Case 1:19-md-02902-RGA Document 137-1 Filed 07/17/20 Page 37 of 235 PageID #: 2040
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`IN RE: SITAGLIPTIN PHOSPHATE (’708
`& ’921) PATENT LITIGATION
`
`
`
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`MDL No. 19-2902-RGA
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`C.A. Nos. 19-310-RGA,
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`19-311-RGA,
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`19-312-RGA,
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`19-313-RGA,
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`19-314-RGA,
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`19-316-RGA,
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`19-317-RGA,
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`19-318-RGA,
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`19-319-RGA,
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`19-321-RGA,
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`19-347-RGA,
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`19-1489-RGA,
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`19-2192-RGA
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`
`
`
`
`
`
`
`
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`DECLARATION OF PROFESSOR ALLAN S. MYERSON, Ph.D.
`REGARDING CLAIM CONSTRUCTION
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`TABLE OF CONTENTS
`
`I.
`II.
`III.
`
`IV.
`
`INTRODUCTION ...............................................................................................................1
`QUALIFICATIONS AND EXPERIENCE .........................................................................1
`BACKGROUND .................................................................................................................4
`A.
`Stereochemistry........................................................................................................4
`B.
`Salts ..........................................................................................................................6
`C.
`Crystals and Polymorphism .....................................................................................7
`D.
`Pseudo-Polymorphism .............................................................................................8
`E.
`Crystallization ..........................................................................................................9
`F.
`X-Ray Powder Diffraction .....................................................................................10
`PATENTS-IN-SUIT ..........................................................................................................11
`A.
`The ’708 Patent ......................................................................................................11
`LEGAL STANDARDS .....................................................................................................14
`V.
`THE PERSON OF ORDINARY SKILL IN THE ART ....................................................14
`VI.
`VII. CLAIM CONSTRUCTION ...............................................................................................15
`A.
`“the salt of claim 1 [or 2] . . .” (claims 2, 3, and 21 of the ’708 patent) ................15
`B.
`“crystalline monohydrate [of the dihydrogenphosphate salt of sitagliptin]”
`(claims 4 and 24 of the ’708 patent) ......................................................................19
`“characteristic absorption bands obtained from the X-ray powder
`diffraction pattern at spectral d-spacings of” (claims 5–7 of the ’708
`patent) ....................................................................................................................20
`“crystallizing the dihydrogenphosphate salt of [sitagliptin] at 25ºC” (claim
`24 of the ’708 patent) .............................................................................................21
`
`C.
`
`D.
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`Case 1:19-md-02902-RGA Document 137-1 Filed 07/17/20 Page 39 of 235 PageID #: 2042
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`I, Allan S. Myerson, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been asked to opine on how a person of ordinary skill in the art would
`
`interpret the terms:
`
` “the salt of claim 1 [or 2]” as used in claims 2, 3, and 21 of U.S. Patent No. 7,326,708
`
`(“the ’708 patent”);
`
` “crystalline monohydrate [of the dihydrogenphosphate salt of sitagliptin]” as used in
`
`claims 4 and 24 of the ’708 patent;
`
` “characteristic absorption bands obtained from the X-ray powder diffraction pattern at
`
`spectral d-spacings of” as used in claims 5–7 of the ’708 patent; and
`
` “crystallizing the dihydrogenphosphate salt of [sitagliptin] at 25ºC” as used in claim 24
`
`of the ’708 patent.
`
`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
`
`3.
`
`I am the Professor of the Practice in the Department of Chemical Engineering at
`
`the Massachusetts Institute of Technology (“MIT”) in Cambridge, Massachusetts. The following
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`is a brief summary of my background, experience, publications, and achievements, which are
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`more fully set out in my curriculum vitae, J.A. 18.
`
`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 30 years.
`
`5.
`
`I began my training at Columbia University in New York, where I obtained my
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`Bachelor of Science in Chemical Engineering in May 1973. Thereafter, I obtained Masters and
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`1
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`Ph.D. degrees in Chemical Engineering from the University of Virginia in January 1975 and
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`January 1977, respectively. I am a registered Professional Engineer in New York and Ohio.
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`6.
`
`In January 1977, I began my academic career as an Assistant Professor of
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`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 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
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`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 emphasis on
`
`nucleation, solid forms of pharmaceuticals, impurity-crystal interactions, and industrial
`
`applications of crystallization, as well as on the manufacturing of pharmaceutical products,
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`including novel pharmaceutical dosage forms.
`
`11.
`
`I served as a co-principal investigator in the Novartis-MIT Center for Continuous
`
`2
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`Manufacturing (2019-2018) and a co-principal investigator in the DARPA funded project,
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`“Pharmacy on Demand” (2012-2018). In both of these projects, my work has focused on
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`pharmaceutical manufacturing methods for both the active pharmaceutical ingredient and final
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`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
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`research associates. I currently supervise a research group consisting of one Ph.D. students and
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`two post-doctoral research associates. In the last two years, I have taught graduate level elective
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`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 published
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`approximately 280 papers in refereed scientific journals. Many of those papers pertain to
`
`crystallization and related subjects.
`
`14.
`
`I have taught short courses in crystallization (sponsored by the Center of
`
`Professional Advancement, the American Chemical Society, and MIT Continuing Education) in
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`the United States, Europe, and Singapore and have taught special crystallization courses at
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`pharmaceutical and chemical companies in the United States, Europe, India and Japan. I have
`
`also consulted for major chemical and pharmaceutical companies in those same regions.
`
`15.
`
`In addition, I have edited five 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.
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`These include the American Institute of Chemical Engineers (“AICHE”) Separations Division,
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`Clarence G. Gerhold Award in 2015, AICHE Process Development Division, Excellence in
`
`3
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`Process Development Research Award in 2015 and the American Chemical Society Award in
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`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 expert in
`
`the fields of solid forms (polymorphs, pseudopolymorphs, salts and co-crystals) and
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`pharmaceutical formulations, including solid dosage forms.
`
`19.
`
`I am being compensated at my customary rate of $825 per hour for my
`
`consultation in connection with this litigation. My compensation is in no way dependent on the
`
`outcome of my analysis or opinions rendered in this litigation.
`
`III. BACKGROUND
`
`A.
`
`20.
`
`Stereochemistry
`
`Despite their depictions on paper, molecules are almost never flat—they exist in
`
`three dimensions.
`
`21. When a carbon atom (“C”) bonds to four atoms or groups of atoms
`
`(“substituents”) through single bonds (“—”), those four substituents arrange themselves around
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`the carbon in a three-dimensional tetrahedron (a pyramid) to minimize crowding, as shown
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`below:
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`
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`4
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`22. When a carbon atom bonds to four different substituents, it has two possible
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`orientations in three dimensions. Each orientation is a non-superimposable mirror image of the
`
`other, called an enantiomer:
`
`
`
`23.
`
`The three-dimensional arrangement of atoms around a central atom is 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
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`industry because biological activity can differ significantly from one enantiomer to the other.
`
`24.
`
`Enantiomers are three-dimensional but often must be drawn on flat surfaces. To
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`depict a molecule in three dimensions, chemists use special bond depictions:
`
`
`
`
`
`25.
`
`In the above drawings, which correspond to the structures in Paragraph 22, 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
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`the paper).1 Depicting bonds with wavy lines (
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`) indicates that the chirality is unknown or
`
`not limited. Straight-line bonds cannot, by themselves, indicate chirality.
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`26.
`
`Conveying the exact three-dimensional structure of a chiral center can also be
`
`accomplished by accepted naming conventions and/or contextual information. Chemists
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`normally designate each of the two possible absolute configurations at a chiral center as either
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`“(R)” or “(S)” according to the Cahn-Ingold-Prelog priority rules. These rules label each chiral
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`center in a molecule as either (R) or (S).
`
`27.
`
`A composition containing substantially equal amounts of both the “(R)” and “(S)”
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`enantiomers is referred to as “racemic” or a “racemate” and can be indicated as “(R,S).” Without
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`a chiral designator, such as (R,S), straight line bonds indicate no particular spatial orientation,
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`and therefore do not restrict a compound to being racemic, an (R) or (S) enantiomer, or any other
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`specific chirality.
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`B.
`
`Salts
`
`28.
`
`Salts are electrically neutral compounds that consist of atoms or molecules held
`
`together via bonds that include some degree of ionic transfer between the acid and the base.
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`When salts are dissolved, they generally dissociate into their constituent ions. The positive ion is
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`known as the cation, and the negative ion is known as the anion. For example, table salt is
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`comprised of sodium and chloride. As a solid, the ions bond together to form NaCl. When the
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`salt is dissolved, it dissociates into the positively charged sodium ions (Na+) and negatively
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`charged chlorine ions (Cl-).
`
`29.
`
`Salts of pharmaceutically active compounds are formed by reacting the parent or
`
`
`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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`“free” form of the compound with either an acid or base, depending on the properties of the
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`parent. If the parent form of the compound is basic, it is reacted with an acid; if acidic, it is
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`reacted with a base. A pharmaceutical salt can exist in many crystalline arrangements or
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`polymorphs, as described further below.
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`C.
`
`30.
`
`Crystals and Polymorphism
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`Crystals are solids in which the constituent atoms or molecules are arranged in a
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`periodic repeating pattern that extends in three dimensions. The internal structure (i.e., the
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`crystal structure) of a crystal is determined by the position of the atoms (or molecules) relative to
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`each other and extending in three dimensions.
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`31.
`
`Depicted below for illustration purposes, is an example of a crystal structure of
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`itraconazole (Sporanox®), an antifungal agent. On the left is the chemical structure of the
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`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
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`unit cell of a crystal structure is the smallest repeating group in a crystal structure. As shown in
`
`this example of itraconazole, the unit cell contains four itraconazole molecules within it.
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`
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`32.
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`The crystal structure of a compound gives a picture of the arrangement of the
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`atoms (or molecules) of the chemical species in the crystalline state. For some compounds, it
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`may be possible to crystallize the compound into more than one distinct crystal structure. This is
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`called polymorphism, and the different crystal structures are called polymorphs.
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`D.
`
`33.
`
`Pseudo-Polymorphism
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`Another related category of solid forms is known as pseudo-polymorphs. Pseudo-
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`polymorphism refers to the ability of certain compounds to crystallize in a structure that contains
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`a solvent as part of the crystal lattice. These crystals are also known as solvates. Solvates are
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`crystalline solid adducts containing solvent molecules within the crystal structure, in either
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`stoichiometric or nonstoichiometric proportions. See J.A. 9 (Newman 2002)2 at 31.
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`34.
`
`A hydrate is a type of solvate where water is the incorporated solvent. In
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`hydrates, the amount of water incorporation can vary, often at stoichiometric amounts, but not
`
`always at a 1:1 ratio of water to organic molecule. Id. Below is a table of common hydrate
`
`ratios and the naming convention.
`
`Id. at 32.
`
`
`
`
`2 A.W. Newman and G.P. Stahly, “Form Selection of Pharmaceutical Compounds,” in
`HANDBOOK OF PHARMACEUTICAL ANALYSIS (2002).
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`E.
`
`35.
`
`Crystallization
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`The process of forming crystals is called crystallization. Crystallization is a phase
`
`change that results in the formation of a crystalline solid. The words “crystallization” and
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`“recrystallization” are typically used to refer to a process of separating a crystalline solute from
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`the solvent in a solution, whereby “crystallization” means the solid crystals are obtained for the
`
`first time from solution and “recrystallization” means dissolving a crystal that was previously
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`obtained to crystallize the same material again.
`
`36.
`
`In order to discuss the process of crystallization from a solution, an understanding
`
`of how crystals form in solutions is required. A solution is made up of two or more components,
`
`of which one is known as the solvent and the other(s) as the solute(s). At a given temperature,
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`there is generally a maximum amount of solute that can dissolve in a given amount of solvent,
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`and, when this occurs, a solution is said to be a saturated solution. The amount of solute required
`
`to make a saturated solution at a given temperature is generally known as the equilibrium
`
`solubility. The equilibrium solubility of most materials varies as a function of temperature and
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`generally increases as temperature rises. For a crystal form, the equilibrium solubility occurs
`
`when the amount of crystals of a given form are in equilibrium with the solution concentration of
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`the compound(s) comprising the crystals at a fixed temperature.
`
`37.
`
`Solutions can also become “supersaturated,” which means the solution contains
`
`more solute than its equilibrium solubility. The term “supersaturation” refers to the difference
`
`between the equilibrium solubility and the actual amount of solute that is dissolved in the solvent
`
`or solvent mixture. When a solution is supersaturated, the solution is metastable, and a phase
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`separation may occur, whereby some of the solute precipitates out of the solution. This phase
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`separation can result in an amorphous solid or a crystalline solid.
`
`38.
`
`The first step in the crystallization process is the known as nucleation. To cause
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`nucleation, the state of the system has to be changed so that a supersaturated solution is formed.
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`See J.A. 19 (Myerson 2002)3 at 43–44. This can be done by cooling a solution, by evaporating
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`the solvent, by changing the solvent composition (that is, adding another miscible solvent that
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`decreases the solubility of the solute in the mixture), by changing the pH, or by inducing a
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`chemical reaction in which the product is not soluble in the solvent. In addition to inducing
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`supersaturation, the rate of supersaturation generation (e.g., rate of cooling), temperature,
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`solvents or solvent mixtures used, and the presence of seed crystals (i.e., a small crystal or
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`crystals) and impurities all can influence the nucleation process. See J.A. 20 (Guillory 1999)4 at
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`188–194 and 201–202.
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`39.
`
`The second step in the crystallization process is called crystal growth. Once
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`crystal nuclei are formed, those nuclei grow using the compound dissolved in the solution to
`
`form the solid crystals.
`
`40.
`
`“Seeding” is a term used to describe adding a small amount of the desired crystal
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`form to avoid having to wait for the form to nucleate. Seeding can also be used to ensure the
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`desired polymorph or pseudo-polymorph forms.
`
`F.
`
`41.
`
`X-Ray Powder Diffraction
`
`X-ray diffraction is an experimental technique used to identify crystalline forms.
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`It can be performed on a single crystal or on a powder sample of a crystalline substance. In the
`
`latter case, it is known as X-ray powder diffraction (“XRPD”) or powder X-ray diffraction
`
`(“PXRD”). XRPD relies on the fact that the array of crystals in the powder sample, randomly
`
`arranged, will present all possible lattice planes for reflection of an incident X-ray beam.
`
`
`3 A. S. Myerson and R. Ginde, “Crystals, Crystal Growth and Nucleation,” in HANDBOOK OF
`INDUSTRIAL CRYSTALLIZATION (A. S. Myerson ed., 2nd ed. 2002).
`4 J. K. 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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`42. When X-rays of particular wavelengths (0.5–2.5 Angstroms) are directed at a
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`sample, they are diffracted. These diffraction angles are measured. Because the distances
`
`between the atoms in a crystal are of a length similar to the X-ray wavelength, the presence of a
`
`crystal structure in the sample will produce an observable pattern.
`
`43.
`
`The relationship between the wavelength of the X-rays and the spacing between
`
`atoms in a crystal is known as Bragg’s law:
`
`nλ = 2d sinθ
`
`where n is an integer (normally 1), “λ” is the wavelength of the incident X-rays, “d” is the
`
`interplanar spacing in the crystal (referred to as “d-spacings”), and “θ” is the angle of incident X-
`
`rays on the crystal. See J.A. 24 (Brittain 1999)5 at 231.
`
`IV.
`
`PATENTS-IN-SUIT
`
`A.
`
`44.
`
`The ’708 Patent
`
`The ’708 patent is titled “Phosphoric Acid Salt of a Dipeptidyl Peptidase-IV
`
`Inhibitor.” The ’708 patent teaches 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
`
`or a crystalline hydrate thereof. In particular, the instant invention provides a crystalline
`
`monohydrate of the dihydrogenphosphate salt of formula I.” J.A. 1 (’708 Patent) at 2:44–65. I
`
`
`
`
`5 H.G. Brittain, “Methods for the Characterization of Polymorphs and Solvates,” in
`POLYMORPHISM IN PHARMACEUTICAL SOLIDS (1999).
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`understand that the (R)-configuration 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 is known
`
`as sitagliptin. For ease of reference, I may refer to the (R)-configuration as “sitagliptin”
`
`throughout the declaration.
`
`45.
`
`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:
`
`or a hydrate thereof.
`
`46.
`
`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 *
`
`47.
`
`Claim 3, in turn, recites:
`
`
`
`The salt of claim 1 of structural formula III having the (S)-
`configuration at the chiral center marked with an *
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`48.
`
`Claim 4 recites the “salt of claim 2 characterized in being a crystalline
`
`
`
`monohydrate.” Claims 5–16 recite characterizations of the crystalline monohydrate, for which
`
`the specification of the ’708 patent provides characterization data in the form of an X-ray
`
`diffraction pattern, solid-state carbon-13 CPMAS NMR spectrum, solid-state fluorine-19 MAS
`
`NMR spectrum, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC).
`
`Id. at 13:29–14:47; Figs. 1–5. In particular, the ’708 patent teaches that the “monohydrate
`
`exhibited characteristic diffraction peaks corresponding to d-spacings of 7.42, 5.48, and 3.96
`
`angstroms. The monohydrate was further characterized by the d-spacings of 6.30, 4.75, and 4.48
`
`angstroms. The monohydrate was even further characterized by the d-spacings of 5.85, 5.21, and
`
`3.52 angstroms.” Id. at 13:31–36; Claims 5–7.
`
`49.
`
`Claims 21–24 recite a process for preparing the dihydrogenphosphate salt of
`
`sitagliptin (claims 21–23) and in particular, the crystalline monohydrate (claim 24). The ’708
`
`patent discloses the following method for obtaining the crystalline monohydrate:
`
`A 250 mL round bottom flask equipped with an overhead stirrer,
`heating mantle and thermocouple, was charged with 31.5 mL of
`isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) of (2R)-4-
`oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a
`]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
`freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid.
`The mixture was heated to 75° C. A thick white precipitate formed
`at lower temperatures but dissolved upon reaching 75° C. The
`solution was cooled to 68° C. and then held at that temperature for
`2 h. A slurry bed of solids formed during this age time [the solution
`can be seeded with 0.5 to 5 wt % of small particle size (alpine
`milled) monohydrate]. The slurry was then cooled at a rate of 4° C./h
`
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`to 21° C. and then held overnight. 105 mL of EPA 10 was then added
`to the slurry. After 1 h the slurry was filtered and washed with 45
`mL IPA (solids can also be washed with a water/IPA solution to
`avoid turnover to other crystal forms).
`
`Id. at 12:64–13:14.
`
`V.
`
`LEGAL STANDARDS
`
`50.
`
`I understand from counsel for Merck that patent claim terms are construed from
`
`the perspective of a person of ordinary skill in the art as of the effective filing date of the patent
`
`application. The filing date of the ’708 patent is June 23, 2004, and the provisional filing date of
`
`the ’708 patent is June 24, 2003. I have been informed by counsel that, for certain claims of the
`
`’708 patent, Merck contends that it conceived and reduced those claims to practice no later than
`
`December 13, 2001. My opinions below would not change if any of the earlier priority dates
`
`apply.
`
`51.
`
`I have been informed by counsel that claim terms should be considered in the
`
`context of the entire patent claim in which they appear, as well as in the context of the other
`
`claims, the specification, and the prosecution history of the patent, taken as a whole.
`
`52.
`
`I also understand that it may be appropriate to consider evidence that is extrinsic
`
`to the patent and its prosecution history, provided this extrinsic evidence is not used to alter or
`
`contradict the meaning established by the intrinsic evidence of the patent and its prosecution
`
`history.
`
`53.
`
`I have been informed by counsel that a patent is only invalid for being indefinite,
`
`if its claims, read in light of the specification and the prosecution history, fail to inform a person
`
`of ordinary skill in the art, with reasonable certainty, as to the scope of the claimed invention.
`
`VI.
`
`THE PERSON OF ORDINARY SKILL IN THE ART
`
`54.
`
`I have been asked to provide my opinion as to the qualifications of the
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`hypothetical person of ordinary skill in the art to whom the inventions disclosed 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.
`
`55.
`
`In my opinion, a person of ordinary skill in the art (“POSA”) of 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.
`
`VII. CLAIM CONSTRUCTION
`
`A.
`
`56.
`
`“the salt of claim 1 [or 2] . . .” (claims 2, 3, and 21 of the ’708 patent)
`
`I understand that Defendants have argued that claims 2, 3, and 21 of the ’708
`
`patent should be interpreted to exclude hydrates. I disagree. In my opinion, taking into account
`
`the claims and specification as a whole, the POSA would understand the term “the salt of claim 1
`
`[or 2]” as used in claims 2, 3, and 21 to include hydrates.
`
`57.
`
`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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`or a hydrate thereof.
`
`J.A. 1 at claim 1.
`
`
`58.
`
`Claim 2 recites:
`
`
`
`The salt of claim 1 of structural formula II having the (R)-
`configuration at the chiral center marked with an *
`
`Id. at claim 2.
`
`
`59.
`
`And claim 3 recites:
`
`
`
`The salt of claim 1 of structural formula III having the (S)-
`configuration at the chiral center marked with an *
`
`Id. at claim 3.
`
`
`60.
`
`The POSA reading claim 1 would understand that it covers the
`
`dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a
`
`
`
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`]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine (compound I) or hydrates thereof
`
`without any restrictions on chirality. This is because the structure of formula I is drawn without
`
`the wedge-dash notation to illustrate a particular enantiomer (wedges indicate the part of the
`
`molecule or functional group coming towards you, out of the page and dashes indicate the part of
`
`the molecule or functional group going away from you and into the page). And the ’708 patent
`
`teaches that the “dihydrogenphosphate salt of the present invention has a center of asymmetry at
`
`the stereogenic carbon atom indicated with an * and can thus occur as a racemate, racemic
`
`mixture, and single enantiomers, with all isomeric forms being included in the present
`
`invention.” Id. at 2:66–3:3.
`
`61.
`
`I understand that Defendants in this case may argue that because claims 2 and 3
`
`use the phrase “The salt of claim 1” and do not repeat the “or a hydrate thereof” language, these
`
`claims were intended to exclude hydrates. But that would be inconsistent with the POSA’s
`
`understanding of the claim scope. The use of “The salt of claim 1” language indicates to the
`
`POSA that claims 2 and 3 incorporate the entirety of claim 1, which includes hydrates. The
`
`POSA would understand that hydrates are a particular type of crystal that salts can form (when
`
`water is incorporated into the crystal structure), and the POSA would interpret the phrase, “The
`
`salt of claim X” in the ’708 paten