`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ENDO PHARMACEUTICALS, INC.
`Petitioner
`
`v.
`
`DEPOMED, INC.
`Patent Owner
`____________
`
`Case IPR2014-00656
`U.S. Patent No. 6,635,280
`____________
`
`DECLARATION OF HAROLD B. HOPFENBERG, Ph.D.
`
`ON THE VALIDITY OF
`
`CLAIMS 1, 2, 8, 9, 13–15, 43, 45 AND 46 OF
`
`U.S. PATENT NO. 6,340,475
`
`
`
`TABLE OF CONTENTS
`
`
`
`I. QUALIFICATIONS ............................................................................1
`
`Page
`
`II. SCOPE OF ASSIGNMENT AND APPROACH .................................7
`
`III. APPLICABLE STANDARDS AND CONTROLLING
`PRINCIPLES .......................................................................................9
`
`A. Obviousness ...............................................................................9
`
`B.
`
`Person of Ordinary Skill in the Art.............................................11
`
`IV. SUMMARY OF MY OPINIONS ........................................................13
`
`V. GENERAL TECHNOLOGY BACKGROUND ..................................14
`
`A.
`
`The '280 Patent Claims a Novel Gastric Retentive,
`Controlled-Release Drug Dosage Form......................................14
`
`B.
`
`Controlled-Release Dosage Forms .............................................20
`
`C. Measurement of Drug Release (Dissolution) ..............................28
`
`VI. CLAIM CONSTRUCTION .................................................................30
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`"gastric fluid" .............................................................................31
`
`"releases substantially all of said drug within about
`[eight/ten] hours after such immersion" and "substantially
`all" .............................................................................................32
`
`"substantially intact" ..................................................................33
`
`"releases said drug by [a particular mechanism]" .......................34
`
`"when swollen in a dimensionally unrestricted manner" ............38
`
`VII. DISCUSSION AND OPINIONS REGARDING THE
`CONTRAST BETWEEN THE CLAIMS OF THE '280 PATENT
`AND THE PRIOR ART ......................................................................39
`
`
`
`- i -
`
`
`
`A.
`
`B.
`
`The '280 Patent Discloses Gastric Retentive, Controlled-
`Release Dosage Forms For Highly Soluble Drugs .....................39
`
`Scope and Content of the Prior Art Asserted Against the
`'280 Patent .................................................................................44
`
`1.
`
`Baveja ..............................................................................45
`
`a) Baveja Does Not Teach or Suggest Drug
`Release by "dissolution and diffusion" ....................47
`
`b) Baveja Does Not Teach or Suggest a
`"polymeric matrix . . . that remains
`substantially intact until all of said drug is
`released" .................................................................49
`
`c) Baveja Does Not Teach or Suggest "fed mode" ......51
`
`d) Dr. Park's Tests are Scientifically Unreliable ..........51
`
`2.
`
`Colombo ..........................................................................58
`
`a) Colombo Does Not Teach or Suggest
`"dissolution and diffusion" ......................................59
`
`b) Colombo Does Not Teach or Suggest "upon
`immersion in gastric fluid" ......................................61
`
`c) Colombo Does Not Teach or Suggest "when
`swollen in a dimensionally unrestricted
`manner" ..................................................................62
`
`d) Colombo Does Not Teach or Suggest "Fed
`Mode" .....................................................................63
`
`3.
`
`Shell '790 Patent ..............................................................64
`
`a)
`
`The Shell '790 Patent Does Not Teach or
`Suggest "dissolution and diffusion" or "releases
`said drug into gastric fluid by the dissolving of
`said drug by said gastric fluid and either erosion
`of said matrix or diffusion of said dissolved
`drug out of said matrix" ..........................................65
`
`
`
`- ii -
`
`
`
`b) The Shell '790 Patent Does Not Teach or
`Suggest "upon immersion in gastric fluid
`retains at least about 40% of said drug one hour
`after such immersion" .............................................66
`
`4.
`
`Shell 1993 Pub. ................................................................67
`
`a)
`
`b)
`
`c)
`
`Shell 1993 Pub. Does Not Teach or Suggest
`"dissolution and diffusion" or "releases said
`drug into gastric fluid by the dissolving of said
`drug by said gastric fluid and either erosion of
`said matrix or diffusion of said dissolved drug
`out of said matrix" ..................................................68
`
`Shell 1993 Pub. Does Not Teach or Suggest
`"releases substantially all of said drug [within
`about [eight/ten]] hours after such immersion" .......71
`
`The Focus of the Shell 1993 Pub. Is on Drugs
`of Limited Solubility ...............................................72
`
`5.
`
`'548 Patent .......................................................................75
`
`a)
`
`The '548 Patent Does Not Teach or Suggest
`Drug Release By "dissolution and diffusion" ..........75
`
`b) The '548 Patent Does Not Teach or Suggest
`"fed mode" ..............................................................76
`
`c)
`
`The '548 Patent Does Not Teach or Suggest "a
`drug whose solubility in water is greater than
`one part by weight of said drug in ten parts by
`weight of water"......................................................77
`
`d) The '548 Patent Does Not Teach Or Suggest A
`"polymeric matrix. . . that remains substantially
`intact until all of said drug is released"....................77
`
`VIII. NO COMBINATION OF REFERENCES PUT FORTH BY
`PETITIONER RENDERS THE INVENTIONS OF THE '280
`PATENT CLAIMS OBVIOUS ............................................................79
`
`
`
`- iii -
`
`
`
`A.
`
`The Product Claims Remain Nonobvious in View of
`Baveja, the '548 Patent, Shell 1993 Pub., and Shell '790
`Patent .........................................................................................79
`
`1.
`
`2.
`
`3.
`
`A Person of Ordinary Skill in the Art Would Not
`Combine Formulations Featuring Different Drug
`Release Mechanisms to Arrive at the Claimed
`Inventions with Any Reasonable Expectation of
`Success ............................................................................79
`
`The Asserted Prior Art References Do Not Teach or
`Suggest the Diffusion-Controlled Mechanism of the
`Product Claims ................................................................82
`
`The Asserted Prior Art Cannot Be Combined to
`Construct the Invention of the Product Claims, While
`at the Same Time Leaving Out Elements That
`Distinguish the Art from the Claimed Invention ..............85
`
`a) A Person of Ordinary Skill in the Art Would
`Not Combine Incompatible Prior Art
`Describing a Dosage Form That Does Not
`Maintain its Mechanical Integrity in Order to
`Achieve a Substantially Intact Dosage Form ...........85
`
`b) Both Shell 1993 Pub. and the Shell '790 Patent
`Do Not Teach or Suggest Critical Controlled
`Drug Release Characteristics ..................................86
`
`c) Baveja Is Also Irrelevant to Gastric Retention ........88
`
`B.
`
`Shell 1993 Pub., in View of Baveja and Colombo Does Not
`Render Method Claim 43 Obvious .............................................88
`
`1.
`
`2.
`
`The Combined Asserted Prior Art References Do Not
`Teach or Suggest the Diffusion-Controlled or
`Erosion-Controlled Mechanisms of the Method
`Claim ...............................................................................88
`
`A Person of Ordinary Skill in the Art Would Not
`Combine Formulations Featuring Different Drug
`Release Mechanisms to Arrive at the Claimed
`
`
`
`- iv -
`
`
`
`Inventions with Any Reasonable Expectation of
`Success ............................................................................89
`
`3.
`
`The Asserted Prior Art Cannot Be Combined to
`Construct the Invention of the Method Claim, While
`at the Same Time Leaving Out Elements That
`Distinguish the Art from the Claimed Invention ..............91
`
`a) Neither Colombo nor Baveja Teaches or
`Suggests a "polymeric matrix being one that . . .
`[is] swollen in a dimensionally unrestricted
`manner" as Required by Method Claim 43 ..............91
`
`b) Baveja and Colombo Are Also Irrelevant to
`Gastric Retention ....................................................92
`
`C.
`
`Secondary Considerations of Non-Obviousness .........................93
`
`1.
`
`2.
`
`3.
`
`Commercial Success ........................................................93
`
`Long-Felt But Unresolved Need ......................................94
`
`Skepticism and Unexpected Results .................................97
`
`
`
`
`
`- v -
`
`
`
`I, Harold B. Hopfenberg, Ph.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am the Camille Dreyfus Professor Emeritus of Chemical and
`
`Biomolecular Engineering at the North Carolina State University, Raleigh, North
`
`Carolina.
`
`2.
`
`I have more than 49 years of academic and practical experience in
`
`the chemical engineering and pharmaceutical industries, including 34 years as a
`
`consultant to the Alza Corporation, for whom I have provided guidance related to
`
`the research and development of a wide variety of pharmaceutical formulations
`
`and controlled drug delivery concepts and products. The Alza Corporation is
`
`widely recognized as a worldwide pioneer in the development of controlled drug
`
`delivery dosage forms.
`
`3.
`
`I received Bachelor's, Master's and Ph.D. degrees in chemical
`
`engineering from the Massachusetts Institute of Technology between 1960 and
`
`1965. After working at the Amicon Corporation and serving in the United States
`
`Army, I joined the faculty of the Department of Chemical Engineering at North
`
`Carolina State University ("NCSU") in 1967. For more than fifty years since I
`
`graduated from MIT, I have conducted research in applied surface, colloid, and
`
`polymer science, with special emphasis upon transport phenomena in polymeric
`
`films, membranes, and matrices used in pharmaceutical formulations and
`
`1
`
`
`
`controlled drug delivery systems for human and veterinary medicine. I have
`
`published more than 100 scientific articles and I have served for more than fifteen
`
`years on the editorial advisory boards of the Journal of Applied Polymer Science,
`
`and Polymer Engineering and Science. I also served for several years on the
`
`editorial advisory board of Gas Separation and Purification, and was a founding
`
`member of the editorial board of The Journal of Membrane Science. I have served
`
`three sequential terms on the Academic Advisory Council of the Industrial
`
`Research Institute.
`
`4.
`
`I am currently the Camille Dreyfus Professor Emeritus of Chemical
`
`and Biomolecular Engineering at NCSU. The Camille Dreyfus Professorship was
`
`established by endowment as a Distinguished Professorship, bestowed in
`
`recognition of outstanding scholarly achievement. Before joining the chemical
`
`engineering faculty of NCSU, I supervised research at the Amicon Corporation,
`
`Cambridge, Massachusetts, in the areas of applied industrial membrane
`
`separations, biomedical products based upon novel, swellable hydrogels, by-
`
`product recovery from pulp mill wastes, and applied colloid chemistry.
`
`5.
`
`I have also served in an administrative capacity at NCSU while
`
`pursuing my teaching and research. I was named Camille Dreyfus Professor and
`
`Head of the Department of Chemical Engineering in July 1980, and served as
`
`Department Head for seven years. I subsequently served as Associate Dean of
`
`2
`
`
`
`Engineering and Special Assistant to the Chancellor through June 1990. I also
`
`served as Executive Assistant to the Chancellor from 1990 through January 1992.
`
`6.
`
`I subsequently served for seven years as the founding Director of the
`
`William R. Kenan, Jr. Institute for Engineering, Technology & Science at NCSU.
`
`On September 1, 1999, I was named Director Emeritus of the Kenan Institute. I
`
`was appointed Camille Dreyfus Professor Emeritus of Chemical and Biomolecular
`
`Engineering, effective January 1, 2004.
`
`7.
`
`Throughout my career, my research and my publications have
`
`directly related to controlled drug delivery systems and to swellable polymers and
`
`their interaction with small molecules. Starting as early as my graduate research
`
`at MIT, I explored and expanded on the complex phenomena that attend the
`
`immersion of swellable polymers in liquids. As a result of my academic pursuits,
`
`I am familiar with the qualifications of the ordinarily skilled artisan in the fields of
`
`swellable polymers and controlled-release drug formulations.
`
`8.
`
`Over the past five decades, I have trained many graduate students
`
`and post-doctoral fellows. Many of my former students have made important
`
`contributions to the field of the relevant patents. An academic collaboration that
`
`is particularly relevant to my testimony in this case is research that I undertook
`
`supervising the thesis and post-graduate research of Dr. Antonio Apicella. The
`
`results of that collaboration are set forth in the publications cited in my curriculum
`
`3
`
`
`
`vitae (attached as Exhibit ("Exh.") 2016) as publication numbers 68, 69, 81, 84,
`
`89, 91, and 93. Professor Apicella has spent his career on the faculty of the
`
`University of Naples since departing my laboratory. He is the lead author on a
`
`prior art article cited on page one of Depomed, Inc.'s (hereinafter "Depomed")
`
`U.S. Patent No. 6,635,280 (" '280 Patent") – which is the patent addressed in this
`
`declaration.
`
`9.
`
`In addition to my tenure at North Carolina State University, in 1977,
`
`I was awarded a Senior Visiting Fellowship from the Science Research Council of
`
`the United Kingdom, and was appointed as a Visiting Fellow at Clare Hall of the
`
`University of Cambridge. I was a visiting professor at the University of Bologna
`
`in Italy in 1982 and 1984, and I participated in the "Invitation Program for Foreign
`
`Researchers" sponsored by the Japanese government in 1984, supporting an
`
`invited lecture tour throughout Japan. In 1984, I was appointed as the Xerox
`
`Lecturer in Chemistry at the University of British Columbia, Canada. In 1985, I
`
`was appointed by the United Nations Industrial Development Organization as a
`
`consultant to the National Chemical Laboratory of India in the general area of
`
`controlled-release of biologically active compounds. I returned to Italy as a
`
`visiting professor at the University of Naples in 1989, and to the University of
`
`Sassari in 1993. I was later elected a Visiting Fellow Commoner of Trinity
`
`4
`
`
`
`College, Cambridge, for the 1997-1998 academic year. I was appointed as the
`
`"Visiting Researcher for the Year 2000" at Kansai University in Osaka, Japan.
`
`10.
`
`I have received a number of awards during my career at North
`
`Carolina State University, including: The Sigma Xi research award at North
`
`Carolina State University as "Young Scientist of the Year" (1971); the Alcoa
`
`Foundation Engineering Research Achievement Award (1978); the Alcoa
`
`Foundation Distinguished Engineering Research Award (1980); the R.J. Reynolds
`
`Industries Award for Research, Teaching, and Extension (1985); and the
`
`Alexander Quarles Holladay Medal of Excellence from the Board of Trustees of
`
`North Carolina State University (1997).
`
`11.
`
`In addition to my experience as a university professor, I have had
`
`significant experience with pharmaceutical formulation in an industrial context,
`
`including the formulation of oral drug delivery dosage forms. I served as a
`
`consultant to the Alza Corporation for 34 years (from 1972 to 2006). The Alza
`
`Corporation was one of the early pioneers developing novel pharmaceutical
`
`formulations to accommodate specific temporal and spatial drug delivery
`
`requirements, including controlled release formulations. My role as a consultant
`
`to Alza ranged from concept development alongside senior technical management,
`
`to brainstorming with laboratory scientists (i.e., bench researchers), to
`
`experimental design, to the analysis of experimental data. I have been involved in
`
`5
`
`
`
`technology development related to many of Alza's commercial products. As a
`
`result of this consulting work over the course of more than 30 years, I have
`
`become knowledgeable about formulations of pharmaceutical products.
`
`12. Dr. Nicholas Peppas, Fletcher S. Pratt Chair in Engineering at the
`
`University of Texas-Austin, recognized me during his plenary lecture to the 2010
`
`Annual Meeting of the Controlled Release Society, in the context of my 34-year
`
`history of consulting for Alza, as among the "[e]xceptional [c]onsultants, inspiring
`
`leaders and pioneers of the field" of rationally-designed drug delivery systems.1
`
`Dr. Peppas further characterized my work as having made "[f]undamental
`
`contributions in swellable and biodegradable delivery systems."2 Others
`
`recognized by Dr. Peppas include luminaries in the field of controlled-release
`
`delivery systems including Drs. Takeru , Judah Folkman, Alejandro Zaffaroni,
`
`Felix Theuwees, Alan Michaels, Kumar Chandrasekaran, Patrick S. L. Wong,
`
`Donald R. Paul, and Allan S. Hoffman.3
`
`
`1 N.A. Peppas, Controlled Release 50 Years Later: Responsive Intelligence and
`Delivery by Design, Controlled Release Society 2010 Annual Meeting at slide 8
`(hereinafter "Peppas", attached as Exh. 2156); see also Program from the 37th
`Annual Meeting & Exposition of the Controlled Release Society (2010), at 33,
`bottom right (plenary lecture by Dr. Nicholas Peppas noted as among "Wednesday
`Program Highlights") (attached as Exh. 2157).
`
`6
`
` Peppas at slide 8 and 18, Exh. 2156.
`
` Id. at slides 4-8.
`
` 2
`
` 3
`
`
`
`13.
`
`In more recent years (since the mid-1990s), I have testified as an
`
`expert on controlled release drug dosage forms in at least 28 different patent
`
`litigation matters brought in the United States and Canada, and including 19
`
`matters involving oral drug dosage forms. My testimony in four of the cases
`
`involving oral drug dosage forms was on behalf of Depomed, involving the patent
`
`currently under review by the Board.
`
`14. My professional experience, education, and publications are
`
`presented in greater detail in my curriculum vitae, which is attached as Exh. 2016.
`
`II.
`
`SCOPE OF ASSIGNMENT AND APPROACH
`
`15.
`
`I have been retained as an expert on behalf of Patent Owner
`
`Depomed, Inc. ("Depomed") to provide information and opinions to the Patent
`
`Trial and Appeal Board (hereinafter "the Board") to assist in the determination of
`
`the validity of certain of Depomed's patent claims of the '280 Patent for which
`
`Inter Partes Review (hereinafter "IPR") proceedings have been instituted by the
`
`Board. Specifically, counsel for Depomed asked me to provide opinions
`
`regarding the validity of claims 1, 2, 8, 9, 13–15, 43, 45 and 46 of the '280 Patent
`
`(Exh. 1001) in view of certain prior art references cited by Petitioner Endo
`
`Pharmaceuticals, Inc. ("Endo").
`
`16.
`
`I have been informed by counsel and I understand that the analysis of
`
`whether a patent is obvious is performed from the perspective of a person of
`
`7
`
`
`
`ordinary skill in the art at the time of the patented inventions. The relevant
`
`timeframe for the patented inventions of the relevant claims of the '280 Patent is
`
`June 1997 for Claims 1, 2, 8, 9, 13–15, 45 and 46 ("Product Claims") and March
`
`1999 for Claim 43 ("Method Claim").
`
`17.
`
`In reaching the opinions expressed in this declaration for this
`
`proceeding, I adopt the claim constructions set forth below as understood by a
`
`person of ordinary skill in the art.
`
`18. A list of the documents and materials that I considered in connection
`
`with the development of my opinions set forth in this declaration is attached
`
`hereto as Exh. 2017. I have reviewed the documents cited by Dr. Wilson in his
`
`declaration. I intend the full-page range of all Exhibits attached to his declaration
`
`be considered as part of this declaration.
`
`19.
`
`I am being compensated for my time spent in connection with this
`
`matter at the rate of $700 per hour. My compensation is in no way contingent on
`
`the outcome of this case.
`
`20.
`
`To the extent that I am presented with new information concerning
`
`the subject matter of this declaration or affecting any assumptions made herein, I
`
`reserve the right to supplement this declaration accordingly.
`
`8
`
`
`
`III. APPLICABLE STANDARDS AND CONTROLLING PRINCIPLES
`
`A. Obviousness
`
`21.
`
`I have been informed by counsel and I understand that an issued
`
`patent claim is invalid as obvious if it can be shown that the differences between
`
`the patented subject matter and the prior art are such that the subject matter as a
`
`whole would have been obvious, at the time the invention was made, to a person
`
`having ordinary skill in the art. Relevant considerations include the level of
`
`ordinary skill in the art; the scope and content of the prior art; differences between
`
`the prior art and the claims at issue; and the so-called objective secondary factors
`
`of nonobviousness.
`
`22.
`
`I have been informed by counsel and I understand that, in order to
`
`evaluate the obviousness of any '280 Patent claim over a given prior art
`
`combination, I should analyze whether the prior art references, included
`
`collectively in the combination, disclose each and every element of the allegedly
`
`invalid claim as those references are read by the person of ordinary skill in the art
`
`at the time of the invention. Then I am to determine whether that combination
`
`makes the claims of the '280 Patent obvious to the person of ordinary skill in the
`
`art by a preponderance of the evidence, at the time of the inventions. I understand
`
`that such preponderance of the evidence is satisfied if the proposition is more
`
`likely to be true than not true.
`
`9
`
`
`
`23.
`
`I have been informed by counsel and I understand that the
`
`obviousness inquiry requires that the prior art be considered in its entirety. I am
`
`further informed and I understand that an invention cannot be obvious to try where
`
`"the breadth of the[] choices and the numerous combinations indicate that the[]
`
`disclosures would not have rendered the claimed invention obvious to try."
`
`24.
`
`I have been informed by counsel and I understand that even where
`
`all of the claim limitations are expressly disclosed in the prior art references, there
`
`must be some showing that a person of ordinary skill in the art would have been
`
`motivated to combine such prior art references and that there would have been a
`
`reasonable expectation of successfully achieving the claimed invention from such
`
`combination.
`
`25.
`
`I have been informed by counsel and I understand that, in
`
`considering the obviousness of a claimed invention, one should not view the
`
`invention and the prior art with the benefit of hindsight. It is for that reason, I am
`
`informed and I understand, that obviousness is assessed by the person of ordinary
`
`skill in the art at the time the invention was made. In this regard, I am informed
`
`and I understand that the invention cannot be used as a guide to selecting and
`
`understanding the prior art. I understand that the appropriate standard is to
`
`determine whether a person of skill in the art would be motivated to combine
`
`references, not whether they could.
`
`10
`
`
`
`26.
`
`I have been informed by counsel and I understand that obviousness
`
`cannot be predicated on what was unknown at the time of the invention, even if
`
`the inherency of a certain feature is later established. I have also been informed
`
`by counsel and I understand that unknown properties of the prior art may not be
`
`relied upon to provide the rationale for modifying or combining the prior art to
`
`reach the claimed subject matter.
`
`27.
`
`I have been informed by counsel and I understand that a reference
`
`may be said to teach away when a person of ordinary skill, upon reading the
`
`reference, would be discouraged from following the path set out in the reference,
`
`or would be led in a direction divergent from the path that was taken by the
`
`applicant.
`
`28.
`
`I am informed by counsel and I understand that the "time of
`
`invention" applicable to the inventions of the Product Claims of the '280 Patent is
`
`no later than June 6, 1997 (which I understand to be the earliest priority date of
`
`the parent application resulting in the '280 Patent) and the inventions of the
`
`Method Claim of the '280 Patent is no later than March 29, 1999 (which I
`
`understand to be the filing date of the related '475 Patent application).
`
`B.
`
`29.
`
`Person of Ordinary Skill in the Art
`
`I have been informed by counsel and I understand that the "person of
`
`ordinary skill in the art" is a hypothetical person who is presumed to be familiar
`
`11
`
`
`
`with the relevant scientific field and its literature at the time of the invention. This
`
`hypothetical person is also a person of ordinary creativity capable of
`
`understanding the scientific principles applicable to the pertinent field.
`
`30.
`
`I am informed by counsel and I understand that the level of ordinary
`
`skill in the art may be determined by reference to certain factors, including (1) the
`
`type of problems encountered in the art, (2) prior art solutions to those problems,
`
`(3) the rapidity with which innovations are made, (4) the sophistication of the
`
`technology, and (5) the educational level of active workers in the field.
`
`31.
`
`It is my opinion that the person of ordinary skill in the art in the field
`
`of the '280 Patent would have a formal education of at least a bachelor's degree in
`
`the fields of chemistry, chemical engineering, pharmaceutical science, and/or
`
`material science with a focus on polymer science, combined with substantial
`
`experience in development of controlled-release drug dosage forms (even more
`
`desirably controlled-release oral dosage forms). Alternatively, if the person had
`
`obtained a Ph.D. in any of the relevant fields, the required amount of experience
`
`would decline to about two years.
`
`32. Based on my training and experience, I believe that I am (and was as
`
`of June 1997 and as of March 1999) a person of greater than ordinary skill in the
`
`relevant art, which permits me to give an opinion about the qualifications of one
`
`of ordinary skill at the time of the invention.
`
`12
`
`
`
`33.
`
`I note that Dr. Wilson's opinion on person of ordinary skill in the art
`
`in his declaration is (Exh. 1011 at ¶ 23):
`
`a POSA in that art would have formal education of at least a
`bachelor's degree in chemistry, chemical engineering, pharmaceutical
`science and/or material science, as well as substantial experience (for
`example, at least several years of industrial or academic work) in the
`design and/or development of controlled-release oral drug dosage
`forms. In addition, since the '280 patent describes that its dosage
`forms, when administered to a patient, swell to achieve gastric
`retention and achieve a therapeutic effect, it is my opinion that a
`POSA would also possess, or have access to, the skill of a
`pharmacologist familiar with how such medicines work in the body.
`And further, the POSA would have experience, or access to other
`persons with experience, in the field of pharmacology, with particular
`emphasis on the pharmacokinetics and pharmacodynamics of oral
`drugs absorbed in the GI tract.
`
`34. My opinions stated in this declaration would be the same if rendered
`
`from the perspective of a person of ordinary skill in the art set out by Dr. Wilson.
`
`IV. SUMMARY OF MY OPINIONS
`
`35.
`
`In this declaration I explain that the person of ordinary skill in the art
`
`understands, and I conclude, that the Product Claims of the '280 Patent (Exh.
`
`1001) remain nonobvious in view of S.K. Baveja et al., "Zero-order release
`
`hydrophilic matrix tablets of β-adrenergic blockers," International Journal of
`
`Pharmaceutics, 39 (1987) 39-45 (Exh. 1008) ("Baveja"), U.S. Patent No.
`
`4,871,548 (Exh. 1006) (" '548 Patent"), International Patent Publication No. WO
`
`93/18755 (Exh. 1007) ("Shell 1993 Pub."), and U.S. Patent No. 5,007,790 (Exh.
`
`1005) ("Shell '790 Patent").
`
`13
`
`
`
`36.
`
`In this declaration, I explain that the person of ordinary skill in the
`
`art understands, and I conclude, that the Method Claim of the '280 Patent (Exh.
`
`1001) remain nonobvious in view of the Shell 1993 Pub. (Exh. 1007) in view of
`
`Baveja (Exh. 1008) and P. Colombo et al., "Drug release modulation by physical
`
`restrictions of matrix swelling," International Journal of Pharmaceutics, 63
`
`(1990) 43-48 ("Exh. 1009") ("Colombo").
`
`V. GENERAL TECHNOLOGY BACKGROUND
`
`A. The '280 Patent Claims a Novel Gastric Retentive, Controlled-
`Release Drug Dosage Form
`
`37.
`
`The inventions of the '280 Patent relate generally to formulations for
`
`drugs, also known as "drug dosage forms," which "benefit from a prolonged time
`
`of controlled release in the stomach and upper gastrointestinal (GI) tract." Exh.
`
`1001 ('280 Patent) at Col. 1:12-14. Dosage forms are directed to a variety of
`
`routes of administration including, for example, intravenous or intramuscular
`
`injections, tablets or capsules for oral administration, patches that adhere to the
`
`skin for administration of drugs across the skin, and suppositories for rectal
`
`administration. The inventions of the '280 Patent relate to an oral drug dosage
`
`form (i.e., a dosage form that is swallowed or ingested), which consists typically
`
`of one or more tablets. Oral drug dosage forms typically contain one or more
`
`"excipients" in addition to an active pharmaceutical ingredient (the drug).
`
`Excipients are biologically inactive components that provide desirable
`
`14
`
`
`
`characteristics to the dosage form. Some excipients, such as binders, disintegrants
`
`and lubricants, do not contribute to the control of release of the biologically active
`
`ingredient (the drug) from the dosage form. Others, termed "release controlling
`
`excipients," contribute to or actually control the release of drug from the dosage
`
`form.
`
`38.
`
`The primary objectives of the invention of the '280 Patent was to
`
`control the duration of drug release and to determine the location of delivery in the
`
`patient's body (e.g., where the active ingredient is released from the dosage form).
`
`Claim 1 of the '280 Patent is directed towards drugs that are highly soluble or
`
`freely soluble in water. Claim 1 of the '280 Patent recites "a drug whose solubility
`
`in water is greater than one part by weight of said drug in ten parts by weight of
`
`water." See Figure 1 below.
`
`
`
`Figure 1
`
`15
`
`
`
`39.
`
`"Controlled release" dosage forms, such as those described in the
`
`'280 Patent, are quite different from "immediate release" dosage forms. With
`
`respect to immediate release dosage forms, the patents explain that "[d]rugs that
`
`are administered in the form of conventional tablets or capsules become available
`
`to body fluids at a rate that is initially very high, followed by a rapid decline."
`
`Exh. 1001 ('280 Patent) at Col. 1:30-33. The problem with conventional
`
`immediate release dosage forms is that they can result in a transient overdose,
`
`followed by a long period of underdosing to the patient. Id. at Col. 1:33-35. The
`
`pharmacokinetic profile corresponding to immediate release, revealing overdosing
`
`and underdosing, is described graphically in Figure 2. Figure 2 further illustrates
`
`how a controlled release dosage form avoids these problems by achieving a more
`
`uniform and prolonged delivery of drug to the patient. The vertical axis of the
`
`graph in Figure 2 represents the concentration of active ingredient found in a
`
`patient's blood plasma while the horizontal axis represents the passage of time
`
`after ingestion.
`
`16
`
`
`
`Figure 2
`
`
`
`40. A variety of controlled release dosage forms have been developed
`
`since the 1970's. The controlled release oral dosage form, described in the '280
`
`Patent, comprises drug dispersed within a polymeric matrix.
`
`41. A polymer is a very large molecule made up of many repeating
`
`subunits. An array of polymeric molecules forms a polymeric matrix. The
`
`polymeric matrix described in the '280 Patent has a special property of being able
`
`to absorb or imbibe water, thereby causing the dosage form to increase in size and,
`
`in turn, slow the rate of release of drug, controlled by diffusion, from t
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