UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Taro Pharmaceuticals U.S.A., Inc.,
`
`v.
`
`Apotex Technologies, Inc.
`
`Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`
`
`
`DECLARATION OF JAYESH MEHTA, M.D., IN SUPPORT OF THE
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 7,049,328 B2
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 3
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 3
`II.
`III. LEGAL PRINCIPLES ..................................................................................... 6
`A. Claim Construction ........................................................................................ 6
`B.
`Invalidation .................................................................................................... 7
`i. Prior Art ........................................................................................................ 8
`ii. Anticipation ................................................................................................... 8
`iii. Obviousness .................................................................................................. 9
`IV. BACKGROUND SCIENTIFIC INFORMATION ....................................... 10
`A. Thalassemia and Red Blood Cells ............................................................... 10
`B. Treating Thalassemia Leads to Iron Overload ............................................ 10
`C. Treating Iron Overload with Iron Chelators ................................................ 11
`V.
`LEVEL OF ORDINARY SKILL IN THE ART ........................................... 20
`VI. U.S. PATENT NO. 7,049,328 ....................................................................... 20
`A. The Claims of the ’328 Patent ..................................................................... 20
`B. The Specification in the ’328 Patent ........................................................... 26
`C.
`Prosecution History of the ’328 Patent ....................................................... 28
`VII. CLAIM CONSTRUCTION .......................................................................... 29
`VIII. GROUNDS FOR INVALIDITY ................................................................... 33
`A. Claims 1–11, 13–17 and 19 Are Anticipated .............................................. 33
`B. Claims 1–17 and 19 Are Obvious ............................................................... 43
`C.
`Secondary Considerations ........................................................................... 46
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`I, Jayesh Mehta, M.D., declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I have been retained by Taro Pharmaceuticals U.S.A., Inc., in
`
`connection with its petition for inter partes review of U.S. Patent No. 7,049,328
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`(Ex. 1001) (“the ’328 Patent”). The statements set forth in this declaration are
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`based on my own personal knowledge. Although I am being compensated for the
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`time spent preparing this declaration, my compensation is not contingent on the
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`outcome of this proceeding, the related litigation, or on any of the opinions
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`provided below. I have no financial interest in these proceedings.
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`2.
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`The opinions set forth in this declaration are my own. My opinions
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`are based on many years of experience in the field of hematology and oncology,
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`teaching medical students, residents and fellows, and treating patients with
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`malignant and non-malignant hematologic diseases. In forming my opinions, I
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`also relied on the documents discussed in this declaration.
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`II.
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`BACKGROUND AND QUALIFICATIONS
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`3.
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`I hold an M.D. and I am a Professor of Medicine and Director of the
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`Hematopoietic Stem Cell Transplant Program at the Northwestern University
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`Feinberg School of Medicine, a position I have held since 2000. I am also Deputy
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`Director of the Northwestern University Comprehensive Transplant Center and
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`have held this position since 2010. I have extensive experience as a hematologist
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`working with patients who have a range of blood disorders, and I have experience
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`with the use of iron chelators.
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`4.
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`Prior to joining Northwestern University, from 1999–2000, I was a
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`Professor of Medicine and Clinical Director of the Division of Transplantation
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`Medicine, and Director of the Myeloma and Lymphoma Program, at the South
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`Carolina Cancer Center and Palmetto Richland Memorial Hospital, University of
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`South Carolina. From 1996–1999, I was an Associate Professor of Medicine and
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`Chief of the Section of Allogeneic Stem Cell Transplantation (1998–1999) in the
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`Myeloma and Transplantation Research Center at the University of Arkansas for
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`Medical Sciences.
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`5.
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`I performed fellowships in the Department of Bone Marrow
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`Transplantation and Cancer Immunobiology at the Hadassah University Hospital in
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`Jerusalem, Israel, from 1991–1992, and in the Leukemia and Myeloma Units in the
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`Department of Medical Oncology at the Royal Marsden Hospital in London,
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`England, from 1992–1996. I was also a lecturer in Hematology at the Seth GS
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`Medical College and King Edward VII Memorial Hospital, in Mumbai, India, in
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`1990.
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`6.
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`I received an M.B.B.S. (a first medical degree) from Bombay
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`University, India, in 1985 and an M.D. in internal medicine from Bombay
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`University in 1990. I practiced clinical hematology in India from 1989-1991.
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`7.
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`I am board certified in internal medicine and hematology and licensed
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`to practice medicine in Illinois.
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`8.
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`I currently treat patients for various blood disorders and also conduct
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`research in the areas of hematopoietic stem cell transplantation, use of
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`hematopoietic stem cells for experimental and clinical tissue repair, multiple
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`myeloma, and opportunistic infections in immunocompromised patients. While
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`practicing in India from 1989-1991, I was directly involved with the care of several
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`transfusion-dependent patients who received deferiprone. These patients were
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`treated with a regimen of deferiprone at a dose range of 75 to 99 mg/kg of body
`
`weight per day. Some of my work from this time period has been published. See,
`
`for example, Mehta J. et al., Autoantibodies in Thalassaemia Major: Relationship
`
`with Oral Iron Chelator L1, J. ASSOC. PHYSICIANS INDIA, 1993, 41(6):339–41 (Ex.
`
`1031). Even after leaving India to practice in Jerusalem, Israel, and London, UK, I
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`continued to collaborate with my Indian colleagues and thus continued be involved
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`with the treatment of these patients through 1995. Since 1995, I have treated many
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`additional patients with iron chelators including deferiprone, and continued to
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`follow the clinical literature describing treatment of blood transfusion-dependent
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`patients with deferiprone. I have always prescribed deferiprone to transfusion-
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`dependent patients in a dose range of 75 to 99 mg/kg of body weight per day.
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`9.
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`I have authored over 280 articles in peer-reviewed journals, including
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`in the area of hematology. In particular, I have frequently published in the field of
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`iron overload and iron chelation. See, e.g. Mehta et al., Deaths in Patients
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`Receiving Oral Iron Chelator L1, BR. J. HAEMATOL. 1993, 85:430–31 (Ex. 1033);
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`Mehta et al., Deferiprone in Iron Overload, N. ENGL. J. MED. 1995, 333:597–99
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`(Ex. 1034); Mehta et al., Oral Iron Chelator L1 and Autoimmunity, BLOOD 1993,
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`81:1970–71 (Ex. 1035).
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`10.
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`I am on the editorial boards for several journals, including Biology of
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`Blood and Marrow Transplantation. I am also a reviewer for several journals,
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`including JAMA.
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`11. A full description of my background and qualifications can be found
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`in my curriculum vitae (Ex. 1003).
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`III.
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`LEGAL PRINCIPLES
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`12.
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`I am not an attorney. For purposes of this declaration, I have been
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`informed about certain aspects of the law that are relevant to my analysis and
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`opinions, as set forth below.
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`A.
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`13.
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`Claim Construction
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`I understand that, in a proceeding such as this, the claims of an
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`unexpired patent are given their broadest reasonable interpretation in view of the
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`patent specification, as understood by one of “ordinary skill in the art” (which I
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`discuss below) and consistent with what the patent says.
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`14.
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`I also understand that under a broadest reasonable interpretation,
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`words of the claim must be given their plain meaning—i.e., the ordinary and
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`customary meaning given to the words by those of ordinary skill at the time of the
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`invention—unless such meaning is inconsistent with the specification of the patent.
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`15.
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`I understand that an “independent claim” is a stand-alone claim
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`containing a set of elements or “limitations,” and that a dependent claim refers
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`back to one or more independent claims, recites new limitations, and incorporates
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`all of the limitations in the independent claim(s) to which it refers. I further
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`understand that an independent claim therefore must be at least as broad as all
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`dependent claims that depend upon it. Furthermore, I have been informed that a
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`dependent claim that refers back to more than one other claim is called a “multiple
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`dependent claim.”
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`B.
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`16.
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`Invalidation
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`I understand that a claim is invalid as “anticipated” or “obvious” if all
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`of the limitations of that claim were known in the “prior art,” as described below. I
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`have been advised that invalidating a claim in multiple dependent form only
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`requires showing that any one of the claimed dependencies is invalid.
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`i.
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`Prior Art and Person of Ordinary Skill in the Art
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`17.
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`I have been instructed to assume for purposes of my analysis that June
`
`30, 2000, is the relevant date for determining what is “prior art.” In other words, I
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`should consider as “prior art” anything publicly available prior to June 30, 2000. I
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`have been instructed to rely only on patents and printed publications for prior art
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`purposes.
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`18.
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`I understand that a “person of ordinary skill in the art” is a
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`hypothetical person who is presumed to have knowledge of all of the relevant prior
`
`art.
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`ii.
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`Anticipation
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`19.
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`I understand that a patent claim is anticipated if a single prior art
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`document describes every element of the claim such that a person of ordinary skill
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`(as discussed below) could practice the claimed method without undue
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`experimentation.
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`20.
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`I understand that anticipation may be by express disclosure in the
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`prior art. I also understand that if the prior art reference does not expressly set
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`forth a particular claim element, the prior art may still anticipate if that element is
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`“inherent” in its disclosure, that is, if it is necessarily found in the prior art. A
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`property is inherent in the prior art even if one of ordinary skill in the art would not
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`have appreciated that property as of the date of that prior art.
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`21.
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`In particular, I have been told that the discovery of a new property or
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`advantage of an old method does not prevent the old method from being
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`anticipated. In other words, if a particular method of use of a known compound or
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`composition is itself known in the prior art, then discovery of new properties of
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`that method of use does not render the method novel.
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`iii. Obviousness
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`22.
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`I understand that a patent claim is obvious if the differences between
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`what is set forth in the claims and what is discussed in the prior art are such that
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`what is claimed would have been obvious to a person of ordinary skill (as defined
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`below) at the relevant time, which I have been told is June 30, 2000.
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`23.
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`I understand that a person of ordinary skill in the art is a hypothetical
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`person presumed to have knowledge of all of the relevant prior art.
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`24.
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`I understand that as part of my analysis of whether a given patent
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`claim is obvious, I should consider: (i) what the prior art says; (ii) the level of
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`ordinary skill in the art; (iii) the differences between what is claimed and the prior
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`art; and (iv) any “secondary considerations” that may indicate that the claims are
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`not obvious.
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`25.
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`I understand that the secondary considerations which are relevant to
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`an obviousness analysis include: (i) commercial success of a product due to the
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`merits of what is provided in the patent claim; (ii) a long-felt but unsolved need for
`
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`the solution provided by the patent claim; (iii) unsuccessful attempts by others to
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`find the solution provided by the patent claim; (iv) copying by others of what is
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`claimed in the patent; (v) unexpected results that arise from what is provided in the
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`patent claim; (vi) industry skepticism regarding what is provided in the patent
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`claim; and (vii) acceptance by others of what is provided in the patent claim as
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`shown by praise from others in the field.
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`IV.
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`BACKGROUND SCIENTIFIC INFORMATION
`
`A.
`
`26.
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`Thalassemia and Red Blood Cells
`
`Thalassemia major (“thalassemia”) is an inherited form of severe
`
`anemia arising from two defective genes that affect the development of red blood
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`cells. Without treatment, the expected lifespan for patients with thalassemia is
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`around 15 or 16 years.
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`B.
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`Treating Thalassemia Leads to Iron Overload
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`27. Because patients with thalassemia have defective red blood cells, they
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`have to be treated with frequent blood transfusions that provide healthy red blood
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`cells to the patient. Patients with thalassemia major must receive frequent and
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`regular blood transfusions their entire lives and are therefore called “transfusion-
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`dependent.” People with thalassemia intermedia, a slightly milder form of the
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`disease, normally receive blood transfusions periodically, and are usually not
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`transfusion-dependent.
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`28. Hemoglobin, the substance in red blood cells that carries oxygen,
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`contains iron. As a result, blood transfusions deposit iron in the body. The body
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`cannot remove iron through normal physiologic processes, and over time a
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`condition called “iron overload” develops in recipients of frequent blood
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`transfusions. High levels of iron in the blood result in iron accumulating in various
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`bodily tissues, including the heart, liver and endocrine glands, causing various
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`diseases. Ex. 1017 (Barman Balfour 19991) at 557–58. Left untreated, iron
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`overload also causes organ dysfunction.
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`29. Without treatment to reduce iron overload, patients die prematurely,
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`most commonly due to heart disease. Id. It is the accumulation of iron in the heart
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`that is responsible for the heart disease so often experienced by patients with iron
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`overload. See Ex. 1024 (Olson 19892) at 116.
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`C.
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`Treating Iron Overload with Iron Chelators
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`30. As discussed above, left untreated, iron overload is fatal. Treating
`
`iron overload requires administration of an agent that binds to iron and removes it
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`1 Barman Balfour & Foster, Deferiprone: A Review of its Clinical Potential in Iron
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`Overload in (cid:533)-Thalassemia Major and Other Transfusion-Dependent Diseases,
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`DRUGS 58(3):553–78, 1999 (“Barman Balfour 1999,” Ex. 1017).
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`2 Olson et al., Endomyocardial Biopsy in Hemochromatosis: Clinicopathologic
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`Correlates in Six Cases, JACC, 13(1):116–20, 1989 (“Olson 1989,” Ex. 1024).
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`from the body in this bound state. An agent that binds to iron is called an “iron
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`chelator.” All iron-overloaded patients, that is, all transfusion-dependent patients,
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`must be treated with an iron chelator in order to prevent disease, treat disease,
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`reduce iron load and reduce dysfunction in any organs affected by iron overload.
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`See, e.g., Ex. 1028 (McDonald 19663) at 563.
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`31. Years of clinical experience have proven that certain symptoms of
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`iron overload, such as heart failure and liver failure (cirrhosis), can be significantly
`
`improved by the continual presence of chelator in the blood. See, e.g., Ex. 1014
`
`(Olivieri 19944) at 574 and Ex. 1017 (Barman-Balfour 1999) at 557–58. Indeed,
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`iron-chelation therapy, widely used since the 1970s, has dramatically altered the
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`prognosis of patients with thalassemia major, most of whom would die
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`prematurely of heart failure or other disease without this therapy. See, e.g., Ex.
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`1017 (Barman-Balfour 1999) at 557.
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`3 McDonald, Deferoxamine and Diethylenetriaminepentaacetic Acid (DTPA) in
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`Thalassemia, THE JOURNAL OF PEDIATRICS 69(4):563–71, 1966 (“McDonald
`
`1966,” Ex. 1028).
`
`4 Olivieri et al., Survival in Medically Treated Patients with Homozygous (cid:533)-
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`Thalassemia, THE NEW ENGLAND JOURNAL OF MEDICINE, 331:574–78, 1994
`
`(“Olivieri 1994,” Ex. 1014).
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`32.
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`The first iron chelator used in clinical applications, desferrioxamine
`
`(“DFO”), was introduced in the early 1960s. See Ex. 1022 (Diav-Citrin 19975) at
`
`235. In the mid-1990s, a typical DFO regimen consisted of subcutaneous infusion
`
`of DFO at the dose of 20 to 40 mg per kg of the patient’s body weight per day
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`(“mg/kg/day”) over 8 to 12 hours, between 5 and 7 times per week. See id. at 235.
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`33. Constant subcutaneous infusions require the presence of a needle
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`beneath the skin and a pump to infuse the drug at a controlled rate. This process is
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`costly and poses significant discomfort and inconvenience to patients. See Ex.
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`1017 (Barman-Balfour 1999) at 554. The necessity for prolonged and frequent
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`subcutaneous therapy is a major drawback of treatment with DFO. See Ex. 1019
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`(Kontoghiorghes 19916) at 1279. In addition to the inconvenience of long nightly
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`infusions, patients often suffer from injection site reactions such as pain, swelling,
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`burning, and irritation. Skin rashes may also result. This side effect profile and
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`the intrusive dosing regimen causes non-compliance in many patients, in
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`particular, adolescents and young adults. Patients who are non-compliant become
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`5 Diav-Citrin & Koren, Oral Iron Chelation with Deferiprone, NEW FRONTIERS IN
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`PEDIATRIC DRUG THERAPY, 44(1):235–47, 1997 (“Diav-Citrin 1997,” Ex. 1022).
`
`6 Kontoghiorghes, Oral Iron Chelation is Here, BMJ, 303:1279–80, 1991
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`(“Kontoghiorghes 1991,” Ex. 1019)
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`more heavily overloaded and eventually die from this iron overload, most
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`commonly from cardiac disease.
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`34. Because of the problems associated with DFO therapy, researchers
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`pursued the development of other clinically active chelators, and were particularly
`
`interested in oral agents. In fact, researchers and physicians met yearly, beginning
`
`in 1990, at an International Conference on Oral Chelators in the Treatment of (cid:69)-
`
`Thalassemia and Other Diseases, for the express purpose of furthering research in
`
`this area. Although I did not attend these meetings, I am aware that they were
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`well-attended, attracting some 200–300 attendees annually.
`
`35. Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) (“L1”) is an oral
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`iron chelator that was patented in 1985 by Professor Robert C. Hider of King’s
`
`College, London. See Ex. 1021 (GB-2118176, “Hider Patent”). The Hider patent
`
`suggests the administration of deferiprone in oral dosage form for the treatment of
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`iron overload. Id. at 1:31–34 and 5:24–27. Deferiprone was first approved for
`
`human use in India in 1995. See, e.g., Ex. 1022 (Diav-Citrin 1997) at 243; see also
`
`Ex. 1009 (MIMS 19987) and Ex. 1025 (Kontoghiorghes 20008). It was approved in
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`7 Monthly Index of Medical Specialties, Vol. 18, No. 12, December 1998 (“MIMS
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`1998”, Ex. 1009).
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`1999 in Europe for patients with thalassemia major when DFO therapy is
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`contraindicated or inadequate. See Ex. 1025 (Kontoghiorghes 2000). Deferiprone
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`was approved in the United States by the FDA in 2011 for “the treatment of
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`patients with transfusional iron overload due to thalassemia syndromes when
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`current chelation therapy is inadequate.” Ex. 1023 (Deferiprone Label 20119).
`
`36. Deferiprone is a bidentate molecule, which means that it can donate
`
`two electrons to a metal atom. Since one iron atom requires six electrons to be
`
`completely bound, three deferiprone molecules are required to form a complex
`
`with one iron atom. See Ex. 1022 (Diav-Citrin 1997) at 236. In contrast, DFO is a
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`hexadentate molecule, which can donate six electrons. Thus, only one DFO
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`molecule is needed to chelate an iron atom. Deferiprone has a short half-life,
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`which means that, to be effective, the drug must be taken multiple times every day.
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`Some patients treated with deferiprone develop dangerously low level of white
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`blood cells. This side effect, called agranulocytosis, is potentially life-threatening
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`because it causes increased vulnerability to infections. Some physicians therefore
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`8 Kontoghiorghes et al., L1-Deferiprone Worldwide Update and New Strategies for
`
`Improving its Therapeutic Efficiency, Millennium ICOC Limassol 22–26 March
`
`2000 (“Kontoghiorghes 2000,” Ex. 1025).
`
`9 Prescribing Information for Ferriprox® (deferiprone) tablets, for oral use
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`(Revised 10/2011) (“Deferiprone Label 2011,” Ex. 1023).
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`only prescribe deferiprone when DFO treatment is contraindicated. However,
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`despite the inefficiencies of deferiprone compared with DFO and its possible side
`
`effects, many patients and doctors prefer deferiprone to DFO because it is easier to
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`comply with an oral medication regimen than with the difficult DFO regimen.
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`Despite the need for multiple doses daily and the potential side effects of
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`deferiprone, by 2000, more than 6000 patients in 40 countries had been using
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`deferiprone for more than 12 years. See Ex. 1025 (Kontoghiorghes 2000).
`
`37. As I discussed above, without chelation, iron-overloaded patients will
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`invariably die prematurely, most commonly from cardiac disease. Clinical
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`experience has shown that treatment with 75 mg/kg/day of deferiprone is effective
`
`at maintaining a non-toxic level of iron in the blood of transfusion-dependent
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`patients, thereby treating iron overload. For example, Agarwal 200010 (Ex. 1011)
`
`describes the “largest and longest” clinical experience with deferiprone, spanning
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`from 1989 until 2000, shortly before the application for the ’328 Patent was filed.
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`Twenty-two patients had been continuously treated with deferiprone during this
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`12-year period (aside for a period of approximately 16 months when deferiprone
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`10 Agarwal, Deferiprone (Kelfer): A Report of 22 Patients Who Have Taken It For
`
`Over a Decade, 10TH INTERNATIONAL CONFERENCE ON ORAL CHELATORS IN THE
`
`TREATMENT OF THALASSEMIA AND OTHER DISEASES AND BIOMED MEETING, March
`
`2000 (“Agarwal 2000,” Ex. 1011).
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`was not available because the clinical trial had completed and the drug was not yet
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`approved for marketing). Ex. 1011 (Agarwal 2000). None of these patients
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`succumbed to the cardiac disease that results in transfusion-dependent patients
`
`without adequate chelation. Id. Agarwal 2000 describes the efficacy of
`
`deferiprone as “excellent.” The inventors named on the ’328 Patent were aware of
`
`the study reported in Agarwal 200011; that study is identified in a list of “technical
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`articles” included in the ’328 Patent. Ex. 1001 at Page 2. The dose of 75
`
`mg/kg/day continues to be the recommended dose to treat iron overload. See, e.g.,
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`Ex. 1023 (Ferriprox Label, 2011).
`
`38. Other articles similarly report on the success of deferiprone as an iron
`
`chelator for transfusion-dependent patients. Olivieri 199512 (Ex. 1012) reports that
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`transfusion-dependent patients who had been inadequately chelated with DFO
`
`experienced reduced iron blood levels after treatment with deferiprone. Ex. 1012
`
`11 Agarwal 2000 was published in a Program Book in conjunction with the 10th
`
`International Conference on Oral Chelators, which took place in March 2000, in
`
`Cyprus. This Program Book was distributed shortly before the conference and on
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`site to all attendees – as is usual with conference Program Books.
`
`12 Olivieri et al., Iron-Chelation Therapy with Oral Deferiprone in Patients with
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`Thalassemia Major, N. ENGL. J. MED., 332:918–22, 1995 (“Olivieri 1995,” Ex.
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`1012).
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`(Olivieri 1995) at 919. Prior to treatment with deferiprone, these patients had
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`blood iron levels that are associated with increased risk of cardiac disease and early
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`death. Id. at 921. The data in Olivieri 1995 “provide direct evidence of the
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`efficacy of deferiprone for the treatment of iron overload in patients with
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`thalassemia major. Deferiprone decreases body iron concentrations and maintains
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`them at levels below those associated with the complications of iron overload.” Id.
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`at 922.13
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`39. A review article written in 1997 reports on studies suggesting that
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`deferiprone successfully reduces iron levels to those associated with cardiac-
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`disease-free survival. Ex. 1022 (Diav-Citrin 1997) at 239. In particular, this
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`article reports that at least one patient with established iron-related cardiomyopathy
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`(i.e., heart disease) experienced improvement in cardiac function following
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`13 Olivieri 1995 was published in April 1995 in The New England Journal of
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`Medicine. The New England Journal of Medicine was a prestigious journal as of
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`2000 and was regularly read by persons of ordinary skill in the art. Olivieri 1995 is
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`listed in the ’328 Patent specification as “technical literature” of which the patent
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`applicants were aware.
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`treatment with deferiprone. Id.; see also Ex. 1005 (Olivieri 199214); Ex. 1030
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`(Matsui15) (discussing a reduction of cardiac iron in a patient with established
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`cardiac disease).
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`40.
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`Since the most common cause of death in transfusion-dependent
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`patients is cardiac disease, researchers have focused on the ability of deferiprone
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`and other chelators to prevent and reverse heart disease. In addition to the data
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`reported in studies regarding individual patients described above, Faa 199916 (Ex.
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`1026) reports that in vitro studies had recently demonstrated the ability of
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`deferiprone to remove excess iron from heart cells. Ex. 1026 (Faa 1999) at 301.
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`Faa 1999 further reports that MRI evidence showed reduction of iron stores in the
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`heart due to treatment with deferiprone. Id.
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`14 Olivieri et al., Reduction of Tissue Iron Stores and Normalization of Serum
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`Ferritin During Treatment with the Oral Iron Chelator L1 in Thalassemia
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`Intermedia, BLOOD, 79(10):2741–48, 1992 (“Olivieri 1992,” Ex. 1005).
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`15 Matsui, Effective Iron Chelation Using the Oral Iron Chelator 1,2,-dimethyl-3-
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`hydroxypyrid-4-one (L1), in Homozygous b-Thalassemia Major (HBT) Patients,
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`Abstract P1-43, Clinical Pharmacology & Therapeutics, 53(2) (1993).
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`16 Faa & Crisponi, Iron Chelating Agents in Clinical Practice, COORDINATION
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`CHEMISTRY REVIEWS, 184:291–310, 1999 (“Faa 1999,” Ex. 1026).
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`V.
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`LEVEL OF ORDINARY SKILL IN THE ART
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`41.
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`I have been asked my opinion concerning the qualifications and
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`experience of a person of ordinary skill in the art pertaining to the ’328 Patent as of
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`June 30, 2000. As of June 2000, physicians had been treating iron overload in
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`blood-transfusion-dependent patients with iron chelators for decades. The art of
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`treating iron overload using iron chelators was very mature, and the level of
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`ordinary skill in the art was relatively high in 2000. A person of ordinary skill in
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`the art would have had an M.D. and several years of clinical work experience in
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`hematology, and would have had research, clinical, and/or testing experience with
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`iron chelators to treat iron overload in the body, including iron overload of the
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`heart. The skilled person would have been familiar with blood disorders such as
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`thalassemia or hemochromatosis,17 including their causes and treatments.
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`VI.
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`U.S. PATENT NO. 7,049,328
`
`A.
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`42.
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`The Claims of the ’328 Patent
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`The ’328 Patent includes 20 claims in total, 10 of which are
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`independent. Independent claims 1-10 are reproduced below:
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`1. A method of treating iron induced cardiac disease in a blood
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`transfusion dependent patient experiencing an iron overload condition of
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`17 Hemochromatosis is a genetic disorder that causes the body to load too much
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`iron.
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`20
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`the heart, said method comprising administering to the patient a
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`therapeutically effective amount of deferiprone or a physiologically
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`acceptable salt thereof sufficient to stabilize/reduce iron accumulation in
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`the heart resulting from being transfusion dependent.
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`2. A method of treating iron loading in the heart of a blood transfusion
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`dependent patient experiencing an iron overload condition of the heart,
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`said method comprising administering to the transfusion dependent
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`patient a therapeutically effective amount of deferiprone or a
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`physiologically acceptable salt thereof sufficient to reduce further iron
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`overload in the heart normally associated with iron induced cardiac
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`disease.
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`3. A method of treating iron loading in the heart of a blood transfusion
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`dependent patient risking iron overload of the heart, comprising the
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`administration of a therapeutically effective amount of deferiprone or a
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`physiologically acceptable salt thereof to the patient.
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`4. A method of stabilizing iron induced heart disease in blood
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`transfusion dependent patients having iron overload, comprising the
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`administration of a therapeutically effective amount of deferiprone or a
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`physiologically acceptable salt thereof sufficient to treat the iron burden
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`in the heart normally associated with iron induced cardiac disease.
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`5. A method of reducing the iron burden in the heart associated with iron
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`induced heart disease in blood transfusion dependent patients having iron
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`overload, comprising the administration of a therapeutically effective
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`amount of deferiprone or a physiologically acceptable salt thereof
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`sufficient to reduce the iron burden of the heart normally associated with
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`iron induced cardiac disease.
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`6. A method of treating iron induced heart disease in a blood transfusion
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`dependent patient having an iron overload condition of the heart
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`comprising administering to the patient a therapeutically effective
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`amount of deferiprone, or a physiologically acceptable salt thereof in
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`order to reduce the iron stores in the heart in preference to general iron
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`stores in the body, such as found in the liver.
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`7. A method of treating iron loading in the heart of blood transfusion
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`dependent patient having an iron overload condition of the heart
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`comprising administering to the patient a therapeutically effective
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`amount of deferiprone or a physiologically acceptable salt thereof to
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`chelate the iron stores in the heart in preference to general iron stores in
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`the body, such as found in the liver.
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`8. A method of treating iron loading in the heart of blood transfusion
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`dependent patient having an iron overload condition of the heart
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`comprising administering to the patient a therapeutically effective
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`amount of deferiprone or a physiologically acceptable salt thereof to
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`reduce the iron stores in the heart in preference to general iron stores
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`organs/tissue in the body, such as found in the liver.
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`9. A method of treatment of iron induced heart disease in a blood
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`transfusion dependent patient having an iron overload condition of the
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`heart comprising administering to the patient a therapeutical