UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`Taro Pharmaceuticals U.S.A., Inc.
`Petitioner,
`v.
`
`Apotex Technologies, Inc.
`Patent Owner
`
`
`
`Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`
`
`
`Inter Partes Review No. IPR2017-01446
`
`
`EXPERT DECLARATION OF DR. JAYESH MEHTA
`IN SUPPORT OF PETITIONER’S REPLY
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`
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`1 of 26
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1060
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`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`Taro Pharmaceuticals U.S.A., Inc.
`Petitioner,
`v.
`
`Apotex Technologies, Inc.
`Patent Owner
`
`
`
`Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`
`
`
`Inter Partes Review No. IPR2017-01446
`
`
`EXPERT DECLARATION OF DR. JAYESH MEHTA
`IN SUPPORT OF PETITIONER’S REPLY
`
`
`
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`
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`1 of 26
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1060
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`1.
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`2.
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`I, Jayesh Mehta, M.D., declare as follows:
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`I am the same Jayesh Mehta who submitted declarations dated May
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`14, 2017, and December 27, 2017, in support of Taro Pharmaceuticals U.S.A.,
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`Inc.’s positions in this matter. I submit this third declaration to respond to
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`assertions made in Exhibits 2001, 2003, 2026, and 2035, the expert declarations of
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`Drs. Pennell and Coates submitted in this proceeding. I reserve the right to further
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`respond to these declarations and to further supplement my opinions in this matter.
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`3.
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`As of the earliest priority date of the ’328 patent (June 30, 2000), my
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`relevant experience was that of a person of at least ordinary skill in the art, based
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`either on the definition of that term that I proposed in my first declaration at
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`paragraph 17 or on the definition of that term proposed by Dr. Coates in his
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`September 8, 2017, declaration at paragraph 27. All of the statements of my
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`opinion set forth in this declaration are presented from the perspective of the
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`hypothetical person of ordinary skill of the art, and I am qualified to opine from
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`this perspective due to my extensive training in blood disorders, my years of
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`experience treating patients with blood disorders, my research into blood disorders,
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`and my review of the cited prior art.
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`4.
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`In my first declaration, I provided my understanding of the relevant
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`legal principles. My understanding of these principles has not changed since I
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`wrote my first declaration.
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`2
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`2 of 26
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1060
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`A. An Iron Overload Condition of the Heart
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`5.
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`The ’328 patent repeatedly uses the term “an iron overload condition
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`of the heart.” (See, e.g., Ex. 1001 at 11:34-35, 11:45, 12:11-12, 12:19-20, 12:27-
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`28, 12:36-37.) In these citations, the patent discusses the prevention, treatment, or
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`reversal of heart disease in patients having “an iron overload condition of the
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`heart.” The patent’s use of both terms “heart disease” and “an iron overload
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`condition of the heart” in a single sentence implies that these terms have different
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`meanings. Further, because the patent discusses the prevention, treatment, and
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`reversal of heart disease in a patient with an iron overload condition of the heart,
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`the term “iron overload condition of the heart” must encompass patients who are at
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`risk for, but do not already have, heart disease (disease that will allegedly be
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`prevented by the method) as well as patients who already have heart disease
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`(disease that will allegedly be treated and/or reversed by the method).
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`6.
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`Thus, the term “iron overload condition of the heart,” which appears
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`in claims 1, 2, 6, 7, 8, and 9, is a broad term that encompasses patients who have a
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`condition on the spectrum of heart disease and patients who have iron in the heart
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`with no measureable heart disease. I explained this meaning in my deposition on
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`this matter. (See Ex. 2024 at 175:3-177:7.)
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`3
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`3 of 26
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1060
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`B. The Patent Contains a Single Example Using 75 mg/kg/day of
`Deferiprone
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`7.
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`The ’328 patent includes one example, in the “DETAILED
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`DESCRIPTION OF THE EMBODIMENTS” section. The example describes a
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`retrospective study that compares the “prevalence and progression of cardiac
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`disease” and “the survival of patients” treated, for 4 or more years, with either
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`deferiprone or deferoxamine. (Ex. 1001 at 14:34-42.) The patients were
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`transfusion-dependent. (Id. at 14:57-58.)
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`8.
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`Patients were assessed for iron overload, which consisted of monthly
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`determinations of iron input from transfusions and quarterly serum ferritin
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`measurements. (Id. at 15:1-3.) Some patients had an annual assessment of liver
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`iron concentration (LIC). (Id. at 15:3-6.)
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`9.
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`Patients were also periodically assessed for cardiac function by a
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`cardiologist, consisting of a physical examination, an echocardiogram and, if
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`indicated, 24-hour electrocardiographic Holter monitoring. (Id. at 15:7-11.) The
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`first cardiac assessment was the baseline value used for each patient. (Id. at 15:7-
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`25.)
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`10. The deferiprone-treated patients were administered a dose of 25
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`mg/kg of body weight, three times per day, for a total of 75/mg/kg per day. (Id. at
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`15:28-30.) The deferoxamine patients were treated with 20 to 60 mg/kg per day, 4
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`to 7 days a week. (Id. at 15:30-33.)
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`4
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`11. The patent reports that, at the first assessment, the prevalence of
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`cardiac disease was “similar” for both groups, with 10% of the 48 patients on
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`deferiprone having cardiac disease and 14% of the 78 patients on deferoxamine
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`having cardiac disease. (Id. at 18, Table 1.) The patent further reports that “the
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`percentage of patients who had more than 50% of their serum ferritin values above
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`the apparent threshold for cardiac disease (2500 μg/L) throughout the review
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`period was similar between the 2 groups.” (Id. at 19:18-21.)
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`12. For patients with cardiac disease at the first assessment, the patent
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`reports an improvement in 2 out the 5 patients treated with deferiprone, and in 3
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`out of the 11 patients treated with deferoxamine. (Id. at 20:19-23.) Among
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`patients who had cardiac disease at the first assessment, cardiac disease worsened
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`over the treatment period for 1 of the 11 patients treated with deferoxamine and for
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`none of the 5 patients treated with deferiprone. (Id. at 20:23-54.) Two patients
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`treated with deferiprone had newly diagnosed cardiac disease during the course of
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`the treatment period, as did nine patients treated with deferoxamine. (Id. at 20:54-
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`61.)
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`13. The patent states that “[c]ardiac disease, as defined by the heart
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`functional capacity classification developed by the New York Heart Association,
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`was an end point in this study . . . Data to establish the diagnosis and progression
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`of cardiac disease were obtained from the medical records of patients, noting in
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`5
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`particular, physical examinations, echocardiograms, and 24-hour
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`electrocardiographic Holter assessments.” (Id. at 22:13-21.)
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`14. The study in the patent does not directly measure iron in the heart, and
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`does not state that patients’ cardiac disease was “iron induced.” The study
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`measured the patients’ heart function and cardiac disease by a clinical examination
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`and electrocardiogram, and measured their serum ferritin. The patent does not
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`describe a method to investigate whether the cardiac disease was iron induced and
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`does not rule out different reasons for the observed cardiac disease. Instead, the
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`patent implies that the observed cardiac disease is due to iron loading in the heart.
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`Attribution of cardiac disease to iron overload is a reasonable inference, based on
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`(1) the fact that the patients were transfusion-dependent and therefore subject to
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`constant increases in body iron, and (2) the improvement seen after treatment with
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`an iron chelator. 1
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`1 The patent also refers to “[t]he successful reversal by deferiprone of the iron-
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`induced congestive heart failure in a patient participating in the study provides
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`evidence for the cardio-protective effect of this iron chelator.” (Id. at 24:55-58
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`(citing Reference 31 and referencing a one-patient report by Dr. Liu).) I’ve
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`reviewed the date and the subject matter of Ex. 1066, and it matches the
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`description of Reference 31 of the ’328 patent, the one-patient report by Dr. Liu.
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`As with the patent study, this patient’s cardiac iron was not measured but his heart
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`6
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`15. The example in the specification does not include any dosage
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`modification to ensure successful treatment for each patient, and, in fact, the patent
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`states that at least two of the patients who were treated with deferiprone were
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`newly diagnosed with cardiac disease during the treatment period. (Id. at 20:54-
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`61.) For these two patients, the fixed 75 mg/kg/day dose that was administered to
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`all of the deferiprone-treated patients was not successful at preventing iron-induced
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`cardiac disease. Despite these treatment failures, the patent reaches the conclusion
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`that 75 mg/kg/day deferiprone reduces cardiac iron by relying on an alleged
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`statistical difference between the deferiprone-treated group and the deferoxamine-
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`treated group. (Id. at 23:49-53.) This statistical evidence of efficacy does not
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`reflect success in every patient treated with deferiprone. Thus, the term
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`“therapeutically effective amount” must be understood to mean an amount that is
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`in general successful, even if not successful in each and every patient treated.
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`C. The Claimed Methods Are All Essentially the Same
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`16. Despite the different words used in each of the claimed results, the
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`claimed results all really require the same thing: a treatment of the iron burden in
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`the heart. The language of the claims themselves does not readily provide an
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`function was assessed. Based on the fact that he was a blood-transfusion
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`dependent patient and that his cardiac function improved after using deferiprone,
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`the named inventors concluded that the patient’s heart failure was iron induced.
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`7
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`understanding of clear differences among the claims, and the specification does not
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`separately define similar terms that appear in the claims, such as “sufficient to
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`reduce iron overload in the heart” and “sufficient to treat the iron burden in the
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`heart.”
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`17. The following is a chart listing certain language that appears in the
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`variously claimed methods:
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`Claim Method of
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`Type of Patient
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`Intended Result
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`1
`
`2
`
`4
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`5
`
`6
`
`7
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`treating iron
`induced cardiac
`disease
`
`experiencing an iron
`overload condition
`of the heart
`
`treating iron
`loading in the
`heart
`
`experiencing an iron
`overload condition
`of the heart
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`to stabilize/reduce iron
`accumulation in the heart
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`to reduce further iron overload in
`the heart
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`stabilizing iron
`induced heart
`disease
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`reducing the
`iron burden in
`the heart
`
`treating iron
`induced heart
`disease
`
`treating iron
`loading in the
`heart
`
`
`having iron
`overload
`
`having iron
`overload
`
`to treat the iron burden in the
`heart
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`to reduce the iron burden of the
`heart
`
`having an iron
`overload condition
`of the heart
`
`having an iron
`overload condition
`of the heart
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`to reduce the iron stores in the
`heart in preference to general iron
`stores in the body, such as found
`in the liver
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`to chelate the iron stores in the
`heart in preference to general iron
`stores in the body, such as found
`in the liver
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`8
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`Claim Method of
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`Type of Patient
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`Intended Result
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`treating iron
`loading in the
`heart
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`having an iron
`overload condition
`of the heart
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`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
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`treatment of
`iron induced
`heart disease
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`having an iron
`overload condition
`of the heart
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`for the direct reduction/removal
`of intracellular iron stores in the
`heart
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`reduce the
`occurrence of
`iron-induced
`cardiac disease
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`with an iron
`overload condition
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`dependent on claims 1, 2, 3, 4, 5, 6, 7,
`8, 9 or 10
`
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`wherein deferiprone’s efficacy is
`cardio preferential when
`compared with its ability to lower
`total iron stores in the body
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`wherein deferiprone has a cardio
`preferred/selective function when
`compared to desferrioxamine or
`other alternative chelating agents
`utilized in patients suffering iron
`overload
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`8
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`9
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`10
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`19
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`18. Claims 2, 5, 7, 8, and 10, are drawn to a method of treating cardiac
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`iron overload. Claims 1, 4, 6, and 9 are drawn to a method of treating a subset of
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`these patients (i.e., patients with iron induced cardiac disease). To the extent that
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`there are appreciable differences between the claimed methods, these differences
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`do not affect how the methods are practiced: administering deferiprone to a
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`transfusion-dependent patient with iron overload. (See, e.g., id. at 25:24-32.) This
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`method is identical to the methods described in the prior art, including in
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`Hoffbrand 1998, Olivieri 1995, and Olivieri Abstract 1995.
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`9
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`D. Olivieri Abstract 1995 Anticipates the Challenged Claims
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`19. Olivieri Abstract 1995 describes a study comparing the treatment of
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`thalassemia major patients with either 75 mg/kg per day of deferiprone or 50
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`mg/kg per day of deferoxamine. (Ex. 1010 at 12.) The study had two endpoints,
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`liver iron concentration (called “hepatic iron concentration” in the abstract) and
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`“cardiac and pituitary iron using MRI.” (Id.) The abstract reports no significant
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`difference in outcome between the patient groups based on liver iron
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`concentration. (Id.) Although serum ferritin was not an endpoint, the abstract
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`reports that, similar to the liver iron concentration, there was no significant
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`difference in outcome between the patient groups based on serum ferritin. (Id.)
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`However, with respect to cardiac iron, the abstract reports MRI “changes
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`consistent with reduction in cardiac iron” in the deferiprone-treated patients. (Id.)
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`20. This abstract therefore anticipates all of the claims, by disclosing the
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`treatment of blood transfusion-dependent patients who, based on their MRI results,
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`had cardiac iron overload and iron-induced cardiac disease, with 75 mg/kg per day
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`of deferiprone. The abstract also reports the success of this treatment in reducing
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`cardiac iron as measured by MRI and reports the preferential activity of
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`deferiprone to chelate iron in the heart, as compared with deferoxamine, and
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`thereby anticipates the claimed results, as explained in the following paragraphs.
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`10
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`21. The abstract states that the MRI measurements of T2 relaxation time
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`(“TRT”), which is a measure directly related to cardiac iron load, were “23.9±6.4
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`msec” (mean±SD) at the beginning of the study. The abstract reports that normal
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`TRT is greater than 32 msec. Because the average TRT at the beginning of the
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`study (23.9 msec) was more than one standard deviation (6.4 msec) less than 32
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`msec, nearly all of the patients in Olivieri Abstract 1995 who were treated with
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`deferiprone started treatment with iron overload of the heart, i.e., an iron overload
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`condition of the heart, as demonstrated by cardiac MRI TRT measurements.
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`22. Further, based on the TRT measures, at least some of the patients in
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`the specific patient population described in the Olivieri Abstract 1995 had a
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`condition on the spectrum of cardiac disease, which ranges from mild dysfunction
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`that may be asymptomatic, to heart failure. My opinion is based on the
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`exceedingly low TRT levels reported in the abstract, which indicate significant
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`iron overload in the heart. (See, e.g., Ex. 1055 at 121.2)
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`23. At the end of the study, the abstract reports that the MRI TRT
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`measurements were 32.4±9.3 msec. Thus, at the end of the study period, the
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`average TRT value was within the “normal” range of > 32 msec, and at least some
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`2 Mavrogeni, Myocardial Iron Deposition in β-Thalassemia Studied by Magnetic
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`Resonance Imaging, INTERNATIONAL JOURNAL OF CARDIAC IMAGING, 14:117-22,
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`1998.
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`11
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`of the patients had TRT values in this range. Therefore, at least some of the
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`patients, most of whom started the trial with abnormal TRT measurements,
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`experienced a decrease in cardiac iron load and were successfully treated with
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`deferiprone.
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`24.
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`In Olivieri Abstract 1995, the success of deferiprone in reducing
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`cardiac iron, as measured by an improvement in MRI TRT is contrasted with
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`deferoxamine’s inability to improve MRI TRT. “Initial TRT in DFO-treated
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`[patients] [21.4±7.9msec] remains unchanged [21.7±6.9msec, p>0.67].” (Ex. 1010
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`at 12.) Thus Olivieri Abstract 1995 explicitly states that deferiprone has a greater
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`ability to remove iron from the heart (i.e., “a cardio preferred/selective function”)
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`when compared to deferoxamine.
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`25. Dr. Coates and Dr. Pennell take the position that, in general, MRI
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`TRT does not accurately measure cardiac iron, and state that only MRI T2*
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`accurately measures cardiac iron. (POR at 4; Ex. 1058 at 203:2-204:9). This is
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`incorrect. TRT and T2* relaxation time are closely related MRI techniques, and
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`both provide reliable, quantitative assessment of cardiac iron. (See, e.g., Ex.
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`10653.) Specifically, T2 and T2* relaxation times are related by the equation
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`3 I downloaded Ex. 1065 from http://mriquestions.com/t2-vs-t2.html (a webpage
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`entitled “Questions and Answers on MRI: T2 vs T2*, What is the difference
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`between T2 and T2*?”) on June 13, 2018.
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`12
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`1/T2* = 1/T2 + 1/T2i, where 1/T2i is the relaxation rate contribution attributable to
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`certain field inhomogeneities. (Id.) Because T2* relaxation time and T2
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`relaxation time (i.e., TRT) are mathematically related measurements, it cannot be
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`said that T2* is reliable but TRT is unreliable.
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`26.
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`Indeed, the prior and post art literature shows that clinicians in the
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`field of iron overload treatment recognized that cardiac MRI TRT was a reliable
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`measure of heart iron concentration. For example, in 1996, Liu et al. studied TRT
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`in a rodent model of iron overload in the heart and other organs and confirmed a
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`linear relationship between cardiac MRI TRT and cardiac iron concentration. (Ex.
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`1062 (Liu 19964) at 163.) Liu 1996 concluded that this “well defined relationship”
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`suggested that cardiac MRI TRT can be used to quantify iron content in various
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`tissues in the body. (Id.) By 1998, Mavrogeni et al. reported with respect to
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`clinical use of cardiac MRI TRT that TRT “is a noninvasive tissue characterization
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`method enabling the simultaneous examination of heart function, and heart and
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`liver iron content. It is easily repeated, facilitating thalassemic patient follow-up
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`and chelation therapy efficacy evaluation.” (Ex. 1055 (Mavrogeni 1998) at 121.)
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`Thus the prior art shows that clinicians in the field of iron overload treatment
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`4 Liu et al., Quantification of cardiac and tissue iron by nuclear magnetic resonance
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`relaxometry in a novel murine thalassemia-cardiac iron overload model, Can. J.
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`Cardiol., Vol. 12, No. 2:155–164, 163 (1996) (“Liu 1996”).
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`13
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`recognized that cardiac MRI TRT was a reliable measure of heart iron
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`concentration.
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`27. The prior art also confirms that the MRI TRT measurements reported
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`in Olivieri Abstract 1995 sufficiently demonstrate that the patients in Olivieri
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`Abstract 1995 had cardiac iron overload and iron-induced cardiac disease, and that
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`the treatment with 75 mg/kg per day of deferiprone was successful. Barman
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`Balfour, a 1999 review article on the clinical potential of deferiprone in treating
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`iron overload in ß-thalassemia patients, cited TRT measurements as evidence
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`“consistent with reduction of iron within the heart.” (Ex. 1017 at 568.) Another
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`example in the prior art is Diav Citrin, a 1997 review article which cited MRI TRT
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`measurements reported by Dr. Olivieri in an earlier abstract5 and stated that “a
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`reduction in cardiac stores [by deferiprone] has been observed by cardiac MR
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`imaging evaluation.” (Ex. 1022 at 239.) The Barman Balfour and Diav Citrin
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`interpretations also prove that the exact words “heart iron overload” or a variation
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`therefore do not need to be used for a POSA to understand what increased TRT
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`and deferiprone-induced reduction in TRT mean—they mean iron overload of the
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`heart that decreased with deferiprone.
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`5 Olivieri et al., Evidence of reduction in hepatic, cardiac and pituitary iron stores
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`in patients with thalassemia major during long-term therapy with the orally active
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`iron chelating agent L1, BLOOD, 84(suppl.):109, 1994.
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`14
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`28. Post art publications from a named inventor of the ’328 patent and
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`from authors affiliated with Apotex further confirm that the MRI TRT
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`measurements reported in Olivieri Abstract 1995 demonstrate successful treatment
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`of the heart. A 2003 paper6 coauthored by named inventor Dr. Antonio Piga and
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`Apotex employee Dr. Fernando Tricta7 stated that “[c]omparative qMRI studies
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`[with MRI TRT measurements] indicated that deferiprone may . . . be more
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`effective than deferoxamine in increasing the heart signal and improving heart
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`function in patients with iron overload.” (Ex. 1061 (Piga 2003) at 494-95.) Yet
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`another 2003 paper8 coauthored by Dr. Tricta described Olivieri Abstract 1995 as
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`6 Piga, A., et al., Comparative effects of deferiprone and deferoxamine on survival
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`and cardiac disease in patients with thalassemia major: a retrospective analysis,
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`HAEMATOLOGICA/JOURNAL OF HEMATOLOGY vol. 88(05): May 2003 489–96
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`(“Piga 2003,” Ex. 1061).
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`7 Dr. Tricta is identified by Piga 2003 as affiliated with “Apotex Research Inc.,
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`Canada.” (Ex. 1061 (Piga 2003) at 489.)
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`8 Fabron et al., Terapia quelante oral com deferiprona em pacientes com
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`sobrecarga de ferro, REV. BRAS. HEMATOL. HEMOTER., 25(3):177-88, 2003
`
`(“Fabron 2003,” Ex. 1063). This article is in Portuguese. I have reviewed a
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`certified English-language translation of the article (Ex. 1064 (Fabron 2003,
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`English translation)).
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`15
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`“show[ing] a significant improvement in T2 relaxation time, compatible with a
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`reduction in heart iron, in patients treated with deferiprone.” (Ex. 1064 (Fabron
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`2003, English translation) at 180.) Both Piga 2003 and Fabron 2003 post-date by
`
`years the alleged invention and adoption after late 2000 of cardiac MRI T2*
`
`measurements of heart iron concentration (see, e.g., Ex. 2003 ¶ 26). These
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`citations show that MRI TRT measurements of the heart continue to be considered
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`reliable, and that doctors continue to understand that the specific MRI TRT
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`measurements reported in Olivieri Abstract 1995 demonstrate successful treatment
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`of the heart.
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`E. Olivieri 1995 Anticipates the Challenged Claims
`
`29. Olivieri 1995 describes a study in which thalassemia major patients
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`who were unwilling or unable to take deferoxamine were treated with 75 mg/kg
`
`per day of deferiprone. (Ex. 1012 at 918-19.) Efficacy was assessed by
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`measurement of serum ferritin and liver iron concentration. (Id. at 919.) Serum
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`ferritin was measured every two months. (Id.) The document states that a
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`treatment was deemed a success if the liver iron concentration was less than 80
`
`μmol per gram (wet weight) and if serum ferritin was less than 2500 μg per liter.
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`(Id.) The study followed twenty-one patients for approximately three years. (Id.)
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`30. Figure 1 of Olivieri 1995 shows that ten patients had liver iron
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`concentration over the 80 μmol per gram threshold at the beginning of the study,
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`16
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`16 of 26
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`and the liver iron concentration of all of these patients decreased during the course
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`of the study. (Id.) Figure 1 of Olivieri 1995 reports two data points for each
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`patient, one initial and one final, but the data must be understood to represent the
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`trend for each patient. Liver iron concentrations over 80 μmol per gram are
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`indicative of cardiac iron overload. At the end of the study, two of these patients
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`had liver iron concentration that remained over the 80 μmol per gram threshold
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`(although the liver iron concentration nonetheless decreased). (Id.)
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`31. Figure 2 of Olivieri 1995 shows that six patients had serum ferritin
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`over the 5,000 μg per liter threshold at the beginning of the study, and two patients
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`had serum ferritin over the 5,000 μg per liter threshold at the study’s conclusion
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`(although serum ferritin nonetheless declined for these patients). (Id. at 920.)
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`Serum ferritin concentrations over 5,000 μg per liter are indicative of cardiac iron
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`overload. (See, e.g., Ex. 2024 at 24:17-25:14; see also Ex. 1002 ¶ 76; Ex. 1017
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`(Barman Balfour) at 563; Ex. 1022 (Diav Citrin) at 239; Ex. 1014 (Olivieri 1994)
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`at 575-76. Figure 2 reports two data points for each patient, one at the beginning
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`of the study and one at the end, but, since the document states that serum ferritin
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`was measured every other month, the data must be understood to represent the
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`trend for each patient.
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`32. Based on the serum ferritin and liver iron concentration data, it is
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`clear that the treated patients had cardiac iron overload. Thus, the treatment of
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`17
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`these patients anticipates the claims drawn to treating cardiac iron overload.
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`Moreover, Olivieri 1995’s treatment was successful, because the patients’ serum
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`ferritin and liver iron concentration declined.
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`33. Olivieri 1995 also anticipates the claims drawn to treating iron
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`induced cardiac disease. The article states that some patients had “complications”
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`with iron overload. (Ex.1012 at 918.) The most common “complication” of iron
`
`overload is iron induced cardiac disease. (Id.) Thus, the treatment of these
`
`patients anticipates the claims drawn to treating iron induced cardiac disease.
`
`34. Olivieri 1995 also reports the success in reducing cardiac iron
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`overload and iron induced cardiac disease: “In 10 patients in whom deferoxamine
`
`had failed to reduce hepatic iron stores to a level below 80 µmol of iron per gram
`
`(levels associated with an increased risk of cardiac disease and early death), the
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`body iron load was uniformly reduced with deferiprone (P<0.005). In 8 of the10
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`patients, hepatic iron concentrations decreased to less than 80 mmol per gram
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`…With the serum ferritin concentration used as an indirect means of assessing the
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`body iron burden, the findings were similar…” (Id. at 921.)
`
`35. These successful results expressly anticipate the results claimed in
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`claims 1, 2, 4, and 5, i.e., a decrease in cardiac iron. These results also inherently
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`anticipate the results claimed in claims 6, 7, 8, 9, and 10, i.e., preferential chelation
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`of cardiac iron because, to the extent that deferiprone preferentially chelated
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`18
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`18 of 26
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`cardiac iron in the claimed population as of the filing date of the patent,
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`deferiprone administered to the claimed population resulted in preferential
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`chelation as of the publication date of Olivieri 1995.
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`36. Despite the later development of other diagnostic tools, both as of the
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`’328 patent’s filing date and today, a person of ordinary skill in the art would have
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`understood that Olivieri 1995 discloses the treatment of blood transfusion-
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`dependent patients who had an iron overload condition of the heart. The serial
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`serum ferritin and liver iron concentration measurements are the same
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`measurements as those used in the ’328 patent measure iron overload. The patients
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`with serum ferritin and liver iron concentrations higher than the given thresholds
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`had iron overload in the range which indicate complications of iron overload, such
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`as cardiac iron overload and cardiac disease.
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`F. Hoffbrand 1998 Anticipates the Challenged Claims
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`37. Hoffbrand 1998 describes a study in which 51 “iron-overloaded
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`regularly transfused” patients were treated with 75 mg/kg/day of deferiprone. (Ex.
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`1007 at 295.) The patients’ cardiac function was annually monitored by multiple
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`uptake gated acquisition scans of the heart (“MUGA” scans), which measures left
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`ventricular ejection fraction (LVEF), and is a reliable measure of cardiac function.
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`(See Ex. 1058 at 49:11-17 (Coates testifying as to the reliability of MUGA scans
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`for measuring LVEF); Ex. 1059 at 19:2-21:20 (Pennell testifying as to the
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`19
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`reliability of MUGA scans for measuring LVEF); Ex. 2022 at 685 (“Radionuclide
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`ventriculography (MUGA scan) is a reproducible and accurate technique that
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`measures resting left ventricular ejection fraction (LVEFrest), and left ventricular
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`function during exercise (LVEFex).”); Ex. 2027 at 101.) LVEF values below 56%
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`are indicative of cardiac dysfunction and disease. (See Ex. 1058 at 44:2-45:2; Ex.
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`1059 at 24:15-25:18.)
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`38. Hoffbrand 1998 expressly states that four patients died of congestive
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`heart failure due to iron overload (“cardiac disease induced by iron overload”).
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`(Ex. 1007 at 296.) One of these patients was a 23-year-old male patient, who was
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`treated with deferiprone for 26 months. (Id.) This patient had iron induced cardiac
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`disease as of the beginning of his treatment: “The initial MUGA scan showed
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`moderately severe cardiomyopathy with a left ventricular ejection fraction (LVEF)
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`of 55% at rest and 40% on cold stress…” (Id.) While this patient ultimately died
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`of iron induced cardiac disease, he survived with deferiprone chelation therapy for
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`26 months after he already had detectable heart disease (“moderately severe
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`cardiomyopathy”). Absent successful chelation therapy, this patient would have
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`died far sooner than 26 months following this initial MUGA scan. This patient had
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`a final LVEF measurement of 54% decreasing to 42% on cold stress, which is
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`further evidence that deferiprone was able to remove cardiac iron and stabilize the
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`20
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`patient’s cardiac disease, at least for a time. This patient therefore was
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`successfully treated with 75 mg/kg/day deferiprone for some time.
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`39. Another patient who died of iron induced cardiac disease was a 24-
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`year-old female who was treated with deferiprone for 19 months. Her MUGA scan
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`showed initially “moderately severe cardiomyopathy,” with an initial LVEF of
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`48% at rest and 40% on cold stress. (Id.) Similar to the first patient, this patient
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`would have died far sooner than the 19 months during which she was treated with
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`deferiprone had she not had successful chelation therapy. This patient had a final
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`LVEF measurement of 46% at rest to 40% on cold stress, which is further evidence
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`that deferiprone was able to remove cardiac iron and stabilize the patient’s cardiac
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`disease, at least for a time. This patient, too, was successfully treated for some
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`time.
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`40. A third patient who died of iron induced cardiac disease as a 30-year-
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`old male who was treated with deferiprone for 24 months. (Id.) His MUGA scan,
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`done as part of “routine yearly testing,” showed initially “moderately severe
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`cardiomyopathy,” with an initial LVEF of 51% at rest falling to 43% on stress.
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`(Id.) This patient was taken off deferiprone treatment 4 months before his death
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`and switched to deferoxamine. (Id.) Similar to the first and second patients, this
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`patient would have died far sooner than the 24 months during which she was
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`treated with deferiprone had she not had successful chelation therapy. This patient
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`21
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`had a final LVEF measurement (after 2 years) of 49% at rest to 41% on cold stress,
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`which is further evidence that deferiprone was able to remove cardiac iron and
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`stabilize the patient’s cardiac disease, at least for a time. This patient, too, was
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`successfully treated for some time.
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`41. The treatment o
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