Paper ____________
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`STEADYMED LTD.
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner.
`
`Case IPR 2016-00006
`
`Patent No. 8,497,393
`
`____________
`
`DECLARATION OF ROBIN D. ROGERS IN SUPPORT OF
`PETITIONER'S REPLY
`
`Mail Stop "Patent Board"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`WEST\271560910.2
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 1
`
`

`
`TABLE OF CONTENTS
`
`I.
`II.
`III.
`IV.
`V.
`
`VI.
`VII.
`VIII.
`
`IX.
`
`OVERVIEW.........................................................................................1
`QUALIFICATIONS.............................................................................2
`MATERIALS CONSIDERED.............................................................8
`MY ROLE AND SUMMARY OF MY OPINIONS ...........................8
`BACKGROUND..................................................................................9
`Polymorphism ......................................................................................9
`A.
`Characterizing crystals .......................................................................15
`B.
`Identifying crystals.............................................................................18
`C.
`Other techniques for characterizing crystals......................................19
`D.
`E. What role does melting point play in polymorph identification? ......25
`MELTING POINT AND THE PURITY OF A CRYSTAL..............26
`THE CRYSTAL FORMS THAT I HAVE REVIEWED ..................28
`NO MATTER HOW FORM B IS MADE, FORM B HAS A
`SINGLE, DEFINED MELTING POINT...........................................30
`Form A Can be Made Using a Number of Different Solvent
`Systems, But the Result is Still Form A.............................................30
`Form B Can be Made Using a Number of Different Solvent
`Systems, But the Result is Still Form B.............................................32
`The Form B Crystals Made in the Phares Reference Have the
`At Least the Same Purity as the Form B Crystals Made in the
`'393 Patent ..........................................................................................34
`The Adhiyaman reference, Ex. 2030, Does Not Suggest that
`Form B Crystals Made with Different Solvents Would Have
`Different Pure Melting Points T0 .......................................................35
`The Phares Reference Correctly Determined the Melting Point
`as 107oC, and the Width of the DSC Peak is Narrow........................36
`CONCLUSION ..................................................................................38
`
`D.
`
`E.
`
`A.
`
`B.
`
`C.
`
`WEST\271560910.2
`
`i
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 2
`
`

`
`I.
`
`OVERVIEW
`
`1.
`
`I have been retained by counsel for the Petitioner, SteadyMed Ltd., to
`
`offer technical opinions with respect to certain technical matters relating to the
`
`inter partes review proceedings concerning U.S. Patent No. 8,497,393 ("the '393
`
`Patent") and certain prior art references cited in regard to the '393 Patent.
`
`2.
`
`In particular, I have been asked to opine regarding crystal forms of
`
`organic molecules, also known as "polymorphs," the melting points of polymorphs,
`
`how melting point and purity of polymorphs are related, how differential scanning
`
`calorimetry and other analytical techniques are used to analyze polymorphs, and
`
`how some of these analytical techniques can be used to compare the purity of two
`
`samples.
`
`3.
`
`This
`
`declaration
`
`presents my
`
`opinion
`
`that
`
`the
`
`treprostinil
`
`diethanolamine Form B polymorph made in the Phares Reference, Ex. 1005, is at
`
`least as pure as the same Form B polymorph made in the '393 Patent, Ex. 1001, and
`
`is likely purer, based on comparing their melting points.
`
`4.
`
`I also opine that the method of making a particular polymorph, such
`
`as Form B, and the solvents used, are irrelevant to the properties of the polymorph:
`
`two crystals of Form B have the properties of Form B, including melting point and
`
`PXRD pattern, regardless of how they were made. Differences present here
`
`between two Form B crystals made using different solvents are due to different
`
`WEST\271560910.2
`
`1
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 3
`
`

`
`impurity profiles and different levels of impurities. In fact, the '393 Patent contains
`
`six examples, called Example 3 Batches 1-4 and Example 4 Batches 1 & 2, where
`
`the melting points, and thus the impurity level and profile, were each different.
`
`II. QUALIFICATIONS
`
`5.
`
`I am currently Canadian Excellence Research Chair
`
`in Green
`
`Chemistry and Green Chemicals at McGill University, Montreal, Quebec, Canada,
`
`a position I started January 1, 2015. Prior to this appointment I served as
`
`Distinguished Research Professor
`
`in the Department of Chemistry at The
`
`University of Alabama, Tuscaloosa, Alabama, USA, where I was Robert Ramsay
`
`Chair of Chemistry and the Director of the Center for Green Manufacturing also at
`
`The University of Alabama. Since 2009, I have held the title of Honorary
`
`Professor in the Institute for Process Engineering at The Chinese Academy of
`
`Sciences in Beijing, China. A copy of my curriculum vitae and list of publications
`
`is attached as Ex. 1023.
`
`6.
`
`I received a B.S. in chemistry (summa cum laude) in 1978 and a Ph.D.
`
`in chemistry in 1982 from The University of Alabama. During the period 1982–
`
`1996, I was successively an assistant, associate, full, and Presidential Research
`
`Professor at Northern Illinois University. During the period of 1991–1998, I also
`
`held a faculty appointment at
`
`the Argonne National Research Laboratory,
`
`Argonne, Illinois. In 1996, I became a Professor of Chemistry at The University of
`
`WEST\271560910.2
`
`2
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 4
`
`

`
`Alabama and, in 1998 I was named Director of The University of Alabama’s
`
`Center for Green Manufacturing. I was awarded the titles Distinguished Research
`
`Professor in 2004 and Robert Ramsay Chair of Chemistry in 2005. From 2007 to
`
`2009, I held a joint appointment as Chair in Green Chemistry in the School of
`
`Chemistry & Chemical Engineering and Director of the Queen’s University Ionic
`
`Liquid Laboratory (“QUILL”) at The Queen’s University of Belfast, Belfast,
`
`Northern Ireland, UK.
`
`7.
`
`I am a member of various professional societies,
`
`including the
`
`American Association for the Advancement of Science (Fellow), American
`
`Chemical Society (Fellow), American Crystallographic Association, American
`
`Institute of Chemical Engineers, Materials Research Society, American
`
`Association of Crystal Growth, and Royal Society of Chemistry (Fellow).
`
`8.
`
`In 1989, I joined the Editorial Board of the Journal of Chemical
`
`Crystallography (then named Journal of Crystallographic and Spectroscopic
`
`Research).
`
`I became Associate Editor of the journal in 1993 and was the Editor
`
`from 1996 to 2000. In 1998, I founded the journal Crystal Engineering and served
`
`as Editor until 1999.
`
`In 2000, I was asked by the American Chemical Society
`
`(“ACS”) to found a new journal called Crystal Growth & Design, for which I
`
`currently serve as Founding Editor-in-Chief. I also have served or currently serve
`
`as editor or on the editorial board of the following journals:
`
`WEST\271560910.2
`
`3
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 5
`
`

`
` Separation Science and Technology: Associate Editor, 1996-99; Editorial
`
`Board, 1999-;
`
` Industrial & Engineering Chemistry Research: Editorial Board, 1999-
`
`2001;
`
` Journal of Chromatography, B, Guest Editor, Volume 743 (1 + 2), 2000;
`
` Solvent Extraction and Ion Exchange, Editorial Board, 2002-;
`
` Green Chemistry, International Advisory Board, 2002-;
`
` Chemical Communications, Editorial Advisory Board, 2005-;
`
` Accounts of Chemical Research, Guest Editor (with G. A. Voth), Special
`
`Issue on Ionic Liquids, Volume 40(11), 2007
`
` ChemSusChem, International Advisory Board, 2008-;
`
` Chemistry Letters, Advisory Board, 2010-;
`
` Australian Journal of Chemistry, Guest Editor, Research Front on Crystal
`
`Engineering, Volume 63(4), 2010;
`
` Separation Science & Technology, Guest Editor (with H. Rodriguez and
`
`J. Chen), Special Issue on Ionic Liquids (2012);
`
` Chemical Communications Guest Editor (with D. MacFarlane and S.
`
`Zhang), Special Issue on Ionic Liquids (2012);
`
` Science China – Chemistry Guest Editor (with S. Zhang), Special Issue
`
`on Ionic Liquids (2012); and
`
`WEST\271560910.2
`
`4
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 6
`
`

`
` Catalysis Today Guest Editor (with S. Zhang), Special Issue on Ionic
`
`Liquids (2012). Green Chemistry and Sustainable Technology, Springer,
`
`Heidelberg, Germany, Book Series Editor (with L.-N. He, D. Su, P.
`
`Tundo, and Z. C. Zhang).
`
` Chimica Oggi/Chemistry Today, Scientific Advisory Board, 2014-
`
` Green Energy & Environment, 2016-
`
`9.
`
`In 2002, the ACS asked me to organize and chair a specialty meeting
`
`devoted to the topic of polymorphism (Polymorphism in Crystals: Fundamentals,
`
`Prediction, and Industrial Practice, Tampa, FL, February 23–27, 2003).
`
`I was
`
`asked to organize and chair follow-up meetings in 2004 (Polymorphism in
`
`Crystals, Tampa, FL, February 8–11, 2004), in 2006 (Process Crystallization in
`
`the Pharmaceutical and Chemical Industries, Philadelphia, PA, April 25–27,
`
`2006), and in 2007 (Crystallization Process Development: Case Studies and
`
`Research, Boston, MA, February 26–27, 2007).
`
`10.
`
`In 2010, I was co-founder, co-organizer, and Vice Chair of the first
`
`Gordon Research Conference devoted to the topic of Crystal Engineering
`
`(Waterville Valley Resort, NH, June 6-11, 2010). I was the organizer and Chair of
`
`the second Gordon Research Conference on Crystal Engineering, which was held
`
`in June of 2012.
`
`WEST\271560910.2
`
`5
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 7
`
`

`
`11.
`
`I have published more than 760 articles in refereed journals, edited 14
`
`books, and have been named as an inventor on 50 domestic and foreign patents. I
`
`have also given over 1,000 presentations before regional, national and international
`
`meetings, and over 200 seminars worldwide. In both 2014 and 2015 I have been
`
`named to the Thomson Reuters Highly Cited Researchers List, ranking among the
`
`top 1% most cited in chemistry.
`
`12.
`
`Since 1996, I have had a leadership role in the development of the
`
`field of ionic liquids (pure salts liquid at
`
`low temperature); probing their
`
`fundamental nature while advancing their technological relevance in areas which
`
`include crystallization and novel pharmaceutical forms. These efforts have been
`
`recognized with several awards including the 2005 Presidential Green Chemistry
`
`Challenge Award, the 2011 American Chemical Society Award in Separations
`
`Science and Technology, and in recently being elected as a Fellow of the American
`
`Association for the Advancement of Science.
`
`13.
`
`I use and have used over the past 40 years X-ray diffraction
`
`techniques, Differential Scanning Calorimetry (“DSC”), and Thermogravimetric
`
`Analysis (“TGA”), among other techniques, in my research efforts.
`
`I have also
`
`used other spectroscopic techniques to analyze crystalline and amorphous forms,
`
`including Infra-red (“IR”), and Raman spectroscopy (“Raman”).
`
`WEST\271560910.2
`
`6
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 8
`
`

`
`14.
`
`I have collaborated with organic chemists in industry and in academia
`
`as part of a team in the discovery and characterization of novel drug compounds. I
`
`have also acted as a consultant in industry in the development of pharmaceutical
`
`drug compounds. I have also trained students in organic synthesis and supervised
`
`their Ph.D. research. Within my research group, I regularly hire and supervise
`
`Ph.D. organic chemists and direct
`
`their
`
`research in the synthesis and
`
`characterization of novel forms of active pharmaceutical ingredients.
`
`15.
`
`In my position as Founding Editor-in-Chief of the American Chemical
`
`Society journal Crystal Growth & Design, I regularly evaluate and judge suitability
`
`for publication of numerous manuscripts which utilize and study crystal
`
`engineering, polymorphism, and crystal growth and the characterization of solid
`
`state materials. Accordingly, I am quite familiar with the academic and scientific
`
`standards for experimental work in this field.
`
`16.
`
`In 2004, 2005, and 2008, I organized three special issues of Crystal
`
`Growth & Design dedicated to the phenomenon of polymorphism, and in 2009, I
`
`organized a special issue dedicated to pharmaceutical co-crystals. Many of these
`
`papers addressed pharmaceutical compounds, hydration, salt selection, and the use
`
`of X-ray diffraction.
`
`17. Based on my experience and qualifications, I consider myself an
`
`expert
`
`in the field of solid-state chemistry including crystal engineering,
`
`WEST\271560910.2
`
`7
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 9
`
`

`
`crystallization, hydration, solvate formation, and polymorphism, including the
`
`isolation and characterization of solvates and hydrates of organic compounds and
`
`their applications in pharmaceutical products. Accordingly, I believe that I am
`
`more than competent to express the opinions set forth below.
`
`18. Additional details of my education and experience, and a complete list
`
`of my publications are set forth in my curriculum vitae, Ex. 1023.
`
`III. MATERIALS CONSIDERED
`
`19.
`
`In forming my opinions, I had the materials cited in the Petition,
`
`including the '393 Patent (Ex. 1001), Patent Owner's Response, and the Phares
`
`Reference (Ex. 1005), the materials cited in this report, Dr. Williams' Declaration
`
`(Ex. 2020), Dr. Ruffolo's Declaration (Ex. 2022), Dr. Winkler's Declaration (Ex.
`
`1009), Dr. Williams' and Dr. Ruffolo's deposition transcripts, and have also relied
`
`on my own known and my numerous publications listed on my curriculum vitae
`
`(Ex. 1023).
`
`IV. MY ROLE AND SUMMARY OF MY OPINIONS
`
`20.
`
`I am not offering an opinion on the invalidity of the '393 Patent's
`
`claims, or commenting on Dr. Winkler's or Dr. Williams' opinions on that ultimate
`
`issue.
`
`21.
`
`I am offering opinions only on certain scientific questions that are
`
`within my expertise, regarding polymorphs, measurement of polymorphs, melting
`
`WEST\271560910.2
`
`8
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 10
`
`

`
`points of polymorphs, techniques to analyze polymorphs, purity and how melting
`
`point relates to purity, and other related issues.
`
`22.
`
`I am also offering an opinion about the ability to compare the melting
`
`point of samples of a polymorph.
`
`23.
`
`I also conclude that a sample of treprostinil diethanolamine salt Form
`
`B made by Phares, Ex. 1005, is at least as pure, and likely purer, than samples
`
`made and described in columns 12 and 13 of the '393 Patent, Ex. 1001.
`
`V.
`
`BACKGROUND
`
`A.
`
`Polymorphism
`
`24. Before addressing what a “polymorph” is, it is helpful to begin with a
`
`short explanation of what crystals are. Crystals are solids made up of highly
`
`organized molecules arranged in a regularly repeating three-dimensional array.
`
`These highly organized arrangements of regularly repeating molecules form what
`
`are known as crystal lattices.
`
`25.
`
`I will explain these concepts using acetaminophen as an example. A
`
`single molecule of acetaminophen has the following structure below:
`
`Acetaminophen Molecule
`
`WEST\271560910.2
`
`9
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 11
`
`

`
`26. When a sample of acetaminophen is crystallized, the molecules in the
`
`sample can arrange themselves into a regularly repeating three-dimensional pattern
`
`as shown below:
`
`Regularly Repeating 3-D Array of Acetaminophen Molecules
`
`27.
`
`This three-dimensional arrangement of molecules is the crystalline
`
`lattice, which is like a framework of molecules packed in a regular and repeating
`
`manner:
`
`WEST\271560910.2
`
`10
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 12
`
`

`
`Crystal Lattice of Acetaminophen
`
`28.
`
`The smallest repeating unit of the crystalline lattice is known as the
`
`unit cell. The crystalline lattice of acetaminophen shown above can also be
`
`depicted in terms of the unit cell, shown below.
`
`WEST\271560910.2
`
`11
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 13
`
`

`
`Acetaminophen Unit Cell
`
`29. As can be seen above, the unit cell is a theoretical construct that aids
`
`scientists in studying and characterizing crystals, and does not correspond to the
`
`shape of the molecules themselves. The ways in which the molecules of the
`
`compound (acetaminophen in my example) arrange themselves in space determine
`
`the size and shape of the unit cell. Each unit cell is like a brick and the crystal
`
`lattice a three-dimensional brick structure. A crystalline solid therefore can be
`
`described by the shape and size of a single unit cell because its three-dimensional
`
`crystal structure is simply a lattice of those unit cells repeating in all three
`
`dimensions.
`
`30.
`
`The unit cell is characterized in terms of three lengths, a, b, and c, and
`
`three angles, α, β, and γ. These lengths and angles are known as the unit cell
`
`parameters. Different unit cells have different values of a, b, c, α, β, and γ, and
`
`WEST\271560910.2
`
`12
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 14
`
`

`
`thus have different sizes and shapes. The unit cell parameters for the crystalline
`
`acetaminophen in my example are shown below.
`
`Unit Cell Parameters for Acetaminophen
`
`31. Molecules of a compound may arrange, or “pack” themselves in more
`
`than one way, which can give rise to different crystalline structures or “forms.”
`
`Many substances, including pharmaceutical compounds, can exist in more than one
`
`crystal form, each form having a different crystalline lattice and different unit cell.
`
`This phenomenon is termed “polymorphism” and the different crystal forms are
`
`called “polymorphs.” A classic example is that of carbon, where one crystal form
`
`is diamond, and another crystal form of the same substance is graphite.
`
`WEST\271560910.2
`
`13
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 15
`
`

`
`32.
`
`Two different crystalline forms of acetaminophen, referred to as
`
`“monoclinic” and “orthorhombic” are shown below.1
`
`Two Different Crystal Forms of Acetaminophen
`
`33. As shown in this example, the size and shape of the unit cell can
`
`differ, depending on how the molecules in the lattice of a particular polymorph are
`
`organized. Different polymorphs of pharmaceutical compounds may exhibit
`
`1 The terms “monoclinic” and “orthorhombic” refer to a specific type of
`crystal lattice. However, for convenience, forms are often named “Form I,” Form
`II,” Form III,” etc. without any indication of its physical properties.
`
`WEST\271560910.2
`
`14
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 16
`
`

`
`different properties, such as crystal shape, melting temperature, solubility, and
`
`stability.
`
`B.
`
`Characterizing crystals
`
`34. Because each crystal form, or polymorph, has its own unique unit cell
`
`and thus three-dimensional lattice, that particular crystal form can be identified by
`
`certain characteristics associated with its crystal
`
`lattice (and unit cell).
`
`For
`
`example, different polymorphs “diffract” (i.e., reflect) X-rays differently. Thus,
`
`one technique that can be used to identify the crystal structure of a crystalline
`
`compound and to distinguish different polymorphs of the same compound is X-ray
`
`diffraction (“XRD”), which when carried out on compounds in powder form is
`
`called powder X-ray diffraction (“PXRD”).2
`
`35.
`
`The molecules within each unit cell of the crystal lattice will diffract
`
`incident radiation, such as X-rays, in a specific pattern due to the orientation of
`
`those molecules within the unit cell. Each different crystal form will diffract X-
`
`rays at different “scattering angles” (the angle of the incident X-ray beam to the
`
`crystal where scattering of the X-rays is observed) and at differing “intensities”
`
`(how many X-rays are scattered). The scattering angles (as shown below) are
`
`measured and reported as diffraction peaks 2θ (“two theta”), and can also be
`
`referred to as the 2θ values or 2θ peaks.
`
`2 PXRD can also be referred to as X-ray powder diffraction, or “XRPD.”
`
`WEST\271560910.2
`
`15
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 17
`
`

`
`X-Ray Diffraction
`
`36. A given crystalline form of a compound will always diffract X-rays at
`
`the same scattering angles. By measuring the scattering angles (2θ) and intensities
`
`of X-rays diffracted from a given sample of a polymorph, the 2θ values can be
`
`plotted against the differing intensities, as “lines” or “peaks,” to produce a specific
`
`“X-ray diffraction pattern” for each polymorph. An X-ray diffraction pattern,
`
`therefore, can act as a fingerprint for that polymorph. For example, this is the X-
`
`ray diffraction pattern for one of the crystalline polymorphs of acetaminophen I
`
`discussed above:
`
`WEST\271560910.2
`
`16
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 18
`
`

`
`X-Ray Diffraction Pattern of Acetaminophen
`
`37. As
`
`discussed
`
`above,
`
`the X-ray
`
`diffraction
`
`patterns
`
`(or
`
`“diffractograms”) obtained from PXRD analysis are unique to a particular crystal
`
`form. The positions of the diffraction peaks provide information about the size and
`
`shape of the unit cell, and the intensities of the peaks provide information as to the
`
`contents of the unit cell, i.e., the arrangement of atoms within the unit cell. The
`
`intensities of the peaks in a given PXRD pattern can be compared to each other.
`
`Different crystal forms yield different diffractograms and the technique can be
`
`used to distinguish one form from another, as shown below for two polymorphs of
`
`acetamimophen.
`
`WEST\271560910.2
`
`17
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 19
`
`

`
`X-Ray Diffraction Patterns of Different Crystal Forms of Acetaminophen
`
`C.
`
`Identifying crystals
`
`38. Once a reference PXRD pattern has been established for a particular
`
`polymorph, an unknown sample can be identified as that polymorph if its PXRD
`
`pattern corresponds to that of the reference PXRD pattern.
`
`39.
`
`For example, the Phares Reference, Ex. 1005, provides a comparison
`
`of the PXRD patterns for treprostinil diethanolamine salt Form A and Form B:
`
`WEST\271560910.2
`
`18
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 20
`
`

`
`(Ex. 1005 at 120.) The technique can accurately distinguish Form B from Form A,
`
`and can even be used to quantitatively assess mixtures of Form A and B.
`
`D.
`
`40.
`
`Other techniques for characterizing crystals
`
`There are other commonly-used analytical techniques besides PXRD
`
`for studying or characterizing crystal forms. While PXRD relays information
`
`about the inherent structure of a crystal form, and is therefore considered the best
`
`method for identifying crystal forms, visual and thermal
`
`techniques provide
`
`additional information about the physicochemical properties of a sample.
`
`WEST\271560910.2
`
`19
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 21
`
`

`
`41. Microscopy (visual observation under a microscope) can reveal the
`
`morphology (size and shape) of the crystals themselves. In hot-stage microscopy,
`
`a sample can be observed as it is heated and/or cooled, which allows one to
`
`observe how the sample changes forms (between different crystal forms, or
`
`between liquid and solid), and at which temperatures they occur.
`
`42.
`
`Thermal analyses provide quantitative information about different
`
`crystal forms. A material can go through changes in physical state when it is
`
`heated, for example, melt, crystalize, or change crystal forms. Each of these
`
`changes in physical state, also called phase transitions, is accompanied by either an
`
`absorption (endotherm) or release (exotherm) of heat. When a material melts, it
`
`absorbs heat, resulting in an endotherm, and when it crystallizes, it releases heat,
`
`resulting in an exotherm.
`
`43. Differential scanning calorimetry (DSC) is a method of analysis that
`
`allows scientists to track these changes in physical state of a sample as it is heated,
`
`by detecting any endotherms (indicative of melting) and/or exotherms (indicative
`
`of crystallizations or changes of form) that occur. For example, in the hypothetical
`
`DSC plot below, the sample melts at about 62°C (endothermic event, resulting in a
`
`downward pointing peak), immediately recrystallizes (exothermic event, resulting
`
`in an upward pointing peak), then melts again at about 118 °C (endothermic event,
`
`resulting in a downward pointing peak).
`
`WEST\271560910.2
`
`20
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 22
`
`

`
`Illustrative DSC
`
`44.
`
`In the Phares Reference (Ex. 1005) melting point data taken using
`
`DSC is used to distinguish and verify the identities of Form A and Form B
`
`treprostinil diethanolamine crystals. The melting point data for Form A shows that
`
`it melts at 103.09oC.
`
`WEST\271560910.2
`
`21
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 23
`
`

`
`(Ex. 1005 at 118.)
`
`45.
`
`Similarly, the melting point of a Form B crystal was also measured in
`
`the Phares Reference:
`
`WEST\271560910.2
`
`22
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 24
`
`

`
`(Ex. 1005 at 121.) A computer has automatically marked the position of the
`
`melting point for this particular Form B crystal, which is indicated as 107.06oC.
`
`And this melting point value is reported in the text as 107oC. (Ex. 1005 at 91.)
`
`46.
`
`In fact, the '393 Patent recognizes the importance of melting point in
`
`identifying which polymorph is present:
`
`At this stage, if melting point of the treprostinil diethanolamine
`salt is more than 104° C., it was considered polymorph B. There
`
`WEST\271560910.2
`
`23
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 25
`
`

`
`is no need of recrystallization. If it is less than 104°C. it is
`recrystallized in EtOH-EtOAc to increase the melting point.
`
`(Ex. 1001 col.12 ll.52-56.)
`
`47.
`
`Thermogravimetric analysis, known as "TGA" or "TG," is another
`
`technique for analyzing polymorphs, and is also used in the Phares Reference, Ex.
`
`1005. TG can be used to determine if a material is a solvate or hydrate. If, upon
`
`heating, the weight of the crystal drops, it may indicate that a solvent has been
`
`released, due to conversion of the crystal from a pseudo-polymorph where the
`
`solvent (or water in the case of a hydrate) is incorporated in the crystal form, to a
`
`real polymorph containing the organic chemical alone.
`
`48.
`
`For example, in the Phares Reference, Figures 18 and 21 show, in
`
`addition to DSC data, a TGA result, which is the upper curve, whose y-axis is the
`
`"Weight (%)" at the right. If there is virtually no weight loss at temperatures at or
`
`below the melting event, it means the crystal is not a solvate or hydrate. In the
`
`Phares Reference, it was demonstrated that neither Form A nor Form B were
`
`solvates or hydrates. (Ex. 1005 at 90 ("The TG data [for Form A] shows no
`
`measurable weight loss up to 100 °C, indicating that the material is not solvated.");
`
`Ex. 1005 at 91 ("The TG [of Form B] shows minimal weight loss up to 100 °C.".)
`
`WEST\271560910.2
`
`24
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 26
`
`

`
`E. What role does melting point play in polymorph identification?
`
`49. Melting point is so closely associated with the identity of polymorphs,
`
`that it has been proposed that polymorphs be identified by their melting points,
`
`instead of by their order of discovery.
`
`50.
`
`For example, in Stephen R. Byrn et al., Solid-State Chemistry of
`
`Drugs, Chapter 10, "Polymorphs," 143-231 (2d ed. 1999), a textbook on crystals of
`
`drugs, it states:
`
`numbered
`be
`polymorphs
`that
`suggested
`been
`has
`It
`consecutively in the order of their stability at room temperature
`or by their melting point.
`
`(Ex. 1024, at 2.) This shows that melting point is so closely identified with the
`
`identity of a polymorph that melting point has been proposed as a means of
`
`distinguishing and identifying polymorphs.
`
`51.
`
`Similarly, in Terence L. Threlfall, "Analysis of Organic Polymorphs:
`
`A Review," Analyst 120(10): 2435 (1995) it is stated that:
`
`Arbitrary systems are to be discouraged, but numbering based
`either on order of melting point or of room temperature stability
`have been recommended.
`
`(Ex. 1025, at 1.)
`
`52. As yet one more example, in the FDA Guidance for Industry, ANDAs:
`
`Pharmaceutical Solid Polymorphism--Chemistry, Manufacturing, and Controls
`
`WEST\271560910.2
`
`25
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 27
`
`

`
`Information, melting point is particularly pointed out as a distinguishing property
`
`of polymorphs:
`
`(Ex. 1026, at 12.)
`
`VI. MELTING POINT AND THE PURITY OF A CRYSTAL
`
`53. As stated in many textbooks, the purity of a crystal can be related to
`
`its melting point:
`
`The method [of differential scanning calorimetry] can also be
`used as an accurate measure of the melting point and purity of
`the sample. In fact, the change of melting point is related to the
`mole fraction of impurities as given by Equation 5.2:
`
`WEST\271560910.2
`
`26
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 28
`
`

`
`ܶ௦= ܶ଴− ்೚మோ௑೔
`ி୼ୌ೑
`
`(5.2)
`
`where Ts, is the sample temperature, T0 is the melting point of
`the pure compound, R is the gas constant, Xi, is the mole fraction
`of the impurity, F is the fraction of the solid melted, and ΔHf is
`the enthalpy of fusion of the pure compound. According to the
`equation, a plot of Ts versus 1/F should give a straight line
`whose slope is proportional to Xi (Brittain et al., 1991).
`
`Stephen R. Byrn et al., Solid-State Chemistry of Drugs, Chapter 5, "Thermal
`
`Methods of Analysis," 81-901 (2d ed. 1999) (Ex. 1027, at 84.)
`
`54.
`
`This phenomenon, known as melting-point depression, may be
`
`familiar, since it is used to melt ice on the roads in the winter. Salt, which can
`
`dissolve in water, is added to roads so that when the water on the road freezes, it
`
`contains salt impurities which lower the melting point. The melting point of ice is
`
`0oC (T0 in the equation above), but it is lower when the ice contains salt as an
`
`impurity. Therefore, even if the road temperature is 0oC, the water on the roads
`
`will be above the melting point Ts of ice containing salt, and thus, will be a liquid.
`
`55.
`
`To simplify, although there is a complex relationship between the
`
`amount of impurities (Xi) and the observed melting point (Ts), the melting point
`
`will decrease if there are more impurities in the sample from the melting point in a
`
`100% pure sample, which is designated T0. The decrease will be greater the more
`
`impurities there are in the sample.
`
`WEST\271560910.2
`
`27
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 29
`
`

`
`56.
`
`The value T0 is unique for each polymorph. If I have two crystals that
`
`are known from their PXRD patterns to be Form B crystals, then both crystals have
`
`the identical T0 value, regardless of how the crystals were made and what solvents
`
`were used to make them.
`
`57.
`
`Thus, if the measured melting point of a Form B crystal, Ts, is below
`
`107oC, then the sample contains impurities, in an amount Xi, that is causing a
`
`decrease in the observed melting point.
`
`58. As explained in Stephen R. Byrn et al., Solid-State Chemistry of
`
`Drugs, Chapter 5, "Thermal Methods of Analysis," 81-901 (2d ed. 1999) (Ex.
`
`1027), differential scanning calorimetry or DSC is used to determine the melting
`
`point and then the purity of a crystalline sample using Equation 5.2. Another
`
`technique, thermal microscopy, is also used for this purpose, and is the technique
`
`used in the '393 Patent.
`
`VII. THE CRYSTAL FORMS THAT I HAVE REVIEWED
`
`59.
`
`The Phares Reference (Ex. 1005), discussed above, is International
`
`Publication No. WO 2005/007081 to Phares, et al., entitled "Compounds and
`
`Methods for Delivery of Prostacyclin Analogs," and published January 27, 2005,
`
`and is assigned to United Therapeutics. I have been told that there is no dispute
`
`that it is prior art to the '393 Patent, but whether it is or not is not relevant to my
`
`opinions in this Declaration.
`
`WEST\271560910.2
`
`28
`
`IPR2016-00006
`SteadyMed - Exhibit 1022 - Page 30
`
`

`
`60.
`
`The Phares Reference (Ex. 1005) provides a detailed description of
`
`the manufacture and characteristics of treprostinil diethanolamine salt, Form A and
`
`Form B, using many different solvent systems. It also provides the PXRD patterns,
`
`the melting points determined by DSC, the Raman and IR spectra, and the TGA
`
`analysis of these crystals.
`
`61.
`
`The '393 Patent (Ex. 1001) is also assigned to United Therapeutics. It
`
`also describes making treprostinil diethanolamine Form B salt at column 12 and
`
`clearly states that Form B is the crystal form that is made. To do so, crystals known
`
`to be Form B salt are added to solution, in a process known as seeding. In seeding,
`
`by using crystals of a chemical having a known form—here Form B—the same
`
`chemical dissolved in that solution will tend to add on to the seed crystal, and thus,
`
`will crystallize in accordance with the same crystal pattern, and thus will also form
`
`Form B. The '393 Patent authors state that