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