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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.
`Petitioner,
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`v.
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`BRISTOL-MYERS SQUIBB COMPANY and PFIZER INC. ,
`Patent Owners.
`
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`U.S. Patent No. 9,326,945 to Patel et al.
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`Inter Partes Review IPR2018-00892
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`
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`DECLARATION OF KINAM PARK, PH.D.
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`MYLAN EXHIBIT 1002
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`1
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`1.
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`I, Kinam Park, Ph.D., have been retained by counsel for Petitioner
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`Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan is petitioning for
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`inter partes review (“IPR”) of U.S. Patent No. 9,326,945 to Patel et al. (the ’945
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`patent”) (Ex. 1001), which is assigned to Bristol Myers Squibb Company and
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`Pfizer Inc. (“Patent Owners”), to request that the United States Patent and
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`Trademark Office cancel certain claims of the ’945 patent as unpatentable. I
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`submit this expert declaration in support of Mylan’s IPR petition for the ’945
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`patent.
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`I. QUALIFICATIONS AND BACKGROUND
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`A. Education and Experience
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`2.
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`I am the Showalter Distinguished Professor of Biomedical
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`Engineering and Professor of Pharmaceutics at Purdue University. I am also
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`President of Akina, Inc., a research company located in West Lafayette that I
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`founded in 2001, and that focuses on polymers for drug delivery and biomedical
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`applications as well as developing new drug delivery technologies.
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`3. My research, training, and experience are all in the areas of
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`pharmaceutical sciences, specifically in the areas of pharmaceutics,
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`biopharmaceutics, and biomedical engineering. My research has focused on drug
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`delivery, including delivery of poorly soluble drugs through use of particle size
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`reduction to nano/micro drug crystals, and oral formulations of fast-dissolving
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`tablets and gastric retention devices, localized drug delivery using drug-device
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`combination products, and injectable long-acting depot formulations using
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`biodegradable polymers. My extensive research in these areas includes in vitro
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`experimentation and in situ and in vivo studies in animals, including evaluating and
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`analyzing the dissolution and absorption of immediate-release and extended-
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`release solid oral dosage forms. I have also conducted theoretical analyses and
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`simulations of drug behavior in the body.
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`4.
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`I received a B.S. degree in Pharmacy from Seoul National University
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`in Seoul, Korea in 1975. I received a Ph.D. degree in Pharmaceutics from the
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`University of Wisconsin, Madison in 1983. In 1985, I completed my postdoctoral
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`training in Chemical Engineering at the University of Wisconsin, Madison.
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`5.
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`I began working at Purdue University in February 1986. From
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`February 1986 through June 1994, I was an Associate Professor in the Department
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`of Pharmaceutics. In July 1994, I became a Professor in the Department of
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`Pharmaceutics and became a Professor in the Department of Biomedical
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`Engineering in July 1998. In 2006, I was named the Showalter Distinguished
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`Professor of Biomedical Engineering at the Weldon School of Biomedical
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`Engineering, Purdue University, while maintaining a Professor position at the
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`College of Pharmacy.
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`6.
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`As noted above, in 2001, I founded Akina, Inc., which provides a
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`variety of research products and services with a focus on controlled release and
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`biomedical applications. Akina, Inc. includes two divisions: PolySciTech, its
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`products division, and Akinalytics, its laboratory services division. The
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`PolySciTech division focuses on providing research reagents and products,
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`including biodegradable/biocompatible polymers, fluorescent products, chemical
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`intermediates, assay kits, and other products used in biomedical research and
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`development. Leveraging the developed experience with synthesis and
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`characterization of novel polymer formulation, as well as in-house research and
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`development, the Akinalytics division provides an array of services that range from
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`simple analysis of a single sample to multi-year contracted research.
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`7.
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`I have authored or co-authored over 560 publications, comprising
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`books, book chapters, cover stories, and referred articles in the area of
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`pharmaceutics, including reducing the particle size of compounds in order to
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`improve solubility and bioavailability. I have given almost 300 invited lectures. I
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`hold 22 patents.
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`8.
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`I have served on the editorial board of numerous journals in the area
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`of drug delivery, including, for example, Advanced Drug Delivery Reviews, Drug
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`Delivery Technology, Encyclopedia of Pharmaceutical Technology, Journal of
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`Drug Delivery Science and Technology, Nano Reviews, and Drug Delivery and
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`Translational Research, to name a few. I served as associate editor and book
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`review editor for Pharmaceutical Research, guest editor for Colloids and Surfaces
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`B: Biointerfaces, and guest editor for Advanced Drug Delivery Reviews.
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`Currently, I have been serving as the Editor-in-Chief of the Journal of Controlled
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`Release since 2005.
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`9.
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`I am a member of numerous professional societies, including the
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`American Association of Pharmaceutical Scientists, American Chemical Society,
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`Controlled Release Society, the Society for Biomaterials, and Biomedical
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`Engineering Society.
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`10.
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`I have also served on scientific advisory boards for numerous
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`symposiums, including the International Symposium on Recent Advances in Drug
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`Delivery System, the Advisory Panel on Excipients: Substance and
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`Characterization Expert Committee for the United States Pharmacopeia (or USP),
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`the European Symposium on Controlled Drug Delivery, and the International
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`Symposium on Microencapsulation.
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`11. A copy of my curriculum vitae, which lists my publications, patents,
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`invited lectures, and professional activities and describes my qualifications in
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`detail, is attached as Exhibit A.
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`B.
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`12.
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`Bases for Opinions
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`In forming my opinions set forth in this declaration, I have considered
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`and relied upon my education, background, and decades of experience in the field
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`of pharmaceutical sciences, including drug delivery, particle size determination
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`and reduction, dissolution, and formulation science. I have also relied on the
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`materials listed in Appendix B of the accompanying Petition for Inter Partes
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`Review by the Petitioner Mylan Pharmaceuticals Inc.
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`C. Retention and Compensation
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`13.
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`I am being compensated for my consulting work on this case at my
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`rate of $500.00 per hour plus expenses. My compensation in this proceeding is
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`not dependent on its outcome.
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`II. LEGAL STANDARDS
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`14. Counsel has informed me that certain legal principles should guide me
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`in my analysis. Counsel has informed me that Mylan carries the burden of proving
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`unpatentability by a preponderance of the evidence, which means Mylan must
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`show that unpatentability is more likely than not.
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`15. Counsel has informed me that the question of whether the claims of a
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`patent are anticipated by, or obvious in view of, the prior art is to be considered
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`from the perspective of the person of ordinary skill in the art (“POSA”). Counsel
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`has further informed me that the answer to this question is ascertained as of the
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`time the invention was made.
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`16. Counsel has informed me that performing an obviousness analysis
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`involves ascertaining, as of the time the invention was made, the scope and content
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`of the prior art, the level of skill of the POSA, the differences between the claimed
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`invention and the scope and content of the prior art, and whether there are
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`additional factors present that may argue against a conclusion of obviousness (i.e.,
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`“secondary considerations”), such as unexpected results attributable to the
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`invention.
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`17. Counsel has informed me that an invention may be found obvious:
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`When there is a design need or market pressure to solve a problem and there are a
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`finite number of identified, predictable solutions, a POSA has good reason to
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`pursue the known options within his or her technical grasp. If this leads to the
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`anticipated success, it is likely the product is not of innovation but of ordinary skill
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`and common sense. In that instance, the fact that a combination was obvious to try
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`might show that it was obvious under § 103.
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`18. Counsel has informed me that a prior art reference anticipates a
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`claimed invention if the prior art reference disclosed each of the claimed elements
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`of the invention. A prior art reference not expressly disclosing a claim element
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`may still anticipate or render obvious the claimed invention, if the missing element
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`is necessarily present, or inherent, in the reference. The missing element, or
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`characteristic, is inherent in the reference, if the characteristic is a natural result
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`flowing from the reference’s explicit disclosure.
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`19. Counsel has informed me that if a patent claims a composition in
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`terms of a function, property, or characteristic, and the composition itself is in the
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`prior art, then the claim may be anticipated or obvious in view of the prior art
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`reference disclosing the composition.
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`III. DEFINITION OF A PERSON OF ORDINARY SKILL IN THE ART
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`20.
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`I understand that a patent claim is evaluated from the perspective of
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`a POSA, which I understand is a hypothetical person considered to have the skill
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`level and knowledge of a particular field related to an alleged invention claimed in
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`a patent. I further understand that this hypothetical skilled artisan is presumed to
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`have before him or her all of the relevant prior art. I understand that this
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`“hypothetical person” can be more than one person or a team of people of different
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`disciplines. The discussions in this declaration are intended to convey the state of
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`the art and the knowledge of a POSA generally prior to the earliest priority date of
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`the patent application that issued as the respective ’945 patent.
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`21.
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`In view of the subject matter of the ’945 patent, a POSA as of the
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`patent’s filing date would typically be a Ph.D.-level (degree or experience)
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`pharmaceutical scientist with two or more years of experience or a person with a
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`Master’s degree with five or more years of experience who would be well versed
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`in the design and release of pharmaceutical dosage forms, and would have a
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`working understanding of the factors relevant to achieving appropriate
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`bioavailability of an active pharmaceutical ingredient, particularly a substance
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`known to have solubility issues.
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`22.
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`As of the priority date of the ’945 patent, I have been a POSA as
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`defined above.
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`IV.
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`SUMMARY OF OPINIONS
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`23. First, a POSA would have understood that the occurrence of a
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`thromboembolic event is a severe medical concern and can be sudden and
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`catastrophic. A POSA would have understood that the current anticoagulation
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`therapies of warfarin and heparin were limited and associated with negative side
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`effects. Therefore, a POSA would have been motivated to develop new,
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`alternative anticoagulation drug formulations to warfarin and heparin formulations
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`and would have understood that such drug(s) would be intended to address or
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`prevent a sudden thromboembolic disorder and would need to be fast-acting and
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`bioavailable.
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`24.
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`Second, a POSA would have been aware that at the time of filing of
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`the ’945 patent, the two most promising anticoagulation targets were Factor Xa and
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`thrombin. However, because of its important role in the coagulation cascade, and
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`more favorable characteristics over thrombin, a POSA would have been motivated
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`to target inhibitors of Factor Xa.
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`25. Third, at the time of filing of the ’945 patent, apixaban was known to
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`be a potent, specific inhibitor of Factor Xa and was actively being pursued for the
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`treatment of thromboembolic events in an oral dosage form. A POSA would have
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`further known that apixaban was polymorphic and that microparticulate, crystalline
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`forms of apixaban were known and desirable. Therefore, a POSA would have had
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`more than a reasonable expectation of success from the prior art of making a
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`crystalline apixaban tablet or capsule formulation containing microcrystalline
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`apixaban particles. A POSA would have been aware of the research and clinical
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`development of apixaban and would have been aware that 2.5 mg or 5 mg b.i.d. or
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`q.d. were identified as efficacious dosages for the treatment and prophylaxis of
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`thromboembolic events or could have arrived at these dosages using routine
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`methods of experimentation and optimization.
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`26. Fourth, although a POSA would have been motivated to develop a
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`crystalline apixaban oral dosage form as a potent drug candidate for the treatment
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`and prophylaxis of thromboembolic events, a POSA would have been aware from
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`Wei and other prior art that apixaban was sparingly soluble, and would have thus
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`been motivated to pursue avenues to address apixaban’s solubility and dissolution
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`issues in order to develop the immediate release profile necessary to treat the
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`serious and often sudden and potentially fatal thromboembolic events.
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`27. Fifth, a POSA would have understood that reducing particle size is
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`one of the first avenues to pursue in addressing solubility and dissolution issues of
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`poorly soluble compounds and would have been aware that a crystalline apixaban
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`with a reduced particle size addressing these concerns was already disclosed and
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`claimed by Wei. It would have been a matter of routine optimization for a POSA
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`to arrive at the claimed particle sizes of the ’945 patent which would result in an
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`optimum immediate-release dissolution and bioavailability profile. Further, a
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`POSA would have had a reasonable expectation of success of arriving at the
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`claimed particle size values because Wei discloses examples where crystalline
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`apixaban particles were made within the claimed ranges.
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`28.
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`Sixth, it is a matter of routine experimentation for a POSA concerned
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`with improving solubility and dissolution to conduct in vitro tests to determine the
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`dissolution profile of the crystalline apixaban with a reduced particle size. A
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`POSA, seeking to develop a drug for eventual FDA approval, would naturally
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`consult with FDA guidances and would utilize the known recommended methods
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`for such dissolution tests. A POSA would have recognized that the dissolution
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`profile is an inherent result or characteristic of the formulation being tested
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`according to the routine dissolution testing method.
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`29.
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`Seventh, all elements recited in the ’945 patent’s dependent claims
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`were already disclosed in the prior art.
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`V. BACKGROUND ON THROMBOEMBOLIC EVENTS AND ANTI-
`COAGULANT AGENTS
`30. A thrombosis refers to the formation of one or more blood clots (i.e.,
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`a thrombus or thrombi) in a blood vessel, and embolism is the blocking of a blood
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`vessel by an embolus or emboli that are fragments broken away from a thrombus.
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`Thus, thromboembolism refers to partial or complete blocking of a blood vessel
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`caused by embolus or emboli. (See, e.g., “The Surgeon General’s Call to Action to
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`Prevent Deep Vein Thrombosis and Pulmonary Embolism, U.S. Department of
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`Health and Human Services, 2008, 7 (Ex. 1018).) Deep vein thrombosis (“DVT”)
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`is the formation of thrombi in one of the body’s large veins. (Id.) Partial or
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`complete blocking of an artery or one of its branches in the lungs by thrombi
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`traveling in the blood stream results in a pulmonary embolism. (Id.) The
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`occurrence of a thromboembolic event is a major medical concern in that it can
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`cause serious life-threatening complications. (Id., 9.) The estimated overall annual
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`incidence of venous thromboembolism (“VTE”) in the United States as of 2010 is
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`between 1 and 2 per 1000 of the population or 300,000-600,000 cases. (See, e.g.,
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`Beckman, M.G. et al., “Venous thromboembolism: a public health concern,” Am.
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`J. Prev. Med., 38(4s):S495-S501, S495 (2010) (Ex. 1019).) The significance of
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`thromboembolism is not limited to the United States. According to a multinational
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`report of European Union countries, more than 370,000 VTE-related deaths are
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`reported per annum, with 34% of these deaths resulting from sudden fatal PE. (See
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`Cohen, “Venous thromboembolism (VTE) in Europe. The number of VTE events
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`and associated morbidity and mortality,” Thromb. Haemost., 98(4):756-764 (2007)
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`(Ex. 1020).) Thus, a POSA understood as of the earliest priority date of the ’945
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`patent that treatment and prevention of VTE events was clinically important and
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`would have been motivated to seek fast-acting treatment options.
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`31. A primary treatment strategy for these disorders is to treat the area or
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`system already impacted by a blood clot and prevent the clots from reoccurring.
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`Treatment of VTE events may involve the use of anticoagulants and/or
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`thrombolytic therapy options, with the use of anticoagulants being the most
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`common. (See Remko, “Molecular structure, lipophilicity, solubility, absorption,
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`and polar surface area of novel anticoagulant agents,” J. Mol. Structure, 916:76-85
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`(2009) (Ex. 1021).) Heparin and warfarin had been the main forms of treatment
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`for patients with venous and arterial thromboembolic disease for half a century
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`before the priority date of the ’945 patent. (Ex. 1004, 1937.) Administration of
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`heparin is hampered because it has to be administered by injection. The
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`administration of warfarin is also limited, due to a “narrow therapeutic index, slow
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`onset of therapeutic effect, numerous dietary and drug interactions, and a need for
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`monitoring as well as dose adjustments.” (Id.) Despite the availability of heparin
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`or warfarin, thrombotic diseases remain the leading cause of death in developed
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`countries. Thus, a POSA was further aware of the great clinical need for
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`alternative oral anticoagulants as a replacement for warfarin and heparin for both
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`the long-term prevention and treatment of patients with venous and arterial
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`thromboembolism. (Ex. 1004, 1937-1938, 1944.)
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`32.
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`Because of its central location in the coagulation cascade and the fact
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`that they block both intrinsic and extrinsic pathways, the art recognized that two
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`favorable targets for the advancement of treatment of thromboembolic disorders
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`were inhibitors of Factor Xa and thrombin. (Id., 1937.) However, because serine
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`proteases were recognized to play an important role in coagulation and the
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`thrombotic process, a POSA was motivated to target Factor Xa over thrombin for
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`further development. (Id.) This was based on the understanding in the art that
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`(1) a smaller dose of a Factor Xa anticoagulant is needed to block the coagulation
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`process earlier than for thrombin; (2) directly inhibiting thrombin may be
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`associated with a rebound hypercoaguable state not seen with Factor Xa inhibitors;
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`(3) Factor Xa inhibitors incompletely block thrombin generation and some existing
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`thrombin in the system has anti-inflammatory functions that may add to an
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`antithrombotic potential; and (4) in vitro assays suggest that Factor Xa inhibitors
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`may have a wider therapeutic window than thrombin inhibitors. (Id., 1937-1938.)
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`33.
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`Thus, apixaban would have been known by a POSA as an effective
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`oral anticoagulant. The coagulation cascade pathway is shown below in Figure 1,
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`and lists many of the agents of the day, including apixaban, and their targeted
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`coagulation factors:
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`(Id., 1938.)
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`VI. BACKGROUND ON DRUG DELIVERY OF POORLY SOLUBLE
`ORAL DOSAGE FORMS
`34.
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`In designing a dosage form for administration to a patient, a POSA
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`generally considers oral dosage forms more desirable over other delivery
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`mechanisms such as parenteral or intravenous. Oral dosage forms are
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`advantageous in that they can be easily self-administered by the patient, are
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`relatively low-cost to manufacture, package and ship, generally have increased
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`stability, and are virtually tamper resistant. (Ex. 1010, 333.) This is reflective in
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`that well over 80% of drugs marketed in the United States are oral dosage forms,
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`with tablets being the most common oral dosage form. (Id.)
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`35.
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`The most important role of a drug delivery system is to get the drug
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`“delivered” to the site of action in a sufficient amount and at the appropriate rate.
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`(Ex. 1013, 2701.) A POSA further recognizes several factors as potentially
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`presenting challenges in oral delivery of new drug substances, including drug
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`absorption and sufficient and reproducible bioavailability and/or pharmacokinetic
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`profile in humans. (Ex. 1011, Abstract.) Drug absorption from an oral solid
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`dosage form depends on the release of the drug substance from the drug product,
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`the dissolution kinetics or solubilization kinetics of the drug under physiological
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`conditions, and the permeability across the gastrointestinal tract. (Ex. 1015, 1.)
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`Drug dissolution is a prerequisite for oral absorption, because if the drug is not
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`fully dissolved it cannot be completely absorbed through the GI epithelium. It is
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`thus extremely important to understand drug dissolution and solubility in aqueous
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`media, both in early drug discovery studies and as a prerequisite for the subsequent
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`formulation development. (See Ungell et al., “Biopharmaceutical Support in
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`Candidate Drug Selection,” in Pharmaceutical Preformulation and Formulation,
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`M. Gibson, ed., Interpharm/CRC, 97-153, 100 (2004) (Ex. 1022).) Drug
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`dissolution/solubility data gives important information that can answer important
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`questions including regarding whether the drug dissolution/solubility limits the
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`bioavailability to the extent that it can endanger the usefulness of the drug or
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`whether the drug substance form should be changed to improve dissolution (e.g.,
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`changing the salt, polymorph, or particle size). (Id.) The solubility and dissolution
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`data of a drug further guides whether dissolution rate-enhancing principles (e.g.,
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`wetting agents, micronisation, solubilizing agents, solid solutions, emulsions, or
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`nanoparticles) should be applied during the formulation development. (Id.)
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`36.
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`Solubility or dissolution in different solvents is an intrinsic
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`characteristic of the molecule. (Ex. 1011, 250.) Solubility is commonly described
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`in the unit of mg/mL or a similar unit indicating the concentration of a dissolved
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`drug. Solubility describes an equilibrium value, and it does not indicate how fast a
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`drug can be dissolved in an aqueous solution. Dissolution refers to the dynamic
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`process by which a drug is dissolved in a solvent and is characterized by a rate,
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`generally the amount dissolved per unit time.
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`37.
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`The time to reach equilibrium varies depending on the drug
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`substance properties, amount of material used, and the equilibrium method used.
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`(See Tong, W-Q, “Practical aspects of solubility determination in pharmaceutical
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`preformulation, in Solvent Systems and Their Selection,” in Pharmaceutics and
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`Biopharmaceutics, P. Augustijns and M. Brewster (eds.), Springer, New York,
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`137-149, 138 (2007) (Ex. 1023).) Samples generally reach equilibrium reasonably
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`quick (e.g., if good agitation is use, often within 24 hours). For poorly soluble
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`drugs, however, the equilibrium time may be unrealistically long due to poor
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`dissolution rate. (Id.)
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`38.
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`Pharmacological activity of a drug is achieved only when it is soluble
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`in physiological intestinal fluids to be present in the dissolved state at the site of
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`absorption. (Ex. 1011, 250.) Thus, a drug needs to be released quickly for
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`absorption, and a poorly soluble drug is usually formulated for fast dissolution.
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`Aqueous solubility and dissolution kinetics of a drug in intestinal fluids is critical
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`to bioavailability issues. Dissolution kinetics of a drug can be altered either
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`through material engineering of the drug substance or through formulation
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`approaches. (Id.) In addition to aqueous solubility/dissolution kinetics, the
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`permeability of a drug substance is also critical for oral bioavailability. (Id.)
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`39.
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`Poorly soluble drugs, in particular, practically insoluble drugs, pose
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`many challenges in formulation development. For clinical applications, an
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`immediate release drug formulation needs to be made to dissolve the drug as soon
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`as possible for efficient absorption from the stomach and the upper small intestine
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`for rapid onset of drug activity. The fast dissolution is also critical for the drugs
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`that decrease the absorption as they move along the GI tract. It is known that in
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`general a drug reaches the ileum in approximately 85 min. (See Yu et al.,
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`“Biopharmaceutics classification system: the scientific basis for biowaiver
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`extensions,” Pharm Res., 19(7): 921-925, 922 (2002) (Ex. 1024).) Thus, it is
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`necessary to prepare an oral immediate release formulation for treating
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`thromboembolic disorders that allows dissolution in the GI tract as soon as
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`possible. For these reasons, there is always a need to improve the dissolution
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`kinetics of a poorly soluble drug. In general, some in the art have proposed that
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`solubility in water of ≥ 10 mg/mL in pH range of 1 to 7 is sufficient to avoid
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`absorption problems, while others suggest that drugs with a solubility in water of
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`less than 0.1 mg/mL often exhibit dissolution limitations on absorption. (Ex. 1022,
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`104-105.) Even if the solubility of a drug substance in the dissolution medium is
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`acceptable, the dissolution rate should be the characteristic of the drug release from
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`the dosage form rather than the solubility of the drug in the dissolution medium.
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`(Brown, C.K., “Dissolution method development: an industry perspective,” in
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`Pharmaceutical Dissolution Testing, J. Dressman and J. Krämer (eds.), Taylor &
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`Francis, New York, 351-372, 354 (2005) (Ex. 1025).) The bioavailability of a
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`drug is essentially determined by the dynamics and kinetics of solubility (i.e.,
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`dissolution rate) of the drug. (See Gong et al., “Principles of solubility,” in Solvent
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`Systems and Their Selection in Pharmaceuticals and Biopharmaceuticals, P.
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`Augustijins and M. Brewster (eds.), Springer, New York, 1-27, 23 (2007) (Ex
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`1026).)
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`40.
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`The art recognized that the gold standard for classifying a drug’s
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`solubility is to refer to the applicable pharmacopeia, such as the United States
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`Pharmacopoeia (“USP”).
`
`A.
`
`41.
`
`Solubility Classification By the United States Pharmacopoeia
`
`The USP, since at least the 1980s, characterizes solubility into seven
`
`(7) different forms based on its parts of solvent required for one part of solute as
`
`19
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`
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`set forth in the Table 1 below:
`
`
`
`(Ex. 1011, 250-251.) As indicated in Table 1, a sparingly soluble drug is defined
`
`as a drug with a solubility range of 10-33 mg/mL, while a very slightly soluble
`
`drug is a drug with a solubility range of 0.1-1 mg/mL, and a practically soluble
`
`drug is a drug with a solubility range less than 0.1 mg/ml. (Id., see also United
`
`States Pharmacopeia XX, 20th Revision, Description and Solubility, United States
`
`Pharmacopeial Convention, Inc., Rockville, MD, 1121 (1980) (Ex. 1027); United
`
`States Pharmacopeia, 27th ed., General Notices and Requirements, United States
`
`Pharmacopeial Convention, Inc., Rockville, MD, 1-12, 9 (2004) (Ex. 1016). As
`
`discussed further herein, the prior art discloses that apixaban has poor solubility.
`
`Such poor solubility is affirmed by the solubility measurement provided by the
`
`applicants in the ’945 patent itself of 40 µg/mL (or 0.04 mg/mL). (Ex. 1001,
`
`1:46.) As can be seen in Table 1, apixaban is classified as practically insoluble,
`
`even when the patent applicants’ own solubility measurement is used.
`
`20
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`
`
`
`
`B.
`
`Enhancing Solubility of Poorly Soluble Drugs Was Known in the
`Art
`
`42. While solubility is intrinsic to the material such that it can only be
`
`influenced by a chemical modification to the drug substance, such as salt complex
`
`formation and prodrug synthesis, dissolution is an extrinsic property that can be
`
`influenced by various chemical and physical means, including complexation,
`
`particle size adjustment, surface properties, solid state modification or
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`solubilization-enhancing formulation strategies. (Ex. 1011, 251.)
`
`43. When a drug substance is identified as having solubility or
`
`dissolution issues, either in vitro or in vivo, several different formulation strategies
`
`are routinely employed to arrive at the desired drug disposition, as indicated in
`
`Table 5 below:
`
`(Id., 255.) As shown above, one of the first strategies a POSA would take to
`
`investigate improving solubility of a poorly soluble drug is particle size reduction.
`21
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`
`
`44.
`
`It has been well known that the dissolution rate, rather than the
`
`saturation solubility, is most often the primary determinant in the absorption
`
`process of a poorly soluble drug. (See, e.g., Ex 1022, 102.) Indeed, since the late
`
`nineteenth century, the dissolution of drugs has been mathematically described by
`
`Noyes-Whitney equation:
`
`(cid:1856)(cid:1829)(cid:1856)(cid:1872)(cid:3404)(cid:1830)(cid:1827)(cid:4666)(cid:1829)(cid:3046)(cid:3398)(cid:1829)(cid:4667)
`(cid:1860)
`
`
`
` where dC/dt is the rate of dissolution of the drug particles, D is the diffusion
`
`coefficient of the drug in solution in the gastrointestinal (GI) fluids, A is the
`
`effective surface area of the drug particles in contact with the GI fluids, h is the
`
`thickness of the diffusion layer around each drug particle, CS is the saturation
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`solubility of the drug in the solution in the diffusion layer, and C is the
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`concentration of drug in the GI fluids. (Ex. 1009, 286; Ex. 1022, 101.) Here, it is
`
`noted that the effective surface area of the drug particles (A) indicates the surface
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`area available for dissolution. (See Diebold, S.M., “Physiological parameters
`
`relevant to dissolution testing: hydrodynamic considerations,” in Pharmaceutical
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`Dissolution Testing, J. Dressman and J. Kramer (eds.), Taylor & Francis, New
`
`York, 127-191, 129 (2005) (Ex. 1028).)
`
`45. As shown in the Noyes-Whitney equation, the rate of drug
`
`dissolution is directly proportional to the surface area (A) of the drug regardless of
`
`the drug solubility. Increasing the surface area is particularly important for drugs
`22
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`
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`that possess poor solubility. (Ex. 1009, 288) Accordingly, the smaller the particle
`
`size, the greater the effective surface area exhibited by a given mass of drug and
`
`the higher the dissolution rate. (Id.; see also Ex. 1013, 2703.) Thus, it has been
`
`well-known for over 100 years that particle size reduction can have a profound
`
`effect on dissolution and is likely to result in increased bioavailability, provided
`
`that the absorption of the drug is dissolution rate limited. (Id.; see also Ex. 1010,
`
`335 (“[f]or many drugs, particularly those for which absorption is limited by the
`
`rate of dissolution, attainment of therapeutic levels may depend on achieving a
`
`small particle size; Ex. 1012, 1:17-19 (“[c]ontrol of crystal size and shape enables
`
`the optimization of the dissolution rate and this may maximize the benefit while
`
`minimizing the side effects.”).) The effect of particle size on the dissolution rate of
`
`sparingly soluble drugs has been demonstrated in many instances at least since
`
`1963 by the superior dissolution rates observed after size reduction. (See, e.g., Ex.
`
`1026, 21-22.)
`
`46.
`
`In addition to particle size, it was well known in the art that
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`dissolution, and hence absorption, of poorly soluble oral dosage forms could also
`
`be improved through use of excipients, such as surfactants. One of the most
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`commonly used surfactant is sodium lauryl sulfate, also referred in the art as
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`sodium dodecyl sulfate, which was recognized in the art as improving the rate of
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`dissolution of poorly soluble drugs. (See Ex. 1013, 2707; Ex. 1012, 3:32-34; Ex.
`
`23
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`
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`1010, 359; Ex. 1022, 141, Tbl. 4.9.) Surfactants, such as sodium lauryl sulfate, can
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`be used as either as a wetting agent or to solubilize the drug substance at above the
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`critical micelle concentration (“CMC”). (Ex. 1025, 358.)
`
`C. The Biopharmaceutical Classification System (“BCS”)
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`47. As stated in sections II(A) and (D) below, both the specification of
`
`the ’945 patent refers to, and the Patent Owners relied upon, the classification of
`
`ap
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