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.
`________________
`
`Case IPR2017-01446
`U.S. Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`________________
`
`
`SECOND DECLARATION OF THOMAS D. COATES, M.D.,
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
`Apotex Tech.
`Ex. 2035
`
`

`

`Table of Contents
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`INSTITUTED GROUNDS .............................................................................. 1
`
`III. BACKGROUND OF THE TECHNOLOGY .................................................. 2
`
`A. Methods to Assess Cardiac Function .................................................... 2
`
`B.
`
`Iron Chelation Therapy in Blood Transfusion Dependent Thalassemia
`Patients .................................................................................................. 3
`
`IV. THE ’328 PATENT ......................................................................................... 4
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART ............................................. 4
`
`VI. CLAIM CONSTRUCTION ............................................................................ 4
`
`VII. THE PRIOR ART ............................................................................................ 6
`
`A. Hoffbrand 1998 (Ex. 1007) ................................................................... 6
`
`B. Olivieri Abstract 1995 (Ex. 1010) ......................................................... 6
`
`C. Olivieri 1995 (Ex. 1012) ....................................................................... 7
`
`VIII. THE PRIMARY REFERENCES FAIL TO DISCLOSE EACH ELEMENT
`OF CLAIMS 1, 2, 4-10, AND DEPENDENT CLAIMS THEREFROM ....... 7
`
`A. Hoffbrand 1998 does not explicitly or inherently disclose or teach or
`suggest each and every claim limitation ............................................... 8
`
`1.
`
`
`
`2.
`
`
`
`
`Hoffbrand 1998 does not disclose or teach or suggest treating a
`blood transfusion dependent patient having a condition on the
`spectrum of cardiac disease due to iron overload ....................... 8
`
`Hoffbrand 1998 does not disclose or teach or suggest
`administering a therapeutically effective amount of deferiprone
`such that the methods of treatment required by claims 1, 2, and
`4-10 were successfully practiced ................................................ 9
`
`B. Olivieri Abstract 1995 does not explicitly or inherently disclose or
`teach or suggest each and every claim limitation ...............................12
`
`ii
`
`Apotex Tech.
`Ex. 2035
`
`

`

`1.
`
`
`
`2.
`
`
`
`
`Olivieri Abstract 1995 does not disclose treating a blood
`transfusion dependent patient having a condition on the
`spectrum of cardiac disease due to iron overload .....................12
`
`Olivieri Abstract 1995 does not disclose administering a
`therapeutically effective amount of deferiprone such that the
`methods of treatment required by claims 1, 2, and 4-10 are
`practiced ....................................................................................13
`
`C. Olivieri 1995 does not explicitly or inherently disclose or teach or
`suggest each and every claim limitation .............................................14
`
`1.
`
`
`
`2.
`
`
`
`
`Olivieri 1995 does not disclose or suggest treating a blood
`transfusion dependent patient having a condition on the
`spectrum of cardiac disease due to iron overload .....................14
`
`Olivieri 1995 does not disclose or suggest administering a
`therapeutically effective amount of deferiprone such that the
`methods of treatment required by claims 1, 2, and 4-10 are
`practiced ....................................................................................16
`
`
`
`iii
`
`Apotex Tech.
`Ex. 2035
`
`

`

`I, Thomas D. Coates, M.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I previously provided a declaration (Ex. 2001) dated September 8,
`
`2017 in these proceedings in support of Patent Owner’s Preliminary Response
`
`(“First Coates Decl.”). In it, I expressed my opinion that the subject matter
`
`claimed in U.S. Patent 7,049,328 (“the ’328 patent”) is novel and non-obvious, as
`
`those concepts have been explained to me, over the prior art references cited by
`
`Taro Pharmaceuticals USA, Inc. (“Taro” or “Petitioner”).
`
`2. My background and qualifications, set forth in paragraphs 1-7 of the
`
`First Coates Decl. (Ex. 2001), remain unchanged. Further, my curriculum vitae
`
`(“CV”), previously submitted as Ex. 2002, remains unchanged.
`
`3.
`
`The opinions I expressed in the First Coates Decl. (Ex. 2001) also
`
`remain unchanged. Thus, the opinions I express in this Second Declaration are in
`
`addition to those expressed in the First Coates Decl. (Ex. 2001.)
`
`II.
`
`INSTITUTED GROUNDS
`
`4.
`
`The following table summarizes the claims of the ’328 patent
`
`challenged by Taro and the bases and references providing grounds for institution
`
`of this Inter Partes Review (“IPR”):
`
`1
`
`Apotex Tech.
`Ex. 2035
`
`

`

`Reference(s)
`
`Basis
`
`Claims Challenged
`
`Hoffbrand 1998
`Olivieri Abstract 1995
`Olivieri 1995
`Hoffbrand 1998
`Olivieri Abstract 1995
`Olivieri 1995
`
`§ 102(b)
`§ 102(b)
`§ 102(b)
`§ 103(a)
`§ 103(a)
`§ 103(a)
`
`(Institution Decision at 41.)
`
`1, 2, 4-11, 13-17, 19
`1, 2, 4-11, 13-17, 19
`1, 2, 4-11, 13-17, 19
`1, 2, 4-17, 19
`1, 2, 4-17, 19
`1, 2, 4-17, 19
`
`5.
`
`It has been explained to me that “§ 102(b)” stands for the section of
`
`the patent statute pertaining to anticipation. My understanding of the legal
`
`standards for anticipation are the same as set forth in the First Coates Decl. (Ex.
`
`2001 at ¶¶ 9-11.)
`
`6.
`
`It has been explained to me that “§ 103(a)” stands for the section of
`
`the patent statute pertaining to obviousness. My understanding of the legal
`
`standards for obviousness are the same as set forth in the First Coates Decl. (Ex.
`
`2001 at ¶¶ 12-15.)
`
`III. BACKGROUND OF THE TECHNOLOGY
`
`7.
`
`The background of the technology, set forth in paragraphs 16-24 of
`
`the First Coates Decl. (Ex. 2001), remains unchanged. I further supplement the
`
`background of the technology as follows.
`
`A. Methods to Assess Cardiac Function
`
`8.
`
`As a hematologist, in order to evaluate cardiac function in blood
`
`transfusion dependent patients, I rely on and work in concert with cardiologists,
`
`2
`
`Apotex Tech.
`Ex. 2035
`
`

`

`such as Dr. Pennell. In evaluating and monitoring cardiac function, I understand
`
`that cardiologists rely upon methodology such as the left ventricular ejection
`
`fraction (“LVEF”), and various other methodology such as echocardiograms,
`
`electrocardiograms (e.g., Holter monitoring), radionuclide ventriculography (e.g.,
`
`using multiple uptake gated acquisition (“MUGA”) scans of the heart), cardiac
`
`computed tomography, and cardiac MRI. I have a general understanding of these
`
`techniques, but defer to cardiologists such as Dr. Pennell for detailed description of
`
`these methods and techniques.
`
`9.
`
`I understand that at the time of the invention, “there was a . . . belief
`
`that a liver iron concentration (“LIC”) >80 µmol of iron per gram of liver
`
`(“µmol/g”), wet weight (or >15 mg/g dry weight), was associated with an
`
`increased risk of heart disease in blood transfusion dependent patients.” (Ex. 2026
`
`at ¶ 3 (citing Ex. 2003 at 7-8; Ex. 1012 at 921; Ex. 2011 at 419; Ex. 1017 at 565).)
`
`I further understand, however, that Dr. Pennell and others have shown that liver
`
`iron concentration “in no way predicts cardiac iron content” and that Dr.
`
`Pennell cited a study by Berdoukas that unequivocally “disproved Olivieri and
`
`Brittenham’s proposed association between cardiac iron levels and LIC.” (Ex.
`
`2026 at ¶¶ 4-5 (citing Ex. 2022 at 685, Table 1).)
`
`B.
`
`Iron Chelation Therapy in Blood Transfusion Dependent
`Thalassemia Patients
`
`10. As I previously explained in the First Coates Decl., patients with TM
`
`3
`
`Apotex Tech.
`Ex. 2035
`
`

`

`require regular and lifelong blood transfusions for survival. (Ex. 2001 at ¶ 18.)
`
`However, because hemoglobin is an iron-rich protein, chronic blood transfusions
`
`in TM patients leads to the progressive accumulation of iron in the body, a
`
`condition called “iron overload.” (Id.) To prevent damage to the organs from this
`
`excess iron, chelation therapy is required. (Id. at ¶ 19.) And, because the blood
`
`transfusions in TM patients are necessarily lifelong, the administration of chelation
`
`therapy (i.e., iron chelators such as deferoxamine, deferiprone, and deferasirox) to
`
`prevent iron excess buildup from these transfusion is correspondingly lifelong.
`
`(See e.g., Ex. 2001 at ¶ 22.) Indeed, if TM patients—who must necessarily receive
`
`blood transfusions for survival—are not maintained on an iron chelation regimen,
`
`the inevitable outcome is death.
`
`IV. THE ’328 PATENT
`
`11. My understanding of the ’328 patent and the claims therein remain the
`
`same as set forth in the First Coates Decl. (Ex. 2001 at ¶ 25.)
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`
`12. My understanding of the level of ordinary skill in the art (“POSA”) at
`
`the time of the invention remains the same as set forth in the First Coates Decl.
`
`(Ex. 2001 at ¶¶ 26-28.)
`
`VI. CLAIM CONSTRUCTION
`
`13.
`
`I have reviewed a copy of the Patent Trial and Appeal Board’s
`
`4
`
`Apotex Tech.
`Ex. 2035
`
`

`

`(“PTAB”) Decision granting Institution of Inter Partes Review pursuant to 37
`
`C.F.R. § 42.108 (“Institution Decision”). I understand that the PTAB has rejected
`
`certain constructions previously adopted by the United States District Court for the
`
`Eastern District of Texas in a related litigation between Patent Owner and
`
`Petitioner (Ex. 2010), including a finding that the results recited in claims 2, 4, 5,
`
`7, 8, 11, and 19 are limitations of these claims, and not merely a recitation of
`
`intended results. (Ex. 2001 at ¶ 32 (citing Ex. 2010 at 30.) I understand that the
`
`PTAB, in contrast, has interpreted these “claimed results” as non-limiting.
`
`(Institution Decision at 7-9.)
`
`14. As set forth in the First Coates Decl., in my opinion a POSA would
`
`view the results recited in claims 2, 4, 5, 7, 8, 11, and 19 as limitations of these
`
`claims. (Ex. 2001 at ¶¶ 29-33.) Specifically, a POSA would view the results in
`
`claims 2, 4, 5, 7, and 8 as reflective of successfully practicing the methods of
`
`treatment recited in the preambles of these claims, which require: treating iron
`
`loading in the heart (claim 2, 7, 8); stabilizing iron induced heart disease (claim
`
`4); and reducing the iron burden in the heart (claim 5). Further, in addition to the
`
`methods of claims 2, 4, 5, 7, and 8, the results required by claims 11 and 19 are
`
`also reflective of the successful practice of: a method of treating iron induced
`
`cardiac/heart disease (claims 1, 6, and 9); and reducing the occurrence of iron-
`
`induced cardiac disease (claim 10). (Ex. 1001.) Thus, regardless of whether the
`
`5
`
`Apotex Tech.
`Ex. 2035
`
`

`

`results of claims 2, 4, 5, 7, 8, 11, and 19 are explicit limitations of these claims, a
`
`POSA would understand that they reflect the successful practice of the claimed
`
`methods. For this reason, should the PTAB maintain that the claimed results are
`
`merely intended results (and therefore non-limiting), this does not change my
`
`opinion that these claims are not anticipated or rendered obvious by any of
`
`Hoffbrand 1998, Olivieri Abstract 1995, or Olivieri 1995.
`
`VII. THE PRIOR ART
`
`A. Hoffbrand 1998 (Ex. 1007)
`
`15.
`
`In addition to the summary provided in the First Coates Decl. (Ex.
`
`2001 at ¶¶ 36-37), I note that Hoffbrand 1998 discloses that “cardiac function was
`
`monitored by annual multiple uptake gated acquisition (MUGA) scans of the heart,
`
`and measuring left ventricular ejection fraction [LVEF] at rest and under stress.”
`
`(Ex. 1007 at 296.) Hoffbrand 1998 reports that MUGA scan results “showed no
`
`significant change at rest and on stress between initial and final values in the 26
`
`patients.” (Id. at 298.) Further, Hoffbrand 1998 concludes that “the efficacy of
`
`deferiprone is dose related and it might be that increasing the dose from 75 to
`
`100 mg/kg/d in those that can tolerate it may be more effective in some patients.”
`
`(Id. at 299.)
`
`B. Olivieri Abstract 1995 (Ex. 1010)
`
`16.
`
`In addition to the summary provided in the First Coates Decl. (Ex.
`
`6
`
`Apotex Tech.
`Ex. 2035
`
`

`

`2001 at ¶¶ 38-39), I note that Olivieri Abstract 1995 discloses that initial LIC in
`
`patients treated with deferiprone was 9.1±5.4 mg/g dry weight, which remained
`
`unchanged during the course of treatment. (Ex. 1010.) I also note that Olivieri
`
`Abstract 1995 provides no discussion of the cardiac function for any patient (e.g.,
`
`LVEF, MUGA scan results, etc.). (Ex. 1010.)
`
`C. Olivieri 1995 (Ex. 1012)
`
`17.
`
`In addition to the summary provided in the First Coates Decl. (Ex.
`
`2001 at ¶¶ 41-42), I note that Olivieri 1995 discloses that in 10 patients who had
`
`previously received ineffective chelation therapy with deferoxamine, 2 patients
`
`exhibited LIC >80 µmol/g after a mean of 34.8±3.8 months of treatment with
`
`deferiprone. (Ex. 1012 at 919-20 (see e.g., Figure 1).) I also note that Olivieri
`
`1995 provides no discussion of the cardiac function for any patient (e.g., LVEF,
`
`MUGA scan results, etc.). (Ex. 1012.)
`
`VIII. THE PRIMARY REFERENCES FAIL TO DISCLOSE EACH
`ELEMENT OF CLAIMS 1, 2, 4-10, AND DEPENDENT CLAIMS
`THEREFROM
`
`18.
`
`I maintain the opinions expressed in the First Coates Decl. that the
`
`Primary References (namely, Hoffbrand 1998, Olivieri Abstract 1995, and Olivieri
`
`1995) do not disclose, either expressly or inherently, each and every limitation of
`
`claims 1, 2, 4-11, 13-17, and 19.
`
`19. Further, I maintain the opinions expressed in the First Coates Decl.
`
`7
`
`Apotex Tech.
`Ex. 2035
`
`

`

`that the Primary References (namely, Hoffbrand 1998, Olivieri Abstract 1995, and
`
`Olivieri 1995) do not teach or suggest each and every limitation of claims 1, 2, 4-
`
`17, and 19. I further supplement my opinions as follows.
`
`A. Hoffbrand 1998 does not explicitly or inherently disclose or teach
`or suggest each and every claim limitation
`
`20. My opinion that Hoffbrand 1998 does not anticipate or make obvious
`
`the instituted claims remains the same as set forth in the First Coates Decl. (Ex.
`
`2001 at ¶¶ 54-57, 81-84.) I further supplement my opinion as follows.
`
`1. Hoffbrand 1998 does not disclose or teach or suggest
`treating a blood transfusion dependent patient having a
`condition on the spectrum of cardiac disease due to iron
`overload
`
`21. Dr. Mehta and Taro assert that Hoffbrand 1998 anticipates claims 1, 2,
`
`and 6-9 because it discloses “that ten patients had a liver iron content above
`
`15.0 mg/g dry weight, which falls in the range of iron content that has been
`
`associated with cardiac disease due to iron overload.” (Ex. 1002 at ¶ 74; Pet. at 35-
`
`36.) I disagree.
`
`22. Specifically, I note that Hoffbrand 1998 states that a liver iron level of
`
`15 mg/g is the threshold level above which “liver and cardiac damage are likely to
`
`occur.” (Ex. 1007 at 298 (emphasis added); see also id. at Abstract (“levels above
`
`15.0 mg, a level associated with a high risk of cardiac disease due to iron
`
`overload.”) (emphasis added).) A POSA would understand that “likely” is not
`
`8
`
`Apotex Tech.
`Ex. 2035
`
`

`

`synonymous with inevitably, and thus the ten patients with LIC >15.0 mg/g dry
`
`weight disclosed in Hoffbrand 1998 did not necessarily or inevitably have cardiac
`
`disease due to iron overload.
`
`23. Further, I understand from Dr. Pennell that “there is no correlation
`
`between LIC and an iron overload condition in the heart” and that there is no
`
`correlation between LIC and cardiac dysfunction. (See Ex. 2026 at ¶¶ 15-16.)
`
`Thus, in the absence of additional information concerning the cardiac condition of
`
`the ten patients disclosed in Hoffbrand 1998 as having LIC >15.0 mg/g dry weight,
`
`a POSA would not have reasonably concluded that those patients had cardiac
`
`disease due to iron overload.
`
`24. Accordingly, I maintain and further support my opinion that a POSA
`
`would not view Hoffbrand 1998 as teaching or suggesting treatment of a blood
`
`transfusion dependent patient having a condition on the spectrum of cardiac
`
`disease due to iron overload, as required by claims 1, 2, and 4-10.
`
`2. Hoffbrand 1998 does not disclose or teach or suggest
`administering a therapeutically effective amount of
`deferiprone such that the methods of treatment required by
`claims 1, 2, and 4-10 were successfully practiced
`
`25. Contrary to Taro and Dr. Mehta’s assertions, administration of
`
`75 mg/kg of deferiprone does not inherently practice the claimed methods of
`
`treatment. As Hoffbrand 1998 reports, despite treatment with 75 mg/kg daily of
`
`deferiprone, MUGA scan results showed “no significant change at rest and on
`
`9
`
`Apotex Tech.
`Ex. 2035
`
`

`

`stress between initial and final values in 26 patients.” (Ex. 1007 at 298.)
`
`26. Further, Hoffbrand 1998 discloses that not only did administration of
`
`75 mg/kg of deferiprone not provide “significant change” in cardiac function, but
`
`also four patients (three of whom had thalassemia) died of iron-induced cardiac
`
`disease despite deferiprone treatment. (Id. at 296, 299.) I understand that Dr.
`
`Mehta expressed doubt that, of the five patient deaths in Hoffbrand 1998, “four
`
`[died] of congestive heart failure [“CHF”] due to iron overload” (Ex. 2024 at 104:2
`
`– 108:2.) In my opinion, a POSA viewing Hoffbrand 1998 would have no reason
`
`to doubt the authors’ conclusion that four patient deaths were due to iron induced
`
`CHF. Thus, a POSA would reasonably conclude that the 75 mg/kg/d deferiprone
`
`was not an effective treatment of an iron overload condition of the heart in these
`
`patients who died.
`
`27. What is more, Hoffbrand 1998 reports that despite treatment with
`
`75 mg/kg of deferiprone for a mean of 40 months, 8 of 17 patients tested (47%)
`
`had LIC “above 15 mg/g dry weight, levels at which . . . cardiac damage are likely
`
`to occur.” (Ex. 1007 at 298.) Both Taro and Dr. Mehta rely on 15 mg/g dry
`
`weight as a threshold value above which there is an association with an increased
`
`risk of cardiac disease due to iron overload. (Pet. at 35-36; Ex. 1002 at ¶ 74.)
`
`Accordingly, although it has been conclusively established that a LIC of >15 mg/g
`
`dry weight has no direct correlation with abnormal cardiac function (see Ex. 2026
`
`10
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`Apotex Tech.
`Ex. 2035
`
`

`

`at ¶¶ 4-5 (citing Ex. 2022)), if a POSA thought that a liver iron content of
`
`>15 mg/g dry weight was associated with cardiac disease (as did Taro and Dr.
`
`Mehta), this would indicate to a POSA that these 8 patients were not experiencing
`
`treatment or stabilization of iron induced heart disease despite treatment with
`
`75 mg/kg daily of deferiprone. Thus, a POSA viewing Hoffbrand 1998 would
`
`reasonably conclude that this study did not successfully treat any patients having
`
`an iron overload condition of the heart.
`
`28. Similarly, Hoffbrand 1998 reports that 9 of 15 patients (i.e., 60% of
`
`patients tested) who had received deferiprone therapy for 3 or more years had
`
`serum ferritin levels above 2500 µg/L, a level considered by some to indicate
`
`inadequate chelation therapy. (Ex. 1007 at 298.) Again, if a POSA thought that a
`
`serum ferritin level >2500 µg/L indicated inadequate chelation therapy, this would
`
`indicate to a POSA that these 9 patients were not adequately chelated, and thus
`
`would not be experiencing treatment or stabilization of iron induced heart disease
`
`despite treatment with 75 mg/kg daily of deferiprone. Indeed, Hoffbrand 1998
`
`concludes that “deferiprone is inappropriate therapy for patients with iron-induced
`
`cardiomyopathy . . . .” (Ex. 1007 at 298-299.)
`
`29. Accordingly, I maintain and further support my opinion that a POSA
`
`would not view Hoffbrand 1998 as teaching or suggesting the administration of a
`
`therapeutically effective amount of deferiprone such that the methods of treatment
`
`11
`
`Apotex Tech.
`Ex. 2035
`
`

`

`required by claims 1, 2, and 4-10 were practiced or such that a POSA could
`
`reasonably expect success in doing so.
`
`B. Olivieri Abstract 1995 does not explicitly or inherently disclose or
`teach or suggest each and every claim limitation
`
`30. My opinion that Olivieri Abstract 1995 does not anticipate or make
`
`obvious the instituted claims remains the same as set forth in the First Coates Decl.
`
`(Ex. 2001 at ¶¶ 58-66, 81-84.) I further supplement my opinion as follows.
`
`1. Olivieri Abstract 1995 does not disclose treating a blood
`transfusion dependent patient having a condition on the
`spectrum of cardiac disease due to iron overload
`
`31. Dr. Mehta and Taro assert that Olivieri Abstract 1995 teaches a
`
`patient having an iron overload condition of the heart because patients described
`
`therein exhibited below average T2 relaxation times (“TRT”) (23.9±6.4 msec vs
`
`normal TRT of >32 msec). (See Pet. at 38; Ex. 1002 at ¶ 75.) I disagree.
`
`32. First, as Dr. Pennell explains, the TRT values disclosed in Olivieri
`
`Abstract 1995 were unreliable. (Ex. 2026 at ¶ 25.) For this reason, caregivers such
`
`as myself did not rely upon TRT relaxation times in order to diagnose iron loading
`
`in the heart or cardiac disease. Thus, based on TRT values in Olivieri Abstract
`
`1995, a POSA would not have concluded that those patients had iron loading in the
`
`heart, had an iron overload condition of the heart, or had cardiac disease due to
`
`iron overload. (See Ex. 2026 at ¶¶ 24-27.)
`
`33.
`
`Second, the prior art (e.g., Ex. 1007 at 297) taught that an LIC of
`
`12
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`Apotex Tech.
`Ex. 2035
`
`

`

`>15 mg/kg was associated with an increased risk of heart disease, and both Taro
`
`and Dr. Mehta relied on this threshold value to assert that ten patients with an LIC
`
`value of >15mg/kg had an iron overload condition of the heart (Pet. at 35-36; Ex.
`
`1002 at ¶ 74). Assuming that an LIC of > 15 mg/kg was associated with an
`
`increased risk of heart disease, which we know not to be the case (see Ex. 2026 at
`
`¶¶ 4-5 (citing Ex. 2022)), a POSA would not have associated an LIC of 9.5±5.4
`
`mg/g dry weight in Olivieri Abstract 1995 with a condition on the spectrum of
`
`cardiac disease. For this additional reason, a POSA would not have reasonably
`
`concluded that the patients in Olivieri Abstract 1995 necessarily had a condition on
`
`the spectrum of cardiac disease due to iron overload.
`
`34. Accordingly, I maintain and further support my opinion that a POSA
`
`would not view Olivieri Abstract 1995 as teaching the treatment of a blood
`
`transfusion dependent patient having a condition on the spectrum of cardiac
`
`disease due to iron overload as required by claims 1, 2, and 4-10.
`
`2. Olivieri Abstract 1995 does not disclose administering a
`therapeutically effective amount of deferiprone such that
`the methods of treatment required by claims 1, 2, and 4-10
`are practiced
`
`35.
`
`It is also my opinion that Olivieri Abstract 1995 does not disclose or
`
`suggest administering a therapeutically effective amount of deferiprone such that
`
`the methods of treatment required by claims 1, 2, and 4-10 are practiced or such
`
`that a POSA could reasonably expect success in doing so.
`
`13
`
`Apotex Tech.
`Ex. 2035
`
`

`

`36. For example, Olivieri Abstract 1995 discloses that the patients therein
`
`had a mean initial liver iron content (“LIC”) of 9.1±5.4 mg/g dry weight that
`
`“remain[ed] unchanged” despite deferiprone therapy. (Ex. 1010.) A POSA would
`
`understand this disclosure to mean that 75 mg/kg daily of deferiprone had no effect
`
`on hepatic iron levels, much less cardiac iron.
`
`37. Accordingly, I maintain and further support my opinion that a POSA
`
`would not view Olivieri Abstract 1995 as teaching the administration of a
`
`therapeutically effective amount of deferiprone such that the methods of treatment
`
`required by claims 1, 2, and 4-10 were practiced.
`
`C. Olivieri 1995 does not explicitly or inherently disclose or teach or
`suggest each and every claim limitation
`
`38. My opinion that Olivieri 1995 does not anticipate or make obvious the
`
`instituted claims remains the same as set forth in the First Coates Decl. (Ex. 2001
`
`at ¶¶ 73-84.) I further supplement my opinion as follows.
`
`1. Olivieri 1995 does not disclose or suggest treating a blood
`transfusion dependent patient having a condition on the
`spectrum of cardiac disease due to iron overload
`
`39.
`
`I understand that in the institution decision, the Board found that
`
`Olivieri 1995 taught patients having an “iron overload condition of the heart” or
`
`“iron induced cardiac disease” (as required by claims 1, 2, and 4-10) based on the
`
`disclosure of ten patients with iron levels “associated with an increased risk of
`
`cardiac disease and early death” who, when treated with a therapeutically effective
`
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`amount of deferiprone showed reduced iron load. (Institution Decision at 30.) I
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`respectfully disagree with that finding.
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`40. First, the ten patients in Olivieri 1995 referenced by the Board had
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`hepatic iron concentrations above 80 µmol/g, a level “associated with an increased
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`risk of cardiac disease . . . .” (Ex. 1012 at 921 (emphasis added).) However, as
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`discussed above concerning Hoffbrand 1998, a patient at risk of cardiac disease
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`does not necessarily or inevitably have cardiac disease due to iron overload.
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`41.
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`Second, as Dr. Pennell explained, LIC is not an effective predictor of
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`cardiac disease because it does not directly correlate with cardiac iron load. (See
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`Ex. 2026 at ¶¶ 4-5 (discussing Ex. 2022).) I have found this to be true in my own
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`practice where a patient with a LIC >15 mg/g wet weight (the amount “associated
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`with cardiac disease”) did not have a clinically significant level of iron in the heart.
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`(See, e.g., Ex. 2025 at 38 showing a patient with dramatic increases in HIC without
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`any significant iron accumulation in the heart.) This is because the rate of iron
`
`loading in the heart is typically much slower than either the body as a whole or the
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`liver. (See, e.g., Ex. 2025 at 38). Thus, it is my opinion that a POSA would not
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`reasonably conclude that all ten patients with the elevated iron levels in Olivieri
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`1995 also necessarily and inevitably fell into the spectrum of patients having an
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`iron overload condition of the heart based on Olivieri 1995’s teaching of the
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`association between LIC and cardiac disease.
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`42. Accordingly, I maintain and further support my opinion that a POSA
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`would not view Olivieri 1995 as teaching or suggesting the treatment of a blood
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`transfusion dependent patient having a condition on the spectrum of cardiac
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`disease due to iron overload as required by claims 1, 2, and 4-10.
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`2.
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`Olivieri 1995 does not disclose or suggest administering a
`therapeutically effective amount of deferiprone such that
`the methods of treatment required by claims 1, 2, and 4-10
`are practiced
`
`43.
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`It is also my opinion that Olivieri 1995 does not disclose or suggest
`
`administering a therapeutically effective amount of deferiprone such that the
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`methods of treatment required by claims 1, 2, and 4-10 are practiced or such that a
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`POSA could reasonably expect success in doing so.
`
`44.
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`For example, Olivieri 1995 discloses that in 10 patients who had
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`previously received ineffective chelation therapy with deferroxamine, 2 patients
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`had liver iron concentrations above 80 µmol/g after a mean of 34.8±3.8 months of
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`treatment with deferiprone. (Ex. 1012 at 919-20 (see e.g., Figure 1).) Based on
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`this information, a POSA would have reasonably concluded (albeit erroneously
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`(see Ex. 2026 at ¶¶ 4-5 (citing Ex. 2022)) that these 2 patients were not effectively
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`chelated, and thus were not experiencing treatment or stabilization of iron induced
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`heart disease despite administration of 75 mg/kg daily of deferiprone.
`
`45. Moreover, I also note that Olivieri 1995 provides no data
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`related to cardiac function (e.g., LVEF, MUGA scan results, etc.). (Ex. 1012.)
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`Thus, a POSA would have no information upon which to reasonably conclude that
`
`the patients in Olivieri 1995 were administered a therapeutically effective amount
`
`of deferiprone such that the methods of treatment required by claims 1, 2, and 4-10
`
`were practiced.
`
`46.
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`Therefore, it is my opinion that a POSA would not view Olivieri 1995
`
`as teaching or suggesting the administration of a therapeutically effective amount
`
`of deferiprone such that the methods of treatment required by claims 1, 2, and 4-10
`
`were practiced.
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`I declare under penalty of perjury that, to the extent of my knowledge andbelief,
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`the foregoing is true and correct.
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`I further declare that all statements made herein
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`of my own knowledgearetrue andthat all statements made on information and
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`belief are believed to be true; and further that these statements were made with the
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`understanding that knowing and willful false statements and the like so made are
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`punishable by fine or imprisonment, or both, under section 1001 oftitle 18 of the
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`United States Code.
`
` Date: February 22, 2018
`homas D. Coates, M.D.
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`Apotex Tech.
`Ex. 2035
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