UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`TARO PHARMACEUTICALS U.S.A., INC.,
`Petitioners,
`
`v.
`
`APOTEX TECHNOLOGIES, INC.,
`Patent Owner.
`________________
`
`Case IPR2017-01446
`U.S. Patent No. 7,049,328
`
`Title: USE FOR DEFERIPRONE
`________________
`
`DECLARATION OF THOMAS D. COATES, M.D.,
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
`
`Apotex Tech.
`Ex. 2001
`
`

`

`Table of Contents
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`BACKGROUND AND QUALIFICATIONS ................................................. 1
`
`III. LEGAL STANDARDS ................................................................................... 4
`
`A. Anticipation ........................................................................................... 4
`
`B. Obviousness ........................................................................................... 5
`
`IV. BACKGROUND OF THE TECHNOLOGY .................................................. 6
`
`A.
`
`B.
`
`C.
`
`Thalassemia ........................................................................................... 6
`
`Iron Overload ........................................................................................ 7
`
`Iron Chelation Therapy ......................................................................... 7
`
`V.
`
`THE ’328 PATENT .......................................................................................10
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ...........................................13
`
`VII. CLAIM CONSTRUCTION ..........................................................................14
`
`VIII. THE ALLEGED PRIOR ART ......................................................................15
`
`A. MIMS (Ex. 1009) ................................................................................15
`
`B. Hoffbrand 1998 (Ex. 1007) .................................................................16
`
`C. Olivieri Abstract 1995 (Ex. 1010) .......................................................17
`
`D. Agarwal (Ex. 1011) .............................................................................17
`
`E.
`
`Olivieri 1995 (Ex. 1012) .....................................................................18
`
`IX. THE PRIMARY REFERENCES OF GROUNDS 1-5 FAIL TO DISCLOSE
`
`EACH ELEMENT OF CLAIMS 1, 2, 4-10, AND DEPENDENT CLAIMS
`THEREFROM ...............................................................................................19
`
`
`A. MIMS does not anticipate claims 1, 2, and 4-10 or dependent claims
`therefrom (Ground 1) ..........................................................................20
`
`
`ii
`
`

`

`1. MIMS does not disclose treating a patient having an iron
`overload condition of the heart .................................................20
`
`
`2. MIMS does not disclose the therapeutically effective amount of
`
`deferiprone required by claims 1, 2, and 4-10 as defined by the
`specific claimed results of claims 1, 2, 4-10, and 19 ................21
`
`
`B. Hoffbrand 1998 (Ground 2) does not disclose the therapeutically
`
`effective amount of deferiprone required by claims 1, 2, and 4-10 as
`defined by the specific claimed results of claims 1, 2, 4-10, and 19 ..23
`
`
`C. Olivieri Abstract 1995 does not anticipate claims 1, 2, and 4-10 or
`dependent claims therefrom (Ground 3) .............................................25
`
`
`1.
`
`
`2.
`
`
`
`
`Olivieri Abstract 1995 does not disclose treating a patient
`having an iron overload condition of the heart .........................25
`
`Olivieri Abstract 1995 does not disclose the therapeutically
`effective amount of deferiprone required by claims 1, 2, and 4-
`10 as defined by the specific claimed results of claims 1, 2, 4-
`10, and 19 ..................................................................................26
`
`D. Agarwal does not anticipate claims 1, 2, and 4-10 or dependent claims
`therefrom (Ground 4) ..........................................................................28
`
`
`1.
`
`
`2.
`
`
`
`Agarwal does not disclose treating a patient having an iron
`overload condition of the heart .................................................28
`
`Agarwal does not disclose the therapeutically effective amount
`of deferiprone required by claims 1, 2, and 4-10 as defined by
`the specific claimed results of claims 1, 2, 4-10, and 19 ..........29
`
`E.
`
`
`Olivieri 1995 does not anticipate claims 1, 2, 4-10 or dependent
`claims therefrom (Ground 5) ...............................................................30
`
`1.
`
`
`2.
`
`
`
`
`Olivieri 1995 does not disclose treating a patient having an iron
`overload condition of the heart .................................................30
`
`Olivieri 1995 does not disclose the therapeutically effective
`amount of deferiprone required by claims 1, 2, and 4-10 as
`defined by the specific claimed results of claims 1, 2, 4-10, and
`19 ...............................................................................................31
`
`iii
`
`

`

`X.
`
`
`Claims 1, 2, 4-17, and 19 Are Not Obvious Over the Primary References in
`View of the Knowledge of a POSA ..............................................................32
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`iv
`
`

`

`I, Thomas D. Coates, M.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Cozen O’Connor LLP, counsel for Apotex
`
`Technologies, Inc. (“Apotex”), to provide my expert testimony in this proceeding.
`
`2.
`
`Although I am being compensated for my work on this matter, my
`
`compensation does not in any way depend on the outcome of this inter partes
`
`review or any related proceeding.
`
`3.
`
`The opinions set forth in this declaration are based on my education,
`
`knowledge, and experience in hematology, particularly the diagnosis and
`
`management of transfusion related iron overload, as well as my review of relevant
`
`materials discussed herein.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`1.
`
`The following is a brief summary of my background and
`
`qualifications, the full extent of which can be found in my curriculum vitae. (Ex.
`
`2002.)
`
`2.
`
`I am a recognized leader in hematology, particularly the diagnosis and
`
`management of transfusion-related iron overload. Since 1991, I have been the
`
`Section Head of the Hematology-Division of Pediatric Hematology-Oncology at
`
`Children’s Hospital Los Angeles (“CHLA”). Since 1992, I have held the positions
`
`of tenured Associate and tenured (since 2005) full Professor of Pediatrics and
`
`1
`
`

`

`Pathology at USC Keck School of Medicine. In addition, since 1995, I have been
`
`the Director of the Red Cell Defects and Hemoglobinopathy Program at Children’s
`
`Hospital Los Angeles. I have also been an Attending Physician in the Division of
`
`Pediatrics, Section of Hematology and Oncology, in the Childrens Center for
`
`Cancer and Blood Diseases, at Children’s Hospital Los Angeles continuously since
`
`1985.
`
`3.
`
`I began my training at the University of Michigan where I received an
`
`undergraduate degree in physics in 1971 and a M.D. in 1975. I undertook a
`
`Pediatrics Internship and Residency at Indiana University Medical Center from
`
`1975 to 1978. I also completed a pediatric hematology/oncology fellowship (both
`
`clinical and research) at Indiana University Medical Center in 1982. I am Board
`
`Certified in Pediatrics and Pediatric Hematology-Oncology by the American Board
`
`of Pediatrics.
`
`4.
`
`I currently treat patients with a variety of blood disorders including
`
`thalassemia (Cooley’s anemia) and sickle cell disease. I direct one of the largest
`
`thalassemia and iron overload centers in the United States. I have been directly
`
`involved in management and research related to transfusional iron overload since
`
`the mid-1990s and have been funded by the Unitized States National Institutes of
`
`Health to do research related to iron overload and iron related heart disease. I and
`
`a pediatric cardiologist/ MRI engineer developed the technology to measure tissue
`
`2
`
`

`

`iron by MRI. This technology is being used worldwide to diagnose patients with
`
`iron-induced heart disease. I have personally treated many patients with heart
`
`failure due to iron, including adults in their fifth and sixth decades who were
`
`referred to our pediatric center for management of their iron overload. I have
`
`lectured nationally and internationally on this topic. I have treated numerous
`
`patients with iron chelators including deferoxamine (Desferal®), deferiprone
`
`(Ferriprox®), and deferasirox (Exjade®), which was approved in 2005. I was the
`
`local principle investigator on the registration studies for use of deferasirox in
`
`sickle cell disease and thalassemia and am a co-author on the papers that describe
`
`this work. I have been treating patients with iron cardiomyopathy with deferiprone
`
`since about 2005 when it was available in the US only by compassionate use and
`
`have many more patients on the drug since its approval in the US in 2015.
`
`5.
`
`I also maintain an active research lab where one of the primary
`
`focuses is the detection and management of transfusion related iron overload. I
`
`work in collaboration with a cardiologist specializing in Magnetic Resonance
`
`Imagining (“MRI”), like Dr. Pennell, to find ways to specifically measure iron in
`
`various parts of the body. We are one of only three centers worldwide that
`
`develops this technology. Our research has changed the understanding of iron
`
`toxicity and how to effectively manage it.
`
`6.
`
`I have published more than 175 peer-reviewed original research
`
`3
`
`

`

`articles in medical and scientific journals, over 200 abstracts, and 31 book
`
`chapters. Many of my publications pertain to thalassemia and iron overload
`
`conditions.
`
`7.
`
`I am or have been a member of the American Society of Pediatric
`
`Hematology-Oncology, the American Society of Hematology, The Society of
`
`Pediatric Research, the European Hematology Association, and the American
`
`Pediatrics Society. I was a member and later the Chair of the Scientific Committee
`
`for Iron and Heme for the American Society of Hematology (2005-2010).
`
`III. LEGAL STANDARDS
`
`8.
`
`I am not an attorney. Thus, counsel has explained to me certain legal
`
`standards which I have relied upon in forming the opinions set forth in this
`
`declaration.
`
`A. Anticipation
`
`9.
`
`I understand that to be patentable, an invention claimed in a U.S.
`
`patent must be novel (not anticipated).
`
`10.
`
`I have been informed that a patent is invalid as anticipated only if a
`
`single prior art reference discloses each and every element of the claimed
`
`invention, either expressly or inherently. I understand that if a prior art reference
`
`lacks even one claim element, that reference cannot expressly anticipate that claim
`
`or any of its dependent claims.
`
`4
`
`

`

`11.
`
`It has also been explained to me that if a prior art reference is missing
`
`a claim element, that reference may still be anticipatory if the missing element is
`
`inherently disclosed. However, I understand that for inherent anticipation the
`
`extrinsic evidence must make clear that the missing descriptive matter is
`
`necessarily present in the thing described in the reference, and that it would be so
`
`recognized by persons of ordinary skill in the art (“POSA”). I further understand
`
`that inherency may not be established by probabilities or possibilities, and the mere
`
`fact that a certain thing may result from a given set of circumstances is not
`
`sufficient.
`
`B. Obviousness
`
`12.
`
`I understand that to be patentable, an invention claimed in a U.S.
`
`patent must also be non-obvious.
`
`13.
`
`I understand that obviousness is assessed from the vantage point of a
`
`POSA as of the priority date of the patent, here June 30, 2000.
`
`14.
`
`I have been informed that when evaluating obviousness, one must
`
`consider: (i) the scope and content of the prior art; (ii) the differences between the
`
`prior art and the claims at issue; and (iii) the level of ordinary skill in the pertinent
`
`art.
`
`15.
`
`I have also been informed that additional factors, referred to as
`
`secondary considerations of non-obviousness, should also be considered. These
`
`5
`
`

`

`objective indicators of non-obviousness, include, for example, unexpected results
`
`of the claimed invention; the claimed invention’s fulfillment of a long felt but
`
`unmet need; and evidence of praise of others for the claimed invention.
`
`IV. BACKGROUND OF THE TECHNOLOGY
`
`A. Thalassemia
`
`16. Thalassemia is an inherited blood disorder wherein the body makes an
`
`abnormal form of hemoglobin or is unable to effectively make sufficient
`
`hemoglobin, the protein in red blood cells that carries oxygen. Thalassemia results
`
`in the excessive destruction of red blood cell precursors, destruction of red blood
`
`cells, and insufficient production of hemoglobin, leading to anemia, a condition in
`
`which the body is deficient in healthy red blood cells.
`
`17. Thalassemia is typically categorized into two different types: alpha
`
`thalassemia and beta thalassemia. Beta thalassemia can be further categorized
`
`based on disease severity, e.g., “minor,” “intermedia,” or “major.” Thalassemia
`
`major (“TM”), also known as Cooley’s anemia, is the most severe form of beta
`
`thalassemia and causes life-threatening anemia.
`
`18. Focusing specifically on beta thalassemia, treatment depends on the
`
`type and severity. For example, a patient with beta thalassemia minor will
`
`generally have very few health problems other than possible mild anemia. Patients
`
`with beta thalassemia intermedia will typically have moderately severe anemia
`
`6
`
`

`

`requiring blood transfusions to improve their quality of life, but not necessarily to
`
`survive. Patients with the most severe form of beta thalassemia, thalassemia
`
`major, require regular and continuous blood transfusions and extensive medical
`
`care. These blood transfusions in beta TM patients provide a life-saving supply of
`
`healthy red blood cells with normal hemoglobin. However, because hemoglobin is
`
`an iron-rich protein, chronic blood transfusions in beta TM patients leads to the
`
`progressive accumulation of iron in the body—a condition called “iron overload.”
`
`B.
`
`Iron Overload
`
`19.
`
`Iron overload is the most common complication resulting from regular
`
`blood transfusions. Because the human body has a very limited capacity for
`
`eliminating iron, excess iron from the transfused blood settles into the organs and
`
`tissues of the body. Typically, the liver accumulates the most iron, and other
`
`organs, such as the heart, accumulate less iron and at a slower rate. Once the
`
`accumulation of iron in the organs exceeds the body’s capacity for safe storage, the
`
`buildup of iron causes damage to the liver, the heart, and other parts of the body.
`
`To prevent damage to the organs from excess iron, chelation therapy is required.
`
`C.
`
`Iron Chelation Therapy
`
`20.
`
`Iron chelators (or iron chelating agents) are medications that are
`
`capable of binding to iron and removing it from the body. Removing excess iron
`
`by chelation is critical to prevent the consequences of iron overload, such as iron
`
`7
`
`

`

`toxicity in the organs and tissues.
`
`21. As of the priority date of U.S. Patent No. 7,049,328 (“the ’328
`
`patent”) (Ex. 1001), there was only one FDA approved medication to treat iron
`
`overload due to transfusion-dependent anemias, Deferoxamine (also known as
`
`desferrioxamine; brand name Desferal®). Deferoxamine was approved in 1968 and
`
`was known to be effective at reducing total body iron and removing iron from the
`
`liver.
`
`22. Deferoxamine is administered subcutaneously (under the skin), and
`
`because it has a short half-life, it must be administered over a long period of time
`
`(e.g., 8-12 hours). Further, to effectively remove excess iron, Deferoxamine is
`
`generally infused every day for the lifespan of a patient.
`
`23. Despite the acknowledged and long-term success of Deferoxamine in
`
`treating iron overload in thalassemia patients, there were several drawbacks to its
`
`use. First, because Deferoxamine has an onerous administration regimen (i.e.,
`
`daily administration for 8-12h), many patients either cannot or will not comply
`
`with the treatment schedule leading to iron build up and resulting complications.
`
`(Id. at col. 2, ll. 26-33; see also Ex. 1026 at 298.) Second, although Deferoxamine
`
`effectively reduces total body iron, and removes iron from the liver, there
`
`nonetheless remained a high level of premature cardiac deaths in deferoxamine-
`
`treated patients. (Ex. 1001 at col. 2, ll. 18-25.)
`
`8
`
`

`

`24. A second known iron chelating agent is Deferiprone (brand name
`
`Ferriprox®). In the 1980’s, deferiprone was being investigated as an alternative to
`
`deferoxamine for the treatment of iron overload. Deferiprone could be taken
`
`orally, and was also known to effectively remove iron from the body, albeit to a
`
`lesser extent that deferoxamine. (Id. at col. 1, l. 63 to col. 2, l. 1.) However, by the
`
`late 1990’s the safety and efficacy of deferiprone came under question. (Exs.
`
`2011-2013.) For example, Dr. Olivieri, an initial proponent of deferiprone,
`
`published a series of abstracts and articles in 1998 critical of the use of deferiprone.
`
`In a 1998 abstract, Dr. Olivieri and colleagues reported that “[i]n cultured
`
`cardiomyocytes, deferiprone fails to mobilize iron and promotes iron-induced
`
`cardiotoxicity” and raised concerns that “deferiprone treatment in patients with TM
`
`may be associated with (i) redistribution of body iron, leading to increased cardiac
`
`iron deposition at lower body iron burdens, and (ii) an exacerbation or acceleration
`
`of cardiac fibrosis.” (Ex. 2012.) In a further publication in 1998, Dr. Olivieri and
`
`colleagues questioned the ability of deferiprone to even reduce total body iron:
`
`“data from two centers conducting ‘long-term trials of deferiprone support our
`
`previous conclusion that long-term therapy with deferiprone may not provide
`
`adequate control of body iron in a substantial portion of patients with thalassemia
`
`major.’” (Ex. 2013 at 220.) Thus, despite Deferiprone’s initial promise, by the
`
`time of the invention of the ’328 patent, Deferiprone’s safety and effectiveness had
`
`9
`
`

`

`been called into serious question by the scientific community.
`
`V. THE ’328 PATENT
`
`25.
`
`I understand that the ’328 is entitled “Use for Deferiprone” and issued
`
`on May 23, 2006, to inventors Michael Spino and Antonio Piga. I further
`
`understand that the ’328 patent issued with 20 claims, of which claims 1-10 are
`
`independent claims and claims 11-20 are multiply dependent therefrom. I also
`
`understand that only claims 1-17 and 19 have been challenged by Taro. The
`
`challenged claims are shown below:
`
`1. A method of treating iron induced cardiac disease in a blood
`transfusion dependent patient experiencing an iron overload condition
`of the heart, said method comprising administering to the patient a
`therapeutically effective amount of deferiprone or a physiologically
`acceptable salt thereof sufficient to stabilize/reduce iron accumulation
`in the heart resulting from being transfusion dependent.
`
`2. A method of treating iron loading in the heart of a blood
`transfusion dependent patient experiencing an iron overload condition
`of the heart, said method comprising administering to the transfusion
`dependent patient a therapeutically effective amount of deferiprone or
`a physiologically acceptable salt thereof sufficient to reduce further
`iron overload in the heart normally associated with iron induced
`cardiac disease.
`
`3. A method of treating iron loading in the heart of a blood
`transfusion dependent patient risking iron overload of the heart,
`comprising the administration of a therapeutically effective amount of
`deferiprone or a physiologically acceptable salt thereof to the patient.
`
`4. A method of stabilizing iron induced heart disease in blood
`transfusion dependent patients having iron overload, comprising the
`administration of a therapeutically effective amount of deferiprone or
`a physiologically acceptable salt thereof sufficient to treat the iron
`burden in the heart normally associated with iron induced cardiac
`
`10
`
`

`

`disease.
`
`5. A method of reducing the iron burden in the heart associated
`with iron induced heart disease in blood transfusion dependent
`patients having iron overload, comprising the administration of a
`therapeutically effective amount of deferiprone or a physiologically
`acceptable salt thereof sufficient to reduce the iron burden of the heart
`normally associated with iron induced cardiac disease.
`
`6. A method of treating iron induced heart disease in a blood
`transfusion dependent patient having an iron overload condition of the
`heart comprising administering to the patient a therapeutically
`effective amount of deferiprone, or a physiologically acceptable salt
`thereof in order to reduce the iron stores in the heart in preference to
`general iron stores in the body, such as found in the liver.
`
`7. A method of treating iron loading in the heart of blood
`transfusion dependent patient having an iron overload condition of the
`heart comprising administering to the patient a therapeutically
`effective amount of deferiprone or a physiologically acceptable salt
`thereof to chelate the iron stores in the heart in preference to general
`iron stores in the body, such as found in the liver.
`
`8. A method of treating iron loading in the heart of blood
`transfusion dependent patient having an iron overload condition of the
`heart comprising administering to the patient a therapeutically
`effective amount of deferiprone or a physiologically acceptable salt
`thereof to reduce the iron stores in the heart in preference to general
`iron stores organs/tissue in the body, such as found in the liver.
`
`9. A method of treatment of iron induced heart disease in a blood
`transfusion dependent patient having an iron overload condition of the
`heart comprising administering to the patient a therapeutically
`effective amount of deferiprone or a physiologically acceptable salt
`thereof for the direct reduction/removal of intracellular iron stores in
`the heart.
`
`10. A method to reduce the occurrence of iron-induced cardiac
`disease in a blood transfusion dependent patient with an iron overload
`condition, comprising administering to said patient a therapeutically
`effective amount of deferiprone or a physiologically acceptable salt
`
`11
`
`

`

`thereof, wherein deferiprone’s efficacy is cardio preferential when
`compared with its ability to lower total iron stores in the body.
`
`11. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein
`deferiprone or a physiologically acceptable salt
`thereof
`is
`administered orally for treating the risk of iron induced heart disease
`in patients having iron overload.
`
`12. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein
`deferiprone or a physiologically acceptable salt thereof is present in an
`oral dosage form with other excipients.
`
`13. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein the
`administration frequency to the patient of an amount of deferiprone or
`a physiologically acceptable salt thereof is daily in the range of up to
`150 mg per kilogram of body weight.
`
`14. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein the
`administration frequency to the patient of a dosage amount of
`deferiprone or a physiologically acceptable salt thereof is daily in the
`range of up to 125 mg per kilogram of body weight.
`
`15. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein the
`administration frequency to the patient of a dosage amount of
`deferiprone or a physiologically acceptable salt thereof is daily in the
`range of 25 mg to 75 mg per kilogram of body weight.
`
`16. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein
`deferiprone is administered in a manner selected from the group of
`intravenously, transdermally, rectally, orally, bucally, or aurally.
`
`17. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein
`deferiprone is administered orally.
`
`19. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein
`deferiprone has a cardio preferred/selective function when compared
`to desferrioxamine or other alternative chelating agents utilized in
`patients suffering iron overload.
`
`(See Ex. 1001 at col. 27, l. 1 to col. 28, l. 51.)
`
`12
`
`

`

`VI. LEVEL OF ORDINARY SKILL IN THE ART
`
`26.
`
`In my opinion, a person of ordinary skill in the art (“POSA”) at the
`
`time of the invention would include physicians who treated iron overload in
`
`patients requiring chronic blood transfusions. Such a person would have had a
`
`medical degree and some experience in hematology, cardiology, or a related field.
`
`A POSA would have worked as a part of a team of health care providers having
`
`experience in the treatment of thalassemia, sickle cell, or other haemochromatosis
`
`disorders.
`
`27.
`
`I understand that Taro and Dr. Mehta have asserted that a POSA
`
`“would have had an M.D. and several years of clinical work experience in
`
`hematology, and would have had research, clinical, and/or testing experience with
`
`iron chelators to treat iron overload in the body, including iron overload of the
`
`heart. The skilled person would have been familiar with blood disorders such as
`
`thalassemia or hemochromatosis, including their causes and treatments.” (Petition
`
`for Inter Partes Review of U.S. Patent No. 7,049,328 B2 (“Pet.”) at 11;
`
`Declaration of Jayesh Mehta, M.D., In Support of the Petition for Inter Partes
`
`Review of U.S. Patent No. 7,049,328 B2 (Ex. 1002) at 41.)
`
`28. As of the earliest priority date of the ’328 patent, I was a person of
`
`ordinary skill in the art according to either definition.
`
`13
`
`

`

`VII. CLAIM CONSTRUCTION
`
`29.
`
`I have reviewed Taro’s claim construction positions and I disagree
`
`with a number of premises therein—in particular the contention that a
`
`“therapeutically effective amount” of deferiprone is “one that causes adequate
`
`chelation” and that the claimed results are not limitations. (Pet. at 23-28.)
`
`30. First, it is clear to me having reviewed claims 1, 2, and 4-10, that a
`
`specific dose of deferiprone is not provided. (Ex. 1001 at col. 27, l. 1 to col. 28, l.
`
`13.) Thus, a POSA would understand that the “therapeutically effective amount”
`
`of deferiprone is defined by the results of claims 1, 2, 4-10, and 19. Meaning, the
`
`amount of deferiprone a physician would administer can vary depending on the
`
`result desired, i.e., stabilization, reduction, or treatment of iron overload in the
`
`heart, including iron-induced heart disease.
`
`31.
`
`Second, I find Taro’s definition of “therapeutically effective amount”
`
`as “one that causes adequate chelation” to be inadequate. This definition leaves a
`
`POSA to question adequate chelation for what? Is it the amount of deferiprone
`
`that reduces total body iron? The amount that reduces hepatic iron and serum
`
`ferritin levels? The amount that reduces cardiac iron? The amount that improves
`
`cardiac function? These questions can only be answered by looking at the claimed
`
`results. Thus, in my opinion a POSA would consider the claimed results to be
`
`necessary limitations of the claims.
`
`14
`
`

`

`32. Finally, I understand that in a related proceeding in the District Court
`
`for the Eastern District of Texas, the court agreed with Apotex’s position (the same
`
`position Apotex advocates here) and held that certain terms of claims 2, 4, 5, 7, 8,
`
`11, and 19 were material claim limitations and not merely a recitation of intended
`
`results. (See Ex. 2010 at 30.)
`
`33.
`
`In forming the opinions set forth herein, I have likewise considered
`
`the disputed terms to be material limitations of the claims. I have also considered
`
`the preamble of independent claims 1-10 to be limiting. Further, it is my opinion
`
`that the words of each of the challenged claims would be readily understood by a
`
`POSA.
`
`VIII. THE ALLEGED PRIOR ART
`
`A. MIMS (Ex. 1009)
`
`34. Monthly Index of Medical Specialties (“MIMS”) discloses the use of
`
`deferiprone for “[t]ransfusion haemosiderosis, acute iron poisoning, iron overload
`
`in liver cirrhosis, [and] diagnosis of iron-storage disease.” (Ex. 1009 at 256.)
`
`MIMS further discloses the use of deferiprone in doses ranging from 50-100 mg/kg
`
`body weight daily. (Id.)
`
`35. MIMS does not disclose the specific use of deferiprone to stabilize,
`
`reduce, or treat iron overload in the heart, including iron-induced heart disease.
`
`Nor does MIMS disclose the specific dose of deferiprone necessary to treat each
`
`15
`
`

`

`identified condition (i.e., transfusion haemosiderosis versus acute iron poisoning
`
`versus iron overload in liver cirrhosis versus iron-storage disease), much less the
`
`specific dose of deferiprone necessary to stabilize, reduce, or treat iron overload in
`
`the heart, including iron-induced heart disease. Further, I note that as of June 30,
`
`2000, a POSA would have understood the term “transfusion haemosiderosis” to
`
`mean an accumulation of iron resulting from repeated blood transfusions, and
`
`“iron-storage disease” to primarily refer to liver disease resulting from iron
`
`overload.
`
`B. Hoffbrand 1998 (Ex. 1007)
`
`36. Hoffbrand 1998 presents the efficacy and side effects of treatment
`
`with 75 mg/kg/body weight of deferiprone in a long-term trial of fifty-one
`
`transfusion-dependent iron overloaded patients (38 with β-thalassemia major).
`
`(Ex. 1007 at 295.) Hoffbrand 1998 discloses that efficacy was assessed by
`
`monthly measurements of serum ferritin concentration and 24-hour urinary iron
`
`excretion. (Id. at 296). Hoffbrand 1998 does not disclose measurements of cardiac
`
`iron.
`
`37. Of the 51 patients studied by Dr. Hoffbrand and colleagues, 20
`
`patients discontinued deferiprone treatment while 5 patients suffered fatal
`
`complications. (Id.) Four of the five reported fatalities resulted from congestive
`
`heart failure. (Id. at 296, 299.) These 4 deaths led the authors to conclude that
`
`16
`
`

`

`“deferiprone is inappropriate therapy for patients with iron-induced
`
`cardiomyopathy” and that patients with iron-induced cardiomyopathy should be
`
`given intravenous DFX [desferrioxamine] rather than deferiprone. (Id. at 299.)
`
`C. Olivieri Abstract 1995 (Ex. 1010)
`
`38. Olivieri Abstract 1995 discloses the first prospective randomized trial
`
`comparing the effectiveness and safety of, and compliance with, deferiprone (L1)
`
`(75 mg/kg/day) and deferoxamine (50 mg/kg/day) in thalassemia major patients.
`
`(Ex. 1010.) Olivieri Abstract 1995 states that reduction of hepatic iron
`
`concentration and cardiac and pituitary iron were endpoints of the study. (Id.)
`
`39. Olivieri Abstract 1995 reports that MRI results in deferiprone-treated
`
`patients purportedly demonstrated “changes consistent with reduction in cardiac
`
`iron” based on T2 relation times (“TRT”). (Id.) More specifically, Olivieri
`
`Abstract 1995 discloses that deferiprone-treated patients had baseline TRT values
`
`of 23.9±6.4 msec (normal >32 msec) that increased to 32.4±9.3 msec following
`
`deferiprone treatment. (Id.) Olivieri Abstract 1995, however, never correlates the
`
`abnormal TRT values with a cardiac pathology, and, in fact, Olivieri Abstract 1995
`
`never uses the phrase cardiac disease or iron overload condition of the heart to
`
`describe any patient in the study. (Id.)
`
`D. Agarwal (Ex. 1011)
`
`40. Agarwal discloses the use of deferiprone (75 to 120 mg/kg/day) in 22
`
`17
`
`

`

`transfusion dependent thalassemia patients for over a decade. (Ex. 1011.)
`
`Agarwal states that efficacy and adverse effects of deferiprone were monitored.
`
`(Id.) Agarwal reports that deferiprone-treated patients experienced a drop in mean
`
`serum ferritin levels, and that “[a]ssessment of cardiac function shows normal
`
`ejection fraction in all [patients] with mild diastolic dysfunction in two.” (Id.) I
`
`note, however, that Agarwal does not disclose whether the cardiac abnormalities in
`
`these two patients was diagnosed before or after initiating deferiprone therapy.
`
`(Id.) I further note that Agarwal does not disclose whether the cardiac
`
`abnormalities observed in 2 patients were iron induced, which I understand is
`
`required by the challenged claims. (Id.) Further, Agarwal presents no data
`
`quantifying the amount of cardiac iron in the heart of a