CONTAINS PROTECTIVE ORDER MATERIAL Paper _____
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`STEADYMED LTD.,
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`
`Patent Owner.
`
`_______________
`
`Case IPR2016-00006
`U.S. Patent 8,497,393
`_______________
`
`
`
`
`
`DECLARATION OF ROBERT R. RUFFOLO, Jr., Ph.D. IN SUPPORT OF
`PATENT OWNER RESPONSE TO PETITION
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`
`
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`4832-5096-2228.1
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`UT Ex. 2022
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`

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`IPR2016-00006
`patent 8,497,393
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`
`
`I. 
`
`B. 
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS AND BACKGROUND .............................................. 3 
`A. 
`Education and Experience ..................................................................... 3 
`LEGAL STANDARDS PROVIDED BY COUNSEL .............................. 10 
`II. 
`III.  THE ’393 PATENT ..................................................................................... 12 
`IV.  SUMMARY OF OPINIONS ....................................................................... 12 
`V. 
`BACKGROUND .......................................................................................... 14 
`A. 
`THE IMPORTANCE OF PURITY IN PHARMACEUTICAL
`PREPARATIONS ........................................................................................ 14 
`EXAMPLES OF TOXIC CONTAMINANTS IN
`PHARMACEUTICAL PREPARATIONS ............................................... 27 
`VI.  THE INVENTION OF THE ’393 PATENT MET A LONG-FELT
`UNMET NEED ............................................................................................ 32 
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`I have been retained by the law firm of Wilson Sonsini Goodrich & Rosati (“WSGR”) as
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`an expert consultant to United Therapeutics Corporation (“UTC”) in connection with the above-
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`identified matter to provide expert testimony concerning U.S. Patent No. 8,497,393 (“the ’393
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`patent”, Ex. 1001) by Batra et al., entitled “Process to prepare treprostinil, the active ingredient
`
`in Remodulin®,” issued on July 30, 2013. At the request of Counsel for UTC, I hereby submit
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`this expert declaration.
`
`I.
`
`Qualifications and Background
`
`A.
`
`1.
`
`Education and Experience
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`I am the retired (as of 2008) President of Research and Development for Wyeth
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`Pharmaceuticals (now Pfizer Inc.) and Corporate Senior Vice President of Wyeth (now Pfizer
`
`Inc.). I am currently Managing Director of Ruffolo Consulting, LLC, a consulting company
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`serving the pharmaceutical and biotechnology industries.
`
`2.
`
`I have studied, researched, taught (in medical and pharmacy schools), worked and
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`managed all aspects of the pharmaceutical drug discovery and development fields for over 35
`
`years. I received my Bachelor of Science (B.S.) degree in Pharmacy (summa cum laude, and
`
`With Distinction) in 1973 from The Ohio State University, and was licensed to practice
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`Pharmacy in 1973. I received my Doctor of Philosophy (Ph.D.) degree in Pharmacology in the
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`fields of autonomic and cardiovascular pharmacology in 1976 also from The Ohio State
`
`University. My doctoral research included the areas of drug-receptor interactions, autonomic
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`pharmacology, cardiovascular pharmacology, adrenergic drugs, stereochemistry and the study of
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`the stereochemical aspects of adrenergic drugs and their receptors. During the period of my
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`undergraduate and graduate education, I authored or co-authored a number of peer-reviewed
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`research articles describing that work.
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`3.
`
`Upon earning my Ph.D. degree, I remained at The Ohio State University as a
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`Postdoctoral Fellow for six months, and extended my research on drug-receptor interactions and
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`drug-receptor theory. From 1977-1978, I worked as a Staff Fellow and Postdoctoral Fellow
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`[Pharmacology Research Associate Training (PRAT) Fellow] at the National Heart Lung and
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`Blood Institute of the National Institutes of Health (NIH) in the laboratory of Dr. Marshall
`
`Nierenberg (Nobel Laureate for breaking the genetic code), where my research focused on
`
`neurobiology, and in particular on synapse formation in brain, spinal cord and skeletal muscle.
`
`4.
`
`In 1978, I began my independent career in the pharmaceutical industry at Eli Lilly
`
`& Company as Senior Pharmacologist in the Department of Cell Biology. I subsequently
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`became Senior Pharmacologist in the Department of Cardiovascular Pharmacology in 1981, and
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`was promoted to Research Scientist in 1982. I then became Chairman of the Cardiovascular
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`Research Committee in 1983, where I continued my research in cardiovascular pharmacology,
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`adrenergic drugs, drug-receptor theory, stereochemistry and the stereochemical basis of drug
`
`action. My work also expanded into the area of structure-activity relationships and drug design.
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`Shortly after joining Eli Lilly & Company, I was also assigned to supervise a medicinal
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`chemistry laboratory that was dedicated to my work in stereochemistry and structure-activity
`
`relationships, and which I personally directed. While working at Eli Lilly & Company, I was
`
`credited with discovering the complex mechanism of action of the newly marketed drug for the
`
`treatment of acute congestive heart failure, dobutamine (Dobutrex®), which involved the
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`complex interplay of the different pharmacological activities of both enantiomers of the drug,
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`each acting on multiple adrenergic receptors and their subtypes..
`
`5.
`
`In 1984, I joined SmithKline Beckman Pharmaceuticals (now GlaxoSmithKline
`
`PLC) as Director of Cardiovascular Pharmacology, where I continued my work in cardiovascular
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`pharmacology, adrenergic drugs, drug-receptor theory, stereochemistry, the stereochemical basis
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`
`
`of drug action, structure-activity relationships and drug design. As Director of the Department of
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`Cardiovascular Pharmacology, I supervised a staff of approximately 40 researchers and scientists
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`in the field of cardiovascular drug discovery and development. Throughout my tenure at
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`SmithKline Beckman Pharmaceuticals (and its subsequent corporate identities that changed
`
`through mergers and acquisitions), I also maintained my own laboratory and conducted studies
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`on the pharmacology of cardiovascular drugs, drug-receptor interactions, adrenergic
`
`pharmacology, stereochemistry, the steric aspects of drug action, and structure-activity
`
`relationships related to new drug discovery.
`
`6.
`
`I remained at SmithKline Beckman Pharmaceuticals (and its subsequent corporate
`
`identities) for approximately 17 years, over which time I rose to the position of Senior Vice
`
`President and Director of Biological Sciences Worldwide, where I was responsible for a staff of
`
`approximately 500 scientists. During my last year at the company, I became the Senior Vice
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`President and Director of all Discovery Research for the Corporation Worldwide, which included
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`all of the areas of Biological Sciences, Chemical Sciences, Medicinal Chemistry, Physical
`
`Chemistry, Process Chemistry, Molecular and Cellular Biology, and Genetics, with
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`responsibility for a staff of approximately 1,700 scientists and an annual budget of approximately
`
`$1.2 billion.
`
`7.
`
`It was during my tenure at SmithKline Beckman Pharmaceuticals (and its
`
`subsequent corporate identities) that I was personally responsible for the discovery and
`
`subsequent development of Coreg® (carvedilol) for the treatment of chronic congestive heart
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`failure, for which I was awarded the Discoverers Award in 2008 by the Pharmaceutical Research
`
`and Manufacturers Association (PhRMA), which is the major trade association for the
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`pharmaceutical industry and is comprised by Industry CEOs and Senior Executives, as well as a
`
`
`
`group of my peers (i.e., Presidents of R&D). Coreg® revolutionized the treatment of chronic
`
`congestive heart failure by markedly reducing death, hospitalization and morbidity from this
`
`devastating disease. Coreg® is now the “standard of care” for the treatment of congestive heart
`
`failure. The FDA approved Coreg® in 1997, after more than 10 years of research and
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`development work that I researched and personally led, and the drug is currently prescribed
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`globally to treat congestive heart failure. The drug has saved tens of millions of lives throughout
`
`the world.
`
`8.
`
`Also during my tenure at SmithKline Beckman Pharmaceuticals (and its
`
`subsequent corporate identities) beginning in 1984, I personally led and managed the discovery
`
`of ropinirole (Requip®) for the treatment of Parkinson’s disease. Ropinirole is a highly selective
`
`dopamine DA2 receptor agonist. Ropinirole was approved by the FDA in 1997 for the treatment
`
`of the signs and symptoms of Parkinson's disease, both as monotherapy and as adjunctive
`
`treatment in combination with Levodopa.
`
`9.
`
`Also during my tenure at SmithKline Beecham Pharmaceuticals (and its
`
`subsequent corporate identities), I personally initiated and led the Angiotensin II Receptor
`
`Antagonist Program, and I was personally involved in the discovery and development of the
`
`marketed angiotensin II receptor antagonist, eprosartan mesylate (Teveten®), which was
`
`approved by the FDA in 2001 for the treatment of hypertension.
`
`10.
`
`As a result of my research at The Ohio State University, Eli Lilly & Company and
`
`SmithKline Beckman Pharmaceuticals (and its subsequent corporate identities), I gained
`
`considerable experience in all aspects of drug discovery and development. In addition,
`
`throughout this entire period, I maintained my own personal laboratories and conducted my own
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`independent research in cardiovascular pharmacology, drug-receptor theory, autonomic
`
`
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`pharmacology, stereochemistry and the stereochemical requirements of drug action and
`
`structure-activity relationships. It was during this period that my laboratory was the first to
`
`discover that three subtypes existed for both alpha-1 and alpha-2 adrenoceptors, which was
`
`subsequently proven to be correct when the human genome was sequenced a decade later,
`
`confirming indeed that three subtypes existed for each of these two adrenoceptor subtypes. My
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`personal laboratory also collaborated with many internationally recognized scientists and their
`
`laboratories throughout the world. In addition, I have been invited to lecture at international
`
`symposia and at leading research institutions and hospitals around the world on most areas of my
`
`research.
`
`11.
`
`In 2000, I assumed the positions of Executive Vice President of Research and
`
`Development at Wyeth Pharmaceuticals as well as Corporate Vice President, and I was
`
`appointed to the Corporate Management Committee and the Board of Directors (as a non-voting
`
`member), both of which were chaired by the CEO. Eighteen months later, I was promoted to the
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`positions of President of Research and Development, as well as Corporate Senior Vice President,
`
`and I was also appointed as Chair of the Science Subcommittee of the Board of Directors. I was
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`responsible for a staff of approximately 7,000 employees globally, with an annual budget in
`
`excess of $3 billion. During this period, I was credited with changing the paradigm for drug
`
`discovery and development at Wyeth by markedly improving R&D productivity. This work has
`
`been highlighted in BusinessWeek magazine, and was the subject of a “Case Study” conducted
`
`by the Harvard Business School, which was published in the Harvard Business Review in 2007.
`
`The Harvard Business School “Case Study” has been covered extensively in business school
`
`textbooks, and is a commonly taught case study in many leading business schools throughout the
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`world, including the Harvard Business School, Wharton Business School, Columbia Business
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`
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`School, Duke University Business School and the London School of Economics. The re-
`
`engineering of Research and Development at Wyeth under my direction was also the subject of
`
`many articles appearing in major newspapers and trade journals globally. In my role as a
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`scientist and senior pharmaceutical executive, I oversaw and managed each and every aspect of
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`the pharmaceutical drug discovery and development processes. My areas of responsibility
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`included Pharmacological Sciences, Biological Sciences, Biochemical Sciences, Medicinal
`
`Chemistry, Physical Chemistry, Molecular Modeling, Spectral Sciences, Pharmaceutics and
`
`Pharmaceutical Sciences, Drug Safety and Toxicology, Drug Metabolism, Clinical R&D (which
`
`included all clinical trials from Phase 1 through Phase 3), Regulatory Affairs [for FDA (U.S.),
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`EMA (Europe), PMDA (Japan) and every regulatory agency in the world], Medical Affairs,
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`Global Safety Surveillance and Epidemiology, Process Chemistry at the pilot plant and kilo plant
`
`levels, as well as the transfer of chemical processes to manufacturing scale, and Post-Marketing
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`Research and Surveillance for all Wyeth drugs throughout their lifetimes on the market.
`
`12.
`
`Following my retirement from Wyeth in 2008, I served for one year as a
`
`consultant to Wyeth Pharmaceuticals and Pfizer, Inc. Since then, I have been a consultant to
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`most of the major large and mid-sized pharmaceutical companies and many biotechnology
`
`companies, as well as other industries outside of biomedical research, as Managing Director of
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`Ruffolo Consulting, LLC. My consulting responsibilities include the areas of R&D Leadership,
`
`Leadership Development, Management of Scientific Innovators, Managing Innovation and
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`Managing Organizational Change.
`
`13.
`
`During my career as an executive in the pharmaceutical industry, both at
`
`SmithKline Beckman Pharmaceuticals (and its subsequent corporate identities) and Wyeth
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`Pharmaceuticals, I managed and oversaw the discovery and development of over two-dozen
`
`
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`innovative new drugs that were approved by the FDA and other regulatory agencies around the
`
`world.
`
`14.
`
`During my career, I have authored or co-authored nearly 500 full-length scientific
`
`publications, over 200 abstracts, and I have edited 17 books. I was founder and editor-in-chief of
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`three international scientific journals, and have served on the editorial boards of 29 international
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`scientific journals devoted to the fields of pharmacology, biochemistry, pharmaceutical sciences,
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`medicinal chemistry, physical chemistry, analytical chemistry, stereochemistry and
`
`stereoselectivity of drugs. I have lectured extensively in scientific and industrial forums
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`worldwide. I have also been invited to speak extensively on the topics of Pharmaceutical
`
`Research and Development Management, Research and Development Productivity,
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`Organizational Change, Federal Regulation of Drug Approval and the Principles of Executive
`
`Leadership at national and international scientific and management meetings and symposia, and
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`since my retirement, also as a consultant to most of the mid-sized and large pharmaceutical
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`companies and many biotechnology companies..
`
`15.
`
`I am a member of several professional organizations including the American
`
`Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological
`
`Society, the International Union of Pharmacology (IUPHAR), where I was also Chairman of the
`
`Committee on Drug Receptor Nomenclature which was responsible for the naming of all drug
`
`receptors and ion channels worldwide, and the professional organization comprised of the
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`international Presidents of Research & Development from large Pharmaceutical Companies (a
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`group called “Hever”). I have served as an elected officer of many of these organizations.
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`16.
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`I have received a number of prestigious awards for accomplishments throughout
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`my career, including two Lifetime Achievement Awards (one from the Scrip Awards and the
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`other from The Ohio State University; one of only three ever to be awarded), two Honorary
`
`Doctorates (one from the University of Catania, Italy, and the other from West Virginia
`
`University), Chief Scientific Officer of the Year (for being the best leader of R&D in the
`
`pharmaceutical and biotechnology industries), the John Jacob Able Award, the Lorenzini Gold
`
`Medal for Biomedical Research, and the Prix Galien Special Commendation for Excellence and
`
`Innovation in Research to name but a few. I was also the winner of “The Great Oxford Debate”
`
`at the world-renowned Oxford Union of Oxford University, UK. Recently, the American Society
`
`for Pharmacology and Experimental Therapeutics (ASPET) has established an annual award in
`
`my name to honor the contributions that I have made to drug discovery and development; the
`
`Award is entitled the “Robert R. Ruffolo Career Achievement in Pharmacology Medal,” which is
`
`awarded annually to the most prestigious scientists in the world at the height of their careers.
`
`The American Society for Information Science & Technology has designated me as a Highly
`
`Cited Scientist for being among the top 100 most cited Pharmacologists in the world for over two
`
`decades.
`
`17. My curriculum vitae is submitted herewith as Ex. 2023.
`
`II.
`
`Legal Standards Provided By Counsel
`
`18.
`
`I have been informed by Counsel that because each claim defines a separate
`
`invention, the validity of each claim in a patent is addressed independently of the validity of the
`
`other claims in that patent.
`
`19.
`
`I have also been informed by Counsel that the claims of the ’393 patent are
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`"product-by-process" claims. I have also been informed by Counsel that the "product" of
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`product-by-process claims include structural and functional differences that are present even if
`
`
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`they are not explicitly claimed.
`
`20.
`
`I understand from Counsel that, in addition to considering the prior art, certain
`
`objective indicia may also provide evidence that a claimed invention is not obvious. I am
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`informed by Counsel that these objective indicia, which are also referred to as secondary
`
`considerations, may include factors such as commercial success, unexpected results, the
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`resolution of long-felt, but previously unmet needs, skepticism by others prior to achieving the
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`invention, failure of others to achieve the invention, praise from others for the invention, and
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`copying by others.
`
`21.
`
`I have been informed by Counsel that a patent is to be interpreted from the
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`perspective of a hypothetical person referred to as the person of ordinary skill in the art ("POSA")
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`to which the patent pertains. I have also been informed by Counsel that a determination of the
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`level of ordinary skill is based on, among other things, the type of problems encountered in the
`
`art, prior art solutions to those problems, rapidity with which innovations are made,
`
`sophistication of the art, and the educational level of active workers in the field. I have been
`
`informed that in any particular case, every factor may not be present, and one or more factors
`
`may predominate. I understand the POSA is presumed to know all prior art that is reasonably
`
`relevant to the subject matter of the claimed invention.
`
`22.
`
`I understand from Counsel that the validity of a patent claim must be assessed
`
`from the perspective of a POSA at the time of the invention.
`
`23.
`
`I have reviewed Dr. Williams' Declaration (Ex. 2020) and his definition of a
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`POSA with respect to the patent-in-suit and I agree with his opinion that a POSA would have
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`had, at the time of the claimed invention, a doctorate degree in chemistry, pharmaceutics,
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`pharmaceutical sciences, medicine, or a related discipline. Alternatively, the POSA may have
`
`
`
`had a lesser degree in one of those fields, with correspondingly more experience. To the extent
`
`necessary, a POSA may have collaborated with others of skill in the art, such that the individual
`
`and/or team collectively would have had experience in synthesizing and analyzing complex
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`organic compounds.
`
`24.
`
`I understand that SteadyMed's expert, Dr. Winkler, in his declaration has opined
`
`that a POSA would have "a master's degree or a Ph.D. in medicinal or organic chemistry, or a
`
`closely related field. Alternatively, a person of ordinary skill would include an individual with a
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`bachelor's degree and at least five years of practical experience in medicinal or organic
`
`chemistry." Ex. 1009 at ¶14.
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`25. My opinions in this declaration are expressed from the view of a POSA at the
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`time of the priority date of the ’393 patent. These opinions apply equally whether Dr. Williams'
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`definition of a POSA or Dr. Winkler's is applied.
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`III. The ’393 Patent
`
`26.
`
`This case relates to a process to prepare an improved treprostinil product, the
`
`active ingredient in Remodulin®, as described in the ’393 patent. As described in the ’393
`
`patent, treprostinil is prepared as an improved drug substance and active pharmaceutical
`
`ingredient (API) in a more pure form. The new preparation of treprostinil described in the ’393
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`patent also has lower levels of impurities.
`
`IV.
`
`Summary of Opinions
`
`27.
`
`This report contains a statement of my present opinions and includes the bases
`
`and reasons therefore, and the data and other information that I have considered in forming these
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`opinions. In this report, I offer herein my opinions on the importance of drug purity and
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`impurities, and on the improvements made in these properties as a result of the new preparation
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`
`
`of treprostinil as described in this patent.
`
`28.
`
`In forming my opinions, I have reviewed several documents, such as the
`
`documents cited by SteadyMed and UTC in this case, the ’393 patent and its file history, as well
`
`as references that I have found through my own research. I have also based my opinions on my
`
`own extensive general knowledge, comprising nearly 40 years of experience, of the areas of
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`pharmaceutical drug synthesis, production of API, manufacturing, formulation and preparation
`
`of final drug product.
`
`29.
`
`If called to testify, I will, as needed, explain the principles and terminology used
`
`in this report, as well as in the materials referenced herein. I may use demonstrative aids and
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`exhibits to illustrate these principles and the opinions expressed. I have not yet prepared any
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`such demonstrative aids.
`
`30.
`
`I may also testify or provide an opinion in rebuttal to testimony or opinions
`
`offered by other witnesses in response to the opinions stated herein. I reserve the right to
`
`supplement or otherwise amend my opinions.
`
`31.
`
`It is my opinion that the invention of the ’393 patent satisfied a long-felt unmet
`
`need by providing a commercial scale synthesis of treprostinil that results in a treprostinil
`
`product with higher overall purity and lower levels of individual impurities. As with all drug
`
`substances such as treprostinil, the FDA seeks to list, quantitate, and minimize impurities, and
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`maximize the overall purity, of such drug substances as much as possible for the benefit of
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`patients. The claimed invention of the ’393 patent invention meets this need.
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`V.
`
`Background
`
`
`
`A.
`
`32.
`
`The Importance of Purity in Pharmaceutical Preparations
`
` The purity of a pharmaceutical drug substance, both active pharmaceutical
`
`ingredient (API) and final or finished drug product, is of the utmost importance to regulatory
`
`agencies, and especially the FDA. Accordingly, the first sentence of the Code of Federal
`
`Regulations (C.F.R.) Title 21, Part 610, Subpart B, Section 610.13 is “Products shall be free of
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`extraneous material except that which is unavoidable in the manufacturing process described in
`
`the approved biologics license application.” 21 C.F.R. § 610.13(b) (2015). Although the FDA
`
`provides no absolute level of purity required for any given drug, based on my experience of
`
`approximately 40 years in the pharmaceutical industry interacting with the FDA on regulatory
`
`issues, it is commonly assumed that, with rare exception, licensed drugs will have purities in
`
`excess of 99%, and often significantly higher. ICH Impurities in New Drug Substances Q3A(R2)
`
`(2006) (“Q3A(R2)”, Ex. 2038) at 12; ICH M7 Assessment and Control of DNA Reactive
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`(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, 2015 (“ICH
`
`M7”, Ex. 2039) at 24-25. There is so much concern with the purity of drug substance and drug
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`product that the highest level of purity possible should be achieved, even if that means changing
`
`the synthetic method as has been done in the ’393 patent. Olsen, Bernard A., What’s New with
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`Impurities in Pharmaceuticals?, Southern California Pharmaceutical Discussion Group, January
`
`15, 2015 (Ex. 2040) at 14. Drug purity is of such importance to regulatory agencies that the
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`purity level of a drug substance and API must appear in the drug product specification, which is
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`the quality control document of the drug’s Certificate of Analysis for each batch of drug
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`substance to be released for subsequent formulation into the final drug product. 21 C.F.R. §
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`600.3 (kk). If a batch of drug substance falls short of its lowest purity limit listed in the
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`IPR2016-00006
`patent 8,497,393
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`specification, that batch of the drug substance must be rejected, even if the deviation in purity is
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`
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`as low as 0.1%. For example, if the actual purity of an API is 99.4% and the lowest limit of
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`purity in the Drug Specification of the Certificate of Analysis is 99.5%, the entire batch of API
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`must be rejected. As the FDA clearly states, “Each component [of API] shall be tested for
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`conformity with all appropriate written specifications for purity, strength and quality.” Id. at §
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`211.84(d)(2).
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`33.
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`The FDA defines purity as “relative freedom from extraneous matter in the
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`finished product, whether or not harmful to the recipient or deleterious to product.” Id. at §
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`600.3 (r). Any batches of drug substance that fail to meet the levels of purity indicated in the
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`product specification must not only be rejected, but rejected batches must also be “identified and
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`controlled under a quarantine system designed to prevent their use in manufacturing or
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`processing operations for which they are unsuitable.” Id. at § 211.110(a). The position of the
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`FDA on the significance of drug purity is absolutely clear, and would be understood by a POSA.
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`34.
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`The function of the FDA is to approve new drugs based on their safety and
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`efficacy, as well as the balance between the benefits and risks of new drugs to patients. Biotech,
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`Janet Woodcock, The Political Economy of FDA Drug Review: Processing, Politics, And
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`Lessons For Policy, FDA) (Ex. 2041) at 1-2. The FDA’s focus on purity relates specifically to
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`their many analyses that are related to the overall assessment of drug safety, and relative risk, of
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`the new product to be marketed, and is done in the interest of patient safety. Ex. 2039 at 5-9, and
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`20.
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`35.
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`Guidelines and requirements for the levels of purity of new drug substances and
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`new drug products have been increasing over the past few decades. The FDA’s requirements for
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`increases in drug purity are based on their prior experiences (both positive and negative) in
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`approving drugs with varying degrees of purity. Based on my experience, the FDA understands
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`
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`that the levels of purity that they require are dependent upon improvements in technologies
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`available to purify drug substances, as well as improvements in the levels of detection of various
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`drug components, including impurities, that are available to pharmaceutical companies to
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`produce, and equally important, manufacture, highly pure compounds. Ex. 2038 at 6-9. The
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`trends for improvements in these technologies have unmistakably improved over the decades,
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`and accordingly, so have the FDA’s requirements for drug purity. Accordingly, in my
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`experience, the drug purity requirements of the FDA represent a constantly moving (and
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`improving) target.
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`36.
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`Regulatory agencies have also sought to increase levels of purity, and
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`consequently decrease levels of impurities, in order to provide to the maximum extent possible,
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`the highest level of safety to patients. Ex. 2038 at 13-15. As indicated above, impurities are
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`extraneous substances that are present in the API and final dosage form which add no value to
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`the new drug product or to the patient. 21 C.F.R. § 600.3(5)(r). Because impurities add no value
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`or benefit to the new drug product, they are, at best, irrelevant, and at worst, sources of potential
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`adverse toxicities to patients. Impurities, therefore, can only add to the risk assessments, which
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`are often unknown, made by regulatory agencies in the evaluation of new drug products. Ex.
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`2040 at 3-4 and 5-8.
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`37.
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`Impurities may be introduced into the API or final dosage form during any of the
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`many steps involved in the synthesis, formulation and manufacturing of the drug product. ICH
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`Q3D Elemental Impurities (“ICH Q3D”, Ex. 2043) at 5; Ex. 2038 at 6-7. It has long been the
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`desire of regulatory agencies, and especially the FDA, to require pharmaceutical companies to
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`produce the highest levels of drug purity that are possible and practicable.
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`IPR2016-00006
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`38.
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`Regulatory agencies have observed toxicities, or adverse events, resulting from
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`drugs in clinical development as well as approved drugs that were not related to the new drug
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`product itself, but rather to the impurities present in these new drugs (see examples below at ¶58).
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`Because impurities add nothing to the benefit of a new drug, by extension, it is the view of
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`regulatory agencies that impurities represent only potential risk to patients. Ex. 2039 at 12-16.
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`Accordingly, regulatory agencies encourage (and may mandate) pharmaceutical manufacturers to
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`increase levels of purity of their new drug substance. Even for products already approved by the
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`FDA and on the market, it has been my experience that the FDA often encourages manufactures
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`to continue to develop new synthetic and/or manufacturing processes to improve purity, and
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`decrease levels of impurities, even further. This desirable goal is one of the objects of the
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`invention of the ’393 patent with respect to the new preparation of treprostinil with a higher level
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`of purity.
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`39.
`