UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`
`PETITIONER
`
`v.
`
`FOREST LABORATORIES HOLDINGS LIMITED
`
`PATENT OWNER
`
`___________________
`
`Case No.: Unassigned
`Patent No. 6,545,040
`Filed: January 24, 1992
`Issued: April 8, 2003
`Inventors: Xhonneux and Van Lommen
`Title: METHOD OF LOWERING THE BLOOD PRESSURE
`
`
`
`
`
`
`
`DECLARATION UNDER 37 CFR § 42.53(a)
`
`BY DR. DANIEL W. ARMSTRONG
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-1
`IPR2016-00379
`
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`
`PETITIONER
`
`v.
`
`FOREST LABORATORIES HOLDINGS LIMITED
`
`PATENT OWNER
`
`___________________
`
`Case No.: Unassigned
`Patent No. 6,545,040
`Filed: January 24, 1992
`Issued: April 8, 2003
`Inventors: Xhonneux and Van Lommen
`Title: METHOD OF LOWERING THE BLOOD PRESSURE
`
`
`
`
`
`
`
`DECLARATION UNDER 37 CFR § 42.53(a)
`
`BY DR. DANIEL W. ARMSTRONG
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-1
`IPR2016-00379
`
`
`
`TABLE OF CONTENTS
`
`
`Introduction ...................................................................................................... 1
`
`Qualifications and Experience ......................................................................... 2
`
`I.
`
`II.
`
`III. Experience with patents ................................................................................... 6
`
`IV. Priority date and POSITA ................................................................................ 7
`
`V. Background Science ...................................................................................... 10
`
`A.
`
`Stereochemistry ................................................................................... 11
`
`B. Conventional Chromatography ........................................................... 15
`
`C. High-Performance Liquid Chromatography (HPLC) ......................... 17
`
`VI. The ’040 Patent .............................................................................................. 26
`
`VII. Claim Construction ........................................................................................ 32
`
`VIII. Combination of prior art references by a POSITA ........................................ 32
`
`IX. SPECIFIC GROUNDS OF INVALIDITY ................................................... 35
`
`A. Ground 1: Combination of ’362 Patent and Handbook of
`Chromatography .................................................................................. 35
`
`B. Ground 2: Combination of the ’362 Patent with Handbook
`of Chromatography, in further combination with Okamoto. .............. 38
`
`C. Ground 3: Combination of the ’362 Patent with Handbook
`of Chromatography, in further combination with
`Armstrong. ........................................................................................... 43
`
`X. Conclusion ..................................................................................................... 49
`
`
`
`i
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-2
`IPR2016-00379
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`
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`I, Dr. Daniel W. Armstrong, hereby testify as follows:
`
`I.
`
`Introduction
`
`1. My name is Dr. Daniel W. Armstrong. I am over the age of eighteen (18)
`
`and I am otherwise competent to make this declaration and provide the testimony
`
`herein.
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`2.
`
`The Petitioner has retained me as an expert in this Inter Partes Review to
`
`provide scientific and technical testimony related to the patentability of the claims
`
`of U.S. Patent No. 6,545,040 (“the ’040 Patent”) (Ex. 1001). I have not been asked
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`to provide an opinion on the ultimate legal issue of whether the claims of the ’040
`
`Patent are patentable. Instead, I have been asked to provide testimony on the
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`discreet scientific and technical topics discussed below.
`
`3.
`
`In connection with my analysis, I have reviewed each of the Exhibits
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`referred to throughout this declaration. If asked, I will review additional relevant
`
`materials (such as, for example, exhibits submitted by the Patent Owner in this
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`IPR) and supplement my testimony as necessary.
`
`4.
`
`I have been compensated at my standard hourly rate of $800 per hour for the
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`time I have expended in putting together this declaration.
`
`5.
`
`Even though I am being compensated for my time by the Petitioner in this
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`matter, I do not consider myself to be an advocate for the Petitioner in any respect.
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`In my testimonial role as an expert, my primary responsibility is to provide
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`1
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-3
`IPR2016-00379
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`
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`objective and unbiased testimony to the Patent Trial and Appeal Board. I take my
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`role as an objective expert very seriously and am obliged to adhere to the standards
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`of professional and or academic integrity that I observe as a researcher, teacher,
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`and scholar. I would not under any circumstances offer testimony that I did not
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`believe to be true and well founded in the facts and evidence. I understand that my
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`declaration and any deposition I might give will be part of the public record of
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`these proceedings and will be publicly accessible to my professional colleagues
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`and peers in the scientific community.
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`II. Qualifications and Experience
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`6. My current curriculum vita is provided as an Exhibit in this IPR. It will be
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`sequentially numbered as the exhibit following this declaration. A summary of my
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`qualifications for providing expert testimony in this matter follows.
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`7.
`
`I am currently the Robert A. Welch Professor in the Department of
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`Chemistry and Biochemistry at the University of Texas at Arlington. I have held
`
`this position since 2006. From 2000-2005, I was the Caldwell Distinguished
`
`Professor at Iowa State University. Prior to my position at Iowa State, from 1991-
`
`1998, I founded and was First Director of the Center for Environmental Science
`
`and Technology at the University of Missouri-Rolla where I was also Curator’s
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`Distinguished Professor of Chemistry and Professor of Chemistry and Head of the
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`Bio-Analytical Division from 1987 to 2000. From 1983 to 1987, I was a Professor
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`
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`2
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-4
`IPR2016-00379
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`
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`of Chemistry and the Head of Analytical Division at Texas Tech University. Prior
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`to that, I was an Assistant Professor of Chemistry at Bowdoin College,
`
`Georgetown University from 1978 through 1982.
`
`8.
`
`I obtained my B.Sc. in Interdepartmental Science and Math from
`
`Washington & Lee University in 1972, my M.S. in Oceanography from Texas
`
`A&M University in 1974, and my Ph.D. in Bio-Organic Chemistry from that same
`
`institution in December 1977.
`
`9.
`
`I have over 600 publications, including twenty-nine book chapters, and one
`
`book: “Use of Ordered Media in Chemical Separations” (originally published in
`
`1987). I am also a named inventor on approximately 27 patents. I have been
`
`named by the Scientific Citation Index as one of the world’s most highly-cited
`
`scientists, and have given over 540 invited seminars and colloquia worldwide. I
`
`am considered a leader in the field of separations with micelles and cyclodextrins; I
`
`elucidated the first chiral recognition mechanism by cyclodextrins, and I was the
`
`first to develop macrocyclic antibiotics as chiral selectors. I am one of the world’s
`
`leading authorities on the theory, mechanism, and use of enantioselective
`
`molecular interactions. Over 30 different chiral columns for liquid
`
`chromatography (LC), e.g., high performance liquid chromatography (HPLC), and
`
`gas chromatography (GC) that were originally developed in my laboratories have
`
`been commercialized and/or copied worldwide, and my work and columns were in
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`
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`3
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-5
`IPR2016-00379
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`
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`part responsible for the revolution in chiral separations led by chromatography and
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`electrophoresis over the last three decades. Prior to 1988, five chiral
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`chromatography columns from my laboratories had been commercialized; fourteen
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`additional columns from my laboratories were commercialized from 1988-1990.
`
`The columns, chiral selectors and techniques developed in my laboratories are
`
`widely used in the world of analytical enantiomeric separations today, and several
`
`of my chiral HPLC columns have been commercially available since at least late-
`
`1983.
`
`10. As reflected in my curriculum vitae, I have received numerous awards and
`
`citations, including the following: the 1991 Great Britain Martin Metal in
`
`recognition of outstanding contributions to Chromatography; the 1992 ISCO
`
`Lectureship Award for Significant Contributions to Instrumentation for
`
`Biochemical Separations; the 1995 American Association of Pharmaceutical
`
`Scientists Fellow Award; the 1999 American Chemical Society Award in
`
`Chromatography; the Dal Nogare Award for Separation Science in 2005; and the
`
`2014 American Chemical Society Award in Separation Science & Technology,
`
`among others. In 2009 I was admitted as a Fellow in the Royal Society of
`
`Chemistry and in 2013 I was named a Fellow of the American Chemical Society.
`
`In 2014 I was elected to the National Academy of Inventors.
`
`
`
`4
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-6
`IPR2016-00379
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`11.
`
`I am and have been on numerous editorial boards of scientific publications
`
`in the field of chromatography, separation science and other fields, including: an
`
`editor of Chirality; Separations Associate Editor for Analytical Chemistry; and a
`
`member of Editorial Board for the Journal of Pharmaceutical & Biomedical
`
`Analysis, Amino Acids Journal, The Journal of Chromatography, The Journal of
`
`Liquid Chromatography, Separation Science and Technology, Chromatographia,
`
`Electrophoresis and the Journal of Separation Science. I was also a member of the
`
`Scientific Advisory Board for Analytical Chemistry.
`
`12. As noted in my curriculum vitae, I have also been a technical reviewer for
`
`numerous research proposals and research manuscripts and have been an invited
`
`speaker, plenary lecturer or keynote lecturer (over 540 times) at universities,
`
`pharmaceutical companies, professional conferences, and governmental agencies,
`
`including the FDA and NIH. I am member of a number of Professional Societies,
`
`have consulted for pharmaceutical companies and have received numerous grants
`
`and research funds from government agencies, pharmaceutical companies and
`
`other entities, totaling well over $20,000,000.
`
`13. From 1983 to 2005, I gave over 300 invited talks, Keynote and Plenary
`
`lectures on the separation of chiral molecules. The majority of these involved
`
`chiral chromatography and molecules of pharmaceutical interest. Additionally, I
`
`have published extensively on the use of chromatography in the separation of drug-
`
`
`
`5
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-7
`IPR2016-00379
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`
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`like molecules. Notable examples from my publication record include the
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`following: J. Chromatogr. Sci., 22, 411-415 (1984); Science, 232, 1132-1135
`
`(1986); Anal. Biochem, 167, 261-264 (1987); J. of Pharm. Biomed Analysis, 8,
`
`123-130 (1990); J. of Chromatogr., 513, 181-194 (1990). Many of these papers
`
`involved the separation of β-blockers drug stereoisomers. Additional information
`
`relating to my background, training and experience can be found in my C.V.
`
`III. Experience with patents
`
`14.
`
`I am not a lawyer, and I have not been asked to provide an opinion on the
`
`ultimate legal issue of patentability. However, I do have a general familiarity with
`
`patents, patent law, and the process of how an inventor applies for and obtains a
`
`patent.
`
`15.
`
`I have been named as an inventor or co-inventor on approximately 27 U.S.
`
`and foreign patents and patent applications, as listed on my C.V. As a result of this
`
`work I was elected to the National Academy of Inventors in 2014.
`
`16.
`
` I have testified and/or been deposed as an expert witness in several
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`previous patent cases, all involving pharmaceutical patents and/or drug
`
`stereochemistry.
`
`17. Through these experiences, I have gained a general familiarity with patent
`
`law and the process by which an individual applies for and receives a patent.
`
`
`
`6
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-8
`IPR2016-00379
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`
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`IV. Priority date and POSITA
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`18.
`
`I have been informed (and I understand from my own experience) that a
`
`patent is read from the perspective of a person of ordinary skill in the art
`
`(“POSITA”) at or about the time or the priority date of the patent. Similarly, I have
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`been informed (and I understand from my own experience) that the obviousness or
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`non-obviousness of a patent claim is determined from the perspective of a POSITA
`
`at or about the time of the priority date of the patent.
`
`19. For purposes of this declaration, I have been asked to assume that the ’040
`
`Patent has a priority date of March 23, 1988, based on the fact that the ’040 Patent
`
`claims priority to a provisional application filed on that date. At times in my
`
`testimony below I may refer to the ’040 Patent’s priority date as the “time of the
`
`invention,” and I use these terms synonymously.
`
`20.
`
` I have been informed (and I understand from my own experience) that a
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`POSITA is defined as a hypothetical person who is presumed to have known the
`
`relevant art at the time of the invention. I am informed that at least the following
`
`factors are all relevant factors for defining the knowledge, skills and experience of
`
`the POSITA: (1) the types of problems encountered in the art; (2) prior art
`
`solutions to those problems; (3) the rapidity with which innovations are made in
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`the art; (4) the sophistication of the technology; and (5) the education level of
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`active workers in the field.
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`
`
`7
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-9
`IPR2016-00379
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`
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`21.
`
` In arriving at the description of the POSITA for the ’040 Patent set forth
`
`below, I have collaborated with Dr. Ronald Millard, who has also been retained as
`
`an expert by the Petitioner for purposes of this IPR, and together we arrived at the
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`following description of the knowledge and skills of the POSITA.
`
`22. The ’040 Patent deals with the scientific and technical art of new
`
`pharmaceutical drug discovery, design and research within the field of
`
`cardiovascular biology, and is particularly related to new drug research for
`
`potential cardioselective β-receptor antagonists for the treatment of hypertension.
`
`The ’040 Patent involves aspects of the separation or purification of chiral
`
`compounds and the laboratory investigation of those compounds to determine their
`
`effectiveness for treating hypertension.
`
`23. New drug discovery of this type is necessarily a multi-disciplinary process
`
`because of the specialized knowledge drawn from multiple fields of scientific
`
`inquiry. A person of ordinary skill in the art of new drug development would rarely
`
`if ever work alone, but instead would work as part of a team of researchers who
`
`would bring an array of knowledge and skills drawn from related but distinct
`
`scientific disciplines such as organic chemistry, analytical chemistry, medicine,
`
`laboratory and clinical medical research, medicinal chemistry, pharmacology, and
`
`others. Thus, a POSITA involved in new drug discovery not only would draw upon
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`
`
`8
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-10
`IPR2016-00379
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`
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`his or her own skills, but also would draw from the specialized skills of other team
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`members to solve any given technical problem encountered.
`
`24. To address the technical issues presented by new drug research in this field,
`
`and to address the technical issues presented by the subject matter of the ’040
`
`Patent specifically, a POSITA would need to possess knowledge and expertise
`
`related to both stereochemistry and the separation and purification of chiral
`
`compounds (in order to create the compounds described by claims 1 and 2 of the
`
`’040 Patent), and also knowledge and expertise related to the laboratory and
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`clinical investigation and evaluation of these compounds as potential drugs for the
`
`treatment of hypertension.
`
`25. Thus, it is my opinion (formed in collaboration with Dr. Millard) that the
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`relevant POSITA for the ’040 Patent would be a highly educated and skilled
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`person who had earned an advanced terminal degree (MS, PhD, MD, DSc, DVM,
`
`or equivalent) in a scientific discipline such as medicine, chemistry, biology, a
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`specialized sub-discipline of one of these, or equivalent. This POSITA would also
`
`have complete at least 3-5 years of advanced specialty training (post-graduate,
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`post-doctoral, research fellow, industry etc.) in areas such as physiology,
`
`pharmacology, cardiovascular medicine, etc. This POSITA would likely be a
`
`member of a team with access to other researchers similarly-trained. Also, for a
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`POSITA encountering the technical problems presented by the ’040 Patent, the
`
`
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`9
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-11
`IPR2016-00379
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`
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`POSITA would have knowledge and experience equivalent to at least a master’s
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`degree in chemistry and at least 3-5 years of working experience in the field of
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`chemical synthesis, including particular experience performing stereochemical
`
`separation of chiral compounds using chromatography and other common
`
`separation techniques.
`
`26.
`
`In providing scientific or technical testimony related to the patentability of a
`
`patent claim, I have been informed (and I also know from my own experience) that
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`it is critically important to avoid “hindsight bias” (i.e. failing to put myself in the
`
`shoes of a POSITA at the time of the patent’s priority date). I have been very
`
`careful to avoid hindsight bias in providing the testimony set forth in this
`
`declaration by doing at least the following: (1) performing a literature review of the
`
`scientific and technical literature (including patents) restricted to time periods prior
`
`to the priority date of the ’040 Patent; (2) wherever possible, providing citations
`
`and support for my testimony from scientific and technical literature that pre-dates
`
`the priority date of the patents; and (3) where testimony is drawn from my own
`
`direct experience, being careful to pay attention to the timeframe within which I
`
`would have obtained the knowledge that allows me to provide the testimony.
`
`V. Background Science
`
`27.
`
`I have been asked to provide testimony related to the background science for
`
`certain technical topics related to the ’040 Patent. Unless otherwise specifically
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`
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`10
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-12
`IPR2016-00379
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`
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`stated, all of the testimony provided in this Background Science section of my
`
`declaration relates to facts and knowledge that would have been generally known
`
`to a POSITA at the time of the invention.
`
`A. Stereochemistry
`
`28.
`
`I have been asked to provide an overview of stereochemistry and to provide
`
`definitions for terms that are relevant to the ’040 Patent.
`
`29. Chiral molecules are stereogenic molecules that can exist in various three-
`
`dimensional configurations. Stereochemistry is a branch of chemistry that studies
`
`the three-dimensional aspects of molecules. Stereoisomers are isomers that share
`
`an identical chemical formula, the same atom connectivity (i.e., all atoms bonded
`
`in the same order or sequence), but with different three-dimensional arrangements
`
`of the atoms or chemical groups.
`
`30. The most common reason for a molecule to be chiral, and therefore to have
`
`multiple stereoisomers, is that the molecule has one or more stereogenic (aka
`
`asymmetric) carbon atoms. A carbon atom is said to be stereogenic if it has four
`
`different atoms or groups attached to it. Such a “chiral carbon” is a “chiral center”
`
`for the molecule. This asymmetric chiral center allows for multiple three-
`
`dimensional configurations of the same chemical elements, with each
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`configuration referred to as a separate stereoisomer.
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`
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`11
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-13
`IPR2016-00379
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`31. The number of possible stereoisomers for a molecule depends on the number
`
`of chiral centers. For any chiral molecule, the maximum number of stereoisomers
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`is equal to 2n, where n is the number of chiral centers for the molecule. For any
`
`particular molecule, the actual number of possible stereoisomers may be fewer
`
`than the theoretical maximum due to geometrical and spatial factors.
`
`32.
`
`In stereochemistry, various stereoisomers of a chiral molecule are typically
`
`labelled according to the orientation of each chiral center, with one orientation
`
`designated as “(R)-” (for Rectus or right) and “(S)-” (for Sinister or left). For a
`
`molecule with one chiral center (and therefore two possible stereoisomers), one of
`
`the stereoisomers is the R-isomer and the other is the S-isomer. For a molecule
`
`with two chiral centers, there would be four possible stereoisomers which would be
`
`labelled: (RR), (RS), (SR) and (SS). A molecule with three chiral centers would
`
`have eight possible stereoisomers: (RRR), (RRS), (RSR), (SRR), (SSR), (SRS),
`
`(RSS), and (SSS).
`
`33. Two stereoisomers are either “enantiomers” or “diastereomers” in relation to
`
`each other. Two stereoisomers are enantiomers if they are non-superimposable
`
`mirror images of each other (often compared to the left and right hand of a human).
`
`Enantiomers are three-dimensionally incapable of being superimposed on one
`
`another. Therefore, they are different molecular species. If two stereoisomers are
`
`enantiomers, and they exist in equal amounts in a mixture (i.e. 1:1 or 50:50
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`
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`12
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-14
`IPR2016-00379
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`mixtures) they are referred to as a “racemates.” For a molecule with three chiral
`
`centers, for example, the following stereoisomers would be racemates: (RRR and
`
`SSS), (RRS and SSR), (RSR and SRS), and (SRR and RSS).
`
`34. Diastereomers are stereoisomers which are neither mirror images nor
`
`superimposable. Typically, diastereomers arise when a molecule contains two or
`
`more stereogenic centers, i.e., two or more chiral centers. While enantiomers have
`
`the same physical and chemical properties, diastereomers do not. For example,
`
`while enantiomers have the same solubility in an organic solvent and will elute on
`
`an achiral chromatography column at the same time, diastereomers have different
`
`solubilities and different elution times. Thus, diastereomers may be separated from
`
`one another by using a variety of ordinary techniques, e.g., selective
`
`crystallization, conventional chromatography, distillation (if volatile), extraction
`
`techniques and so forth. Conversely, enantiomers can only be separated by
`
`specific stereoselective techniques.
`
`35. The following schematic illustrates the difference between enantiomers and
`
`diastereomers, using 2-chloro-3-iodobutane as an example:
`
`
`
`
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`
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`13
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-15
`IPR2016-00379
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`36. For additional background on stereochemistry and the relevant terminology
`
`as would have been understood by a person of skill in the art of 1988 at the time of
`
`the invention, I would refer the reader to any basic undergraduate organic
`
`chemistry text book such as: Organic Chemistry, R.T. Morrison and R.N. Boyd,
`
`Ch. 4, pp. 115-140 (3d. Edition, 1973).
`
`
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`14
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-16
`IPR2016-00379
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`B. Conventional Chromatography
`
`
`37. Stereochemistry frequently requires researchers to separate various
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`stereoisomers into more purified stereochemical forms—either pairs of racemate
`
`enantiomers or individual stereoisomers. As previously mentioned, diastereomers
`
`have different chemical and physical properties from one another, including
`
`different boiling points, evaporation rates, solubility, or freezing points. The
`
`separation of diastereomers is straightforward and can be done via conventional
`
`methods such as heating, cooling, and dissolving that rely on the different chemical
`
`and physical properties of the individual stereoisomers. However the separation of
`
`enantiomers (as in a racemate) requires the intervention of a chiral entity because
`
`enantiomers have identical properties in an isotropic environment except for the
`
`direction of their rotation of plane polarized light.
`
`38. The first documented separation of stereoisomers was performed by Louis
`
`Pasteur in 1849. Pasteur noticed that, at cold temperatures, crystals of certain
`
`tartaric acid salts formed with left-handed and right-handed orientations. Pasteur
`
`painstakingly used a microscope and tweezers to separate the two types of “mirror
`
`image” crystals from each other. Pasteur’s technique would only work in rare
`
`instances, however. Very few stereoisomers naturally crystallize in this fashion. In
`
`1882, Pasteur demonstrated a technique called spontaneous resolution, in which he
`
`used a supersaturated solution of sodium ammonium tartrate with the d-crystal on
`
`
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`15
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-17
`IPR2016-00379
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`one side of the reactor and the l-crystal on the other side to cause opposing crystals
`
`to form on each side of the reactor.
`
`39. Various conventional techniques have been used for the last century to
`
`separate diastereomers, since diastereomers exhibited different chemical
`
`properties. These conventional techniques are known as conventional
`
`chromatography. For a general overview of chromatography techniques, I refer the
`
`reader to Exhibit 1005, Handbook of Chromatography, Vol. II (Edited by Zweig
`
`and Sherma), published in 1971.
`
`40.
`
`It should be noted that chromatography (and high performance liquid
`
`chromatography or “HPLC” in particular) is the most widely-used instrument in
`
`the pharmaceutical industry. There are more HPLC instruments deployed in the
`
`pharmaceutical industry than most other instruments combined. This prevalence of
`
`HPLCs was true before the priority date of the ’040 Patent in 1988. Well before the
`
`priority date of the invention, conventional chromatography techniques essentially
`
`had been perfected for the separation of diastereomers, impurities, metabolites and
`
`most other substances of concern to the pharmaceutical industry.
`
`41. As of the mid-1970s, however, it was generally understood that
`
`chromatography was limited in its ability to separate racemate enantiomers from
`
`each other. Separation of enantiomers from each other presents a more difficult
`
`problem because enantiomers have identical chemical properties (e.g. they have
`
`
`
`16
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-18
`IPR2016-00379
`
`
`
`the same boiling point, evaporation rate, etc.) and thus conventional techniques at
`
`that time were limited in their ability to separate pairs of enantiomers to create
`
`purified individual stereoisomers.
`
`C. High-Performance Liquid Chromatography (HPLC)
`
`
`42. The late 1970s and early 1980s was a period of remarkable advances in the
`
`chromatography of enantiomers using HPLC. This field experienced
`
`extraordinarily rapid development, commercialization, and mass adoption within
`
`the field of stereochemistry. During this time-frame, HPLC “chiral” techniques
`
`were demonstrated to be very effective at resolving pairs of enantiomers to create
`
`purified individual stereoisomers for a wide array of chiral molecules. For an
`
`overview of the development of chiral HPLC techniques during this timeframe, I
`
`would refer the reader to the following two articles, each of which I authored or
`
`co-authored:
`
` Exhibit 1008, Armstrong, Chiral Stationary Phases for High Performance
`
`Liquid Chromatographic Separation of Enantiomers: A Mini-Review,
`
`Journal of Liquid Chromatography, v. 7 p. 353-76 (1984);
`
` Exhibit 1009, Armstrong & Han, Enantiomeric Separations in
`
`Chromatography, CRC Critical Reviews in Analytical Chemistry, v. 19 p.
`
`175-224 (1988).
`
`
`
`17
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-19
`IPR2016-00379
`
`
`
`43. The advent of a variety of commercial chiral HPLC columns provided a
`
`facile means to do pharmacokinetics and pharmacodynamics on both enantiomers
`
`of a racemate, determine enantiomeric purities of chiral drugs, prepare usable
`
`quantities of pure enantiomers from racemates and do quality control on the
`
`manufacture of chiral drugs—regardless of the method by which they were
`
`obtained.
`
`44.
`
`It was well known to persons of skill in the art prior to the priority date of
`
`the ’040 Patent in 1988 that HPLC techniques could generally be used to separate
`
`enantiomers. I refer the reader to the following exhibits:
`
` Exhibit 1010, Meyer, Practical High-performance Liquid Chromatography,
`
`Chapter 22 (1988) – shows that it was well-known that HPLC could be used
`
`to successfully separate enantiomers.
`
` Exhibit 1011, Meyer, Practical High-performance Liquid Chromatography,
`
`Chapter 22 (1988) – shows that many varieties of kits for performing HPLC
`
`were commercially available at the time. Of particular interest is the list of
`
`Chiral Phase columns listed in Section 25.18 on pp. 293-95.
`
` Exhibit 1016 – Bakerbond advertisement. The Bakerbond kit was an early
`
`chiral phase kit that was particularly widely adopted and would have been
`
`well-known to a person of ordinary skill at the time. Exhibit 1016 is a copy
`
`of an advertisement that I located in my personal archive of documents and
`
`
`
`18
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`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-20
`IPR2016-00379
`
`
`
`bears a copyright date of 1983. I have personal knowledge of the fact that it
`
`would have been a published advertisement that was publicly distributed at
`
`least as early as the 1983 copyright date it bears.
`
` Exhibits 1012, 1013, and 1014 – Allenmark, Chromatographic
`
`Enantioseparation: Methods and Applications, Chapters 4, 5 and 7 (1988) –
`
`provides an overview and description of HPLC techniques and methods used
`
`for separation of enantiomers.
`
`45. Moreover, it was specifically well-known in the art that HPLC was effective
`
`for pharmaceutical applications such as separating the stereochemical components
`
`of compounds of interest for pharmaceutical new drug research. I direct the reader
`
`to the following additional publication:
`
` Exhibit 1015 - Allenmark, Chromatographic Enantioseparation: Methods
`
`and Applications, Chapter 8.3 (1988) –discussing HPLC separation of
`
`compounds so that purified stereoisomeric forms can be tested for differing
`
`pharmacokinetic effects.
`
`46.
`
`In particular, given the known importance of stereoselectivity in connection
`
`with the effectiveness of known β-blockers such as propranolol, scientists were
`
`actively searching for better and more effective techniques for performing
`
`stereochemical separation of known β-blocking compounds such as propranolol
`
`
`
`19
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-21
`IPR2016-00379
`
`
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`and related drugs. This is illustrated by the following publications, each of which
`
`shows the separation of stereoisomers of known β-blocking drugs:
`
` Exhibit 1017 – Gubitz and Mihellyes, Optical Resolution of β-blocking
`
`Agents by Thin-layer Chromatography and High-Performance Liquid
`
`Chromatography as Diastereomeric R-(--)-1-(1-naphthyl)ethylureas, Journal
`
`of Chromatography, v. 314, p. 462-66 (1984).
`
` Exhibit 1018 – Lindner, Leitner, and Uray, Liquid Chromatography
`
`Separation of Enantiomeric Al-Kanolamines via Diastereomeric Tartatic
`
`Acid Monoesters, Journal of Chromatography, v. 316, p. 605-16 (1984).
`
` Exhibit 1019 – Hermansson, Resolution of Racemic Aminoalcohols (β-
`
`Blockers), Amines and Acids as Enantiomeric Derivatives Using a Chiral
`
`α1-Acid Glycoprotein Column, Journal of Chromatography, v. 325, p. 379-
`
`84 (1985).
`
` Exhibit 1020 – Schill, Wainer, and Barkan, Chiral Separation of Cationic
`
`and Anionic Drugs on an α1-Acid Glycoprotein-Bonded Stationary Phase
`
`(Enantiopac®), Journal of Chromatology, v. 365, p. 73-88 (1986).
`
`47. As can be seen from these publications, it would have been well known to a
`
`POSITA at the time of the invention that HPLC techniques would be effectively
`
`adapted to separate and resolve β-blocking compounds, specifically compounds
`
`
`
`20
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1050-22
`IPR2016-00379
`
`
`
`that are racemic mixtures of two enantiomers, into their constituent purified
`
`stereoisomers.
`
`48. Moreover, a POSITA at the time of the invention would have understood
`
`that β-blocking compounds would generally fall on the “easy end” of the
`
`separation scale. It was understood by a POSITA at the time of the ’040 Patent in
`
`1988 that enantiomers can range from easy to difficult to separate, and that it is the
`
`distinct structural features of the molecule that determines whether it lies toward
`
`the easy end or the difficult end of the separation scale. All β-blockers are amino
`
`alcohols. This means that they have an amine functional group and an alcohol (-
`
`OH) fu
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