) 216:17-19
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`(“Well, upon dehydration, any hydrate will convert to an amorphous form, yes,
`
`
`5 Kobayashi, Phy