IPR2017-01446
`U.S. Patent No. 7,049,328
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`
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`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 No. IPR2017-01446
`
`U.S. Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`________________
`
`
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`
`
`
`

`

`I. 
`II. 
`
`E. 
`
`
`Table of Contents
`INTRODUCTION ........................................................................................... 1 
`BACKGROUND ............................................................................................. 2 
`A. 
`The Treatment and Care of Thalassemia Major Patients ...................... 2 
`B. 
`Prior Art Testing of Deferiprone in TM Patients .................................. 5 
`C. 
`The Invention of the ’328 Patent ........................................................... 6 
`The ’328 Patent & FERRIPROX® ............................................................ 7 
`D. 
`1. 
`The Teachings of the ’328 Patent ............................................... 7 
`2. 
`The Challenged Claims of the ’328 Patent ................................. 9 
`Procedural History ............................................................................... 10 
`1. 
`The Grounds for Inter Partes Review ...................................... 10 
`2. 
`Related District Court Litigation .............................................. 10 
`III.  THE LEVEL OF SKILL IN THE ART ........................................................ 11 
`IV.  CLAIM CONSTRUCTION .......................................................................... 11 
`A.  An “Iron Overload Condition of the Heart” Requires a Condition on
`
`the Spectrum of Cardiac Disease ........................................................ 11 
`B. 
`The “Claimed Results” Would be Understood by a POSA to Define
`
`Whether the Methods of Treatment of Claims 1, 2, and 4-10 are
`
`Successfully Achieved ........................................................................ 13 
`1. 
`Claims 1, 2, 4-10, and 19 require different results ................... 14 
`2. 
`The intrinsic record shows that the claimed results were
`
`relevant to patentability ............................................................. 15 
`Bristol-Myers and its Progeny Are Distinguishable from this Case ... 17 
`The Board’s Reliance on Catalina is Misplaced ................................ 20 
`
`C. 
`D. 
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`U.S. Patent No. 7,049,328
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`V. 
`
`
`Even if the Board Finds that the Results Following “therapeutically
`E. 
`effective amount” Are Not Limiting, Taro’s Petition Acknowledges
`
`that the Preambles of Claims 1, 2, and 4-10 Are Limiting ................. 21 
`
`CLAIMS 1, 2, 4-11, 13-17, AND 19 ARE NOT EXPRESSLY OR
`INHERENTLY ANTICIPATED BY THE PRIOR ART ............................. 23 
`The Patient Populations Required by Claims 1, 2, and 4-10 Are Not
`A. 
`
`Explicitly or Inherently Disclosed by Hoffbrand 1998, Olivieri 1995
`
`or Olivieri Abstract 1995 ..................................................................... 26 
`Hoffbrand 1998 does not expressly or inherently disclose
`1. 
`
`treating a blood transfusion-dependent patient having iron-
`
`induced cardiac disease ............................................................. 26 
`2. 
`Olivieri 1995 does not expressly or inherently disclose treating
`
`a blood transfusion-dependent patient having iron-induced
`
`cardiac disease ........................................................................... 29 
`3. 
`Olivieri Abstract 1995 does not expressly or inherently disclose
`
`treating a blood transfusion-dependent patient having iron-
`
`induced cardiac disease ............................................................. 31 
`The Claimed Methods of Treatment Required by Claims 1, 2, and 4-
`10 Are Not Explicitly or Inherently Disclosed by Hoffbrand 1998,
`Olivieri 1995 or Olivieri Abstract 1995 .............................................. 36 
`Hoffbrand 1998 does not expressly or inherently disclose that
`1. 
`
`the claimed methods were successfully practiced .................... 37 
`2. 
`Olivieri 1995 does not expressly or inherently disclose that the
`
`claimed methods were successfully practiced .......................... 39 
`3. 
`Olivieri Abstract 1995 does not expressly or inherently disclose
`
`that the claimed methods were successfully practiced ............. 42 
`C.  Anticipation Requires that the Claimed Methods of Treatment Were
`
`Successfully Practiced in the Prior Art ............................................... 45 
`VI.  CLAIMS 1, 2, 4-17, AND 19 ARE NOT OBVIOUS .................................. 47 
`
`B. 
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`iii
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`A. 
`
`B. 
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`
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`Taro Fails to Set Forth a Proper Obviousness Analysis under Graham .
` ............................................................................................................. 49 
`Claims 1, 2, 4-17, or 19 of the ’328 Patent Are Not Obvious Over
`Hoffbrand 1998, Olivieri 1995, or Olivieri Abstract 1995, Alone or in
`Combination with the Background Knowledge of a POSA ............... 51 
`Hoffbrand 1998 Provides a POSA No Reasonable Expectation
`1. 
`
`that the Claimed Methods Could be Practiced Successfully and
`
`Teaches Away from Treating Patients with an Iron Overload
`
`Condition of the Heart Using Deferiprone ............................... 51 
`2. 
`A POSA Would Have Been Aware of Later Publications
`
`Questioning the Disclosure of Olivieri 1995 and Olivieri
`
`Abstract 1995, Which Fail to Teach or Suggest the Claimed
`
`Methods ..................................................................................... 53 
`C.  Objective Indicia Of Non-Obviousness .............................................. 56 
`1. 
`Unexpected Results ................................................................... 56 
`2. 
`Long-Felt, but Unmet Need ...................................................... 57 
`3. 
`Industry Praise .......................................................................... 57 
`
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`
`
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`iv
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`IPR2017-01446
`U.S. Patent No. 7,049,328
`
`
`TABLE OF AUTHORITIES
`
`PAGE(S)
`
`CASES
`
`Allergan, Inc. v. Apotex, Inc.,
`
`754 F.3d 952 (Fed. Cir. 2014) ................................................................. 46, 47
`
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) ..................................................................... 48
`
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs.,
`246 F.3d 1368 (Fed. Cir. 2001) ............................................................... 17-19
`
`
`Catalina Mktg., Intl. v. Coolsavings.com,
`
`289 F.3d 801 (Fed. Cir. 2002) ................................................................. 20, 21
`
`Comark Commc’ns v. Harris Corp.,
`156 F.3d 1182 (Fed. Cir. 1998) ..................................................................... 14
`
`
`Cont’l Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) ............................................................... 23, 41
`
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct 2131 (2016) .................................................................................... 14
`
`
`D’Agostino v. MasterCard Int’l, Inc.,
`
`844 F.3d 945 (Fed. Cir. 2016) ....................................................................... 16
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`
`800 F.3d 1375, 1378-79 (Fed. Cir. 2015) ...................................................... 34
`
`Eli Lilly & Co. v. L.A. Biomedical Research Inst. at Harbor-UCLA Med. Ctr.,
`
`849 F.3d 1073 (Fed. Cir. 2017) ..................................................................... 23
`
`Endo Pharm. Inc. v. Depomed, Inc.,
`IPR2014-00653, Paper 12 (PTAB Sep. 29, 2014) ........................................ 23
`
`
`Front Row Techs., LLC v MLB Advanced Media, L.P.,
`IPR2015-01932, Paper 7 (PTAB Mar. 25, 2016) .................................... 49, 50
`
`
`
`v
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`

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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`Glaxo Inc. v. Novopharm Ltd.,
`
`52 F.3d 1043 (Fed. Cir. 1995) ....................................................................... 25
`
`Glaxosmithkline LLC v. Glenmark Pharm. Inc., USA,
`No. 14-877, 2016 WL 3186657 (D. Del. June 3, 2016) .......................... 15, 19
`
`
`Graham v. John Deere Co.,
`
`383 U.S. 1 (1966) ..................................................................................... 48, 49
`
`
`KSR Int’l Co. Teleflex Inc.,
`
`550 U.S. 398 (2007) ................................................................................ 48-50
`
`In re Copaxone 40 Mg,
`No. 14-1171, 2016 WL 873062 (D. Del. Mar. 7, 2016) ................................ 19
`
`
`In re King,
`
`801 F.2d 1324 (Fed. Cir. 1986) ..................................................................... 21
`
`In re Magnum Oil Tools Int’l, Ltd.,
`
`829 F.3d 1364 (Fed. Cir. 2016) ..................................................................... 49
`
`In re Montgomery,
`
`677 F.3d 1375, 1384 (Fed. Cir. 2012) ..................................................... 24, 38
`
`In re NuVasive, Inc.,
`
`842 F.2d 1376 (Fed. Cir. 2016) ..................................................................... 51
`
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ........................................................... 23-24, 35
`
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ....................................................................... 24
`
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01402, Paper 18 (PTAB Oct. 21, 2015) ................................... 49, 50
`
`
`King Pharm., Inc. v. Eon Labs, Inc.,
`
`616 F.3d 1267 (Fed. Cir. 2010) ............................................................... 45, 46
`
`
`vi
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`

`L.A. Biomedical Research Inst. at Harbor-UCLA Med. Ctr. v. Eli Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) ..................................................................... 18
`
`IPR2017-01446
`U.S. Patent No. 7,049,328
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`
`
`Microsoft Corp. v. Proxyconn, Inc.,
`
`789 F.3d 1292 (Fed. Cir. 2015) ..................................................................... 14
`
`Nike, Inc. v. Adidas AG,
`
`812 F.3d 1326 (Fed. Cir. 2016) ............................................................... 48, 49
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ............................................................... 35, 36
`
`
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) ..................................................................... 19
`
`PAGE(S)
`
`
`Winner Int’l Royalty Corp. v. Wang,
`202 F.3d 1340 (Fed. Cir. 2000) ..................................................................... 52
`
`
`
`STATUTES AND REGULATIONS
`
`35 U.S.C. § 101 ........................................................................................................ 21
`35 U.S.C. § 102(b) (pre-AIA) .................................................................................. 47
`35 U.S.C. § 103 (pre-AIA) ....................................................................................... 49
`35 U.S.C. § 112 ¶ 4 .................................................................................................. 47
`35 U.S.C. § 316(e) ................................................................................... 1, 24, 33, 47
`37 C.F.R. § 42.65(a) ................................................................................................. 25
`37 C.F.R. § 42.100(b) .............................................................................................. 14
`37 C.F.R. § 42.120(a) ................................................................................................. 1
`
`vii
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`

`

`INTRODUCTION
`Pursuant to 37 C.F.R. § 42.120(a), Patent Owner Apotex Technologies, Inc.
`
`IPR2017-01446
`U.S. Patent No. 7,049,328
`
`
`I.
`
`(“Apotex” or “Patent Owner”), hereby submits its Response to Taro
`
`Pharmaceuticals USA, Inc.’s (“Taro” or “Petitioner”) Petition for Inter Partes
`
`Review of U.S. Patent No. 7,049,328 (“Taro’s Petition” or “Pet.”). The Board
`
`instituted inter partes review of claims 1, 2, 4-11, 13-17, and 19 of U.S. Patent No.
`
`7,049,328 (“the ’328 patent”) on three anticipation grounds (Hoffbrand 1998,
`
`Olivieri Abstract 1995, and Olivieri 1995) and claims 1, 2, 4-17, and 19 on
`
`obviousness grounds concerning the same three references. In view of the
`
`evidence of record, the Board should find that Taro has not established by a
`
`preponderance of the evidence that any of the challenged claims of the ’328 patent
`
`are unpatentable. (35 U.S.C. § 316(e).)
`
`First, the prior art of record fails to expressly or inherently disclose the
`
`successful practice of the claimed methods in the patient population required by
`
`the claims of the ’328 patent. Thus, Taro’s Petition relies upon conclusory expert
`
`testimony that lacks evidentiary support, is based on incorrect assumptions, and is
`
`contradicted by other reports in the scientific literature.
`
`Second, Taro’s Petition lacks a meaningful obviousness analysis, as
`
`differences between the prior art and the challenged claims are not discussed and
`
`prior art teaching away from the challenged claims is ignored. Thus, Taro has
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`1
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`failed to meet its burden of establishing a prima facie case of obviousness. In
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`addition, Taro’s Petition is incomplete as it failed to account for secondary
`
`considerations of non-obviousness including unexpected results, long-felt but
`
`unmet need, and industry praise.
`
`Accordingly, in view of the evidence now before the Board, Taro has not
`
`satisfied its burden to prove that the challenged claims are anticipated or obvious
`
`over Hoffbrand 1998, Olivieri 1995, or Olivieri Abstract 1995.
`
`II. BACKGROUND
`A. The Treatment and Care of Thalassemia Major Patients
`Thalassemia major (“TM”) is an inherited blood disorder characterized by
`
`the body’s inability to produce healthy red blood cells, and requires blood
`
`transfusions every three to five weeks for survival. (Ex. 2001 at ¶¶ 16-18.)
`
`Chronic blood transfusions lead to excess iron in the body (i.e., iron overload) (id.;
`
`see also Ex. 1001, col. 1, ll. 29-32), which, left untreated, eventually leads to
`
`cardiac siderosis and death. (Ex. 1001, col. 2, ll. 16-17; Ex. 1004 at 227.)
`
`An iron “chelator” is a compound that binds to iron so that it can be excreted
`
`from the body. (See Ex. 1001, col. 1, l. 52.) Deferoxamine (also called
`
`“desferrioxamine,” and marketed as DESFERAL®) was the first iron chelator
`
`approved to manage iron levels in TM patients. (Id. at col. 1, ll. 52-54; Ex. 1004 at
`
`227.) Prior to iron chelation therapy, blood transfusion-dependent patients
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`2
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`typically succumbed to iron-induced heart failure or other complications from iron-
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`overload within the first 20 years of life. (See id. at col. 2, ll. 9-13.) While the
`
`introduction of deferoxamine was a significant milestone, its onerous dosing
`
`regimen (daily subcutaneous infusion over 8-12 hours) and limited effect in
`
`removing cardiac iron meant that many TM patients taking deferoxamine
`
`nonetheless died from iron-induced heart disease. (See Ex. 1001, col. 1, ll. 54-62;
`
`col. 2, ll. 18-33, ll. 48-54.)
`
`The central importance of cardiac health to TM patient survival, and the
`
`difficulty of directly measuring cardiac iron, led physicians to develop guideposts
`
`based on available data to identify TM patients at risk of cardiac complications.
`
`(Ex. 1004 at 227.) The two most common measurements of iron levels in the body
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`were serum ferritin (“SF”) and liver iron concentration (“LIC”). (See Ex. 2003 at
`
`¶ 25.) Historically, TM patients having SF >2,500 micrograms per liter (“μg/L”),
`
`LIC >80 micromoles per gram (“μmol/g”) wet weight, or LIC >15 milligrams per
`
`gram (“mg/g”) dry weight were assumed to have an increased risk of heart disease.
`
`(Id.) However, it was clinically and statistically shown that neither SF nor LIC
`
`correlate with cardiac iron levels or cardiac health in TM patients. (See Ex. 2007;
`
`Ex. 2015 at 2171, 2178; Ex. 2016 at 519; Ex. 2022.) Thus, high SF or LIC were, at
`
`best, indicative of an increased risk of cardiac iron loading, but in no way indicate
`
`that a patient has iron buildup in the heart.
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`In 2000, a new technique emerged that used magnetic resonance imaging
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`(“MRI”) to, for the first time, accurately measure cardiac iron deposits. (See Ex.
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`2007; see also Ex. 2003 at ¶ 26.) Cardiac MRI T2* (“CMR T2*”) can
`
`quantitatively measure cardiac iron, and has become an invaluable tool in assessing
`
`the risk of heart disease. (Ex. 2003 at ¶ 26; Ex. 2026 at ¶ 7 (discussing Ex. 2036);
`
`Ex. 2037.) In the 1990s, cardiac MRI based on T2 relaxation time (“TRT”) was
`
`investigated as a tool to assess cardiac iron, but significant operator- and patient-
`
`dependent variability meant that TRT could not quantitatively assess cardiac iron
`
`levels. (See Ex. 2003 at ¶ 27.) Conversely, CMR T2* was quantitative and
`
`reproducible, and is currently the acknowledged standard for monitoring cardiac
`
`iron levels and cardiac health in TM patients. (See Ex. 2036 at 2140-2141; Ex.
`
`2037.) Further, CMR T2* data on large cohorts of TM patients conclusively
`
`demonstrated the lack of any meaningful relationship between mean SF or LIC and
`
`cardiac iron concentration. (See Ex. 2007; see also Ex. 2003 at ¶ 26.)
`
`In order to evaluate cardiac function in blood transfusion-dependent patients,
`
`physicians 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.,
`
`multiple uptake gated acquisition (“MUGA”) scans), cardiac computed
`
`tomography, and cardiac T2* MRI. (Ex. 2035 at ¶ 8.)
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`4
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`B.
`Prior Art Testing of Deferiprone in TM Patients
`Deferiprone was developed in the 1980s and began to be used
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`experimentally around that time to treat TM patients who could not comply with
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`daily deferoxamine injections, or who wished to try an orally administered iron
`
`chelator. (See Ex. 1001 at col. 1, l. 63 – col. 2, l. 1.) Although deferiprone showed
`
`initial promise as an iron chelator, it appeared to be less effective than
`
`deferoxamine at removing iron from the body, as judged by LIC. (See id. at col. 1,
`
`l. 66 – col. 2, l. 1; Ex. 1004 at 227-28; Ex. 1012 at 921; Ex. 1017 at 574.) Further,
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`there was no evidence that deferiprone provided any cardio-protective benefit to
`
`TM patients. (See Ex. 1001 at col. 9, ll. 34-43; see Ex. 1004 at 228.) Instead, there
`
`was significant disagreement in the scientific community whether deferiprone
`
`could be safely administered, and at least one article from a world-renowned expert
`
`posited that deferiprone was responsible for a decline in cardiac function. (See Ex.
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`1001, col. 7, ll. 55-67 (citing Ex. 2011); Ex. 1004 at 228-29.) Even Petitioner’s
`
`expert, Dr. Mehta, questioned the safety of administering deferiprone on more than
`
`one occasion, and has not prescribed deferiprone to a patient since 1993. (See Ex.
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`2021 at 1480; Ex. 1034 at 588; Ex. 2024 at 30:9-40:17, 41:13-24.) Thus, by the
`
`late 1990s, deferiprone had failed to progress beyond its use as an experimental
`
`medicine, and the scientific community disagreed as to whether deferiprone was
`
`safe and effective. Accordingly, at the time of the invention there was a need for a
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`treatment that could improve the life expectancy of TM patients by removing iron
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`U.S. Patent No. 7,049,328
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`from the heart. (See id. at col. 1, l. 59-62; col. 2, ll. 55-63.)
`
`C. The Invention of the ’328 Patent
`Despite all evidence to the contrary, the inventors, Drs. Michael Spino and
`
`Antonio Piga, discovered that deferiprone unexpectedly prevented, stabilized, and
`
`reduced the risk of heart disease, such as heart failure and iron-induced cardiac
`
`complications in TM patients suffering from iron overload in the heart. (Ex. 1001,
`
`col. 9, l. 60 – col. 10, l. 6.) In a study in Dr. Piga’s patients, it was revealed that
`
`deferiprone preferentially protected the heart, resulting in a decreased incidence of
`
`iron-induced cardiac disease and an improvement in overall survival, which could
`
`not be explained by the removal of iron from the body alone. (See Ex. 1004 at
`
`229.) This preferential cardiac benefit in deferiprone-treated patients occurred
`
`despite the fact that patients who received deferoxamine achieved a greater decline
`
`in total body iron (measured by changes in LIC). (Ex. 1001, col. 10, ll. 2-5; Figs.
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`1-2; see Ex. 1004 at 229.) Indeed, the study’s findings were wholly unforeseeable
`
`based on the previous experimental use of deferiprone, and demonstrated a new
`
`and valuable use for deferiprone in the treatment of TM. (See Ex. 1001, col. 23, l.
`
`48-61; col. 25, ll. 17-32; Figs. 1-2; Tables 2-4; see also Ex. 1004 at 229.)
`
`Upon discovering this new method of administering deferiprone to provide
`
`cardioprotective benefits to TM patients having iron overload in the heart or
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`6
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`suffering from iron-induced heart disease, Drs. Spino and Piga sought a patent for
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`their invention.
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`D. The ’328 Patent & FERRIPROX®
`The ’328 patent is titled “Use for Deferiprone” and issued on May 23, 2006.
`
`(Ex. 1001.) The ’328 patent claims priority to Canadian Patent No. 2313270,
`
`which was filed on June 30, 2000. (Id.)
`
`1.
`The Teachings of the ’328 Patent
`The ’328 patent is generally directed to methods of treating iron-induced
`
`cardiac disease by administering to the patient a therapeutically effective amount
`
`of deferiprone sufficient to treat iron-induced cardiac disease normally associated
`
`with iron overload. (Id. at Abstract.) The ’328 patent explains that deferiprone
`
`had been used extensively on an experimental basis in TM patients, and that “there
`
`are more than 250 articles” that “refer to deferiprone and 48 of these . . . present
`
`data on the use of deferiprone in patients with iron overload.” (Id. at col. 6, ll. 57-
`
`60.) However, “there is no literature that demonstrates that deferiprone has a
`
`greater cardio-protective effect than desferrioxamine, or that it might have such
`
`activity beyond its general ability to reduce the total body iron overload.” (Id. at
`
`col. 7, 1-9; see also id. at col. 9, ll. 39-42.) To the contrary, several publications
`
`near the priority date of the ’328 patent not only discounted the use of deferiprone
`
`to control hepatic and cardiac iron levels, but also suggested that deferiprone is
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`toxic to the heart. (See Ex. 2011; Ex. 2012; Ex. 1026 at 302.)
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`The inventors of the ’328 patent were the first to discover that deferiprone
`
`“provides for unexpected prevention/stabilization/reduction of the risk of heart
`
`disease” and unexpectedly has a “cardio selective/preferred function when
`
`compared to desferrioxamine or alternative chelating agents utilized in patients
`
`suffering iron overload.” (Ex. 1001 at col. 9, l. 62 – col. 10, l. 5.) These results
`
`were particularly surprising given that deferiprone “is not more effective than
`
`desferrioxamine in generally removing iron from the body,” (id. at col. 1, l. 66 –
`
`col. 2, l. 1.), and given that prior art literature “suggested that deferiprone may
`
`contribute to heart failure and cardiac fibrosis” (id. at col. 7, ll. 55-67).
`
`ApoPharma USA, Inc. is the licensee of the ’328 patent and markets
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`FERRIPROX® in the United States pursuant to FDA’s approval of NDA No. 21-825,
`
`which was approved in 2011 after an accelerated review. (Ex. 2008.) The ’328
`
`patent is listed in the FDA’s publication “Orange Book: Approved Drug Products
`
`with Therapeutic Equivalence Evaluations,” as covering the FDA-approved
`
`method of administering FERRIPROX® “for the treatment of patients with
`
`transfusional iron overload due to thalassemia syndromes when current chelation
`
`therapy is inadequate.” (See Ex. 1023 at 1.)
`
`As noted in Ex. 2014, Drs. Spino and Piga’s contributions to the clinical
`
`testing and regulatory approval of FERRIPROX® in the United States has prolonged
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`the lives of countless TM patients and enhanced their quality of life.
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`2.
`The Challenged Claims of the ’328 Patent
`The challenged claims1 of the ’328 patent are directed to various methods of
`
`treating blood transfusion-dependent patients at risk of or suffering from various
`
`iron overload conditions. (See Ex. 1001 at col. 27, l. 3 – col. 28, ll. 43, 47-51.)
`
`Specifically, claims 1, 2, and 4-10 of the ’328 patent are directed to methods of
`
`treating/stabilizing/reducing iron-induced cardiac disease/iron loading in the
`
`heart/iron burden in the heart in blood transfusion-dependent patients:
`
`(i)
`(ii)
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`having iron overload, including in the heart, (claims 4, 5, and 10); and
`having/experiencing2 an iron overload condition of the heart (claims
`1, 2, and 6-9).
`Claims 11-17 and 19 depend multiply from claims 1, 2, and 4-10 and are
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`directed to oral administration (claims 11, 16, and 17), a pharmaceutical dosage
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`form (claim 12), a daily dose up to 150 mg/kg of body weight (claim 13), a daily
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`dose up to 125 mg/kg body weight (claim 14), a daily dose of 25 to 75 mg/kg body
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`weight (claim 15), and wherein deferiprone has a cardio preferred/selective
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`function when compared to desferrioxamine or other alternative chelating agents
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`utilized in patients suffering iron overload (claim 19). (See id. at col. 28, ll. 14-51.)
`
`
`1 Taro has not challenged the validity of claims 18 or 20 of the ’328 patent. (See
`Pet. at 9-10.)
`2 Apotex submits that the terms “having” and “experiencing” are synonymous, and
`thus Apotex will use the term “having” to refer generally to both.
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`E.
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`Procedural History
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`1.
`The Grounds for Inter Partes Review
`The Board instituted IPR proceedings concerning the anticipation of claims
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`1, 2, 4-11, 17, and 19 by Hoffbrand 1998, Olivieri 1995, and Olivieri Abstract
`
`1995. (Paper 7 at 41.) The Board further instituted IPR proceedings concerning
`
`the obviousness of claims 1, 2, 4-17, and 19 over the same three references,
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`respectively, in combination with the knowledge of the ordinary artisan. (Paper 7
`
`at 34, 41.)
`
`2.
`Related District Court Litigation
`On May 18, 2016, ApoPharma Inc., ApoPharma USA, Inc., and Apotex
`
`Technologies Inc. filed a patent infringement action against Taro Pharmaceutical
`
`Industries, Ltd. and Taro Pharmaceuticals U.S.A., Inc. in United States District
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`Court for the Eastern District of Texas. Apotex alleges that Taro’s ANDA seeking
`
`to market a generic version of FERRIPROX® infringes claims 1, 2, 4, 5, 11-17, and
`
`19 of the ’328 patent.
`
`The district court issued a Claim Construction Opinion and Order on May
`
`17, 2017, rejecting Taro’s arguments and holding that the “results” recited in
`
`claims 2, 4, 5, 7, 8, 11, and 19 of the ’328 patent are limitations and not merely
`
`intended results. (See Ex. 2010.) A trial on infringement and validity of the ’328
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`patent is scheduled for October 2018.
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`III. THE LEVEL OF SKILL IN THE ART
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`IPR2017-01446
`U.S. Patent No. 7,049,328
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`As Drs. Coates and Pennell explain, a person of ordinary skill in the art
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`(“POSA”) at the time of the invention would include physicians who treated iron
`
`overload in patients requiring chronic blood transfusions. (See Ex. 2001 at ¶ 26;
`
`Ex. 2003 at ¶ 29.) Such a person would have a medical degree and some
`
`experience in hematology, cardiology, or a related field. (Id.) A POSA would
`
`have worked as a part of a team of health care providers having experience in the
`
`treatment of thalassemia, sickle cell, or other haemochromatosis disorders. (Id.)
`
`As of the earliest priority date of the ’328 patent, Drs. Coates and Pennell were
`
`persons of at least ordinary skill in the art.
`
`IV. CLAIM CONSTRUCTION
`A. An “Iron Overload Condition of the Heart” Requires a Condition
`on the Spectrum of Cardiac Disease
`Claims 1, 2, and 6-9 require administering deferiprone to blood transfusion-
`
`dependent patients who have an iron overload condition of the heart. (See Ex.
`
`1001 at col. 27, l. 3 – col. 28, l. 13.) The Board noted that the ’328 patent does not
`
`explicitly define “iron overload condition of the heart.” (Paper 15 at 3.) Patent
`
`Owner respectfully disagrees. The ’328 patent equates an “iron overload condition
`
`of the heart” with cardiac disease. (See Ex. 1001 at col. 10, ll. 18-20, ll. 29-31.)
`
`Further, the ’328 patent states that iron-induced cardiac disease includes heart
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`11
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`failure and iron-induced cardiac complications. (Id. at col. 10, ll. 12-13.)
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`U.S. Patent No. 7,049,328
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`As Drs. Coates and Pennell explain, an iron overload condition of the heart
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`requires sufficient iron accumulation in the heart to manifest as a diagnosable
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`condition using, e.g., LVEF, MUGA, Holter monitoring, and the like. (Ex. 2035 at
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`¶ 8; Ex. 2026 at ¶ 11.) An iron overload condition of the heart could manifest as
`
`arrhythmia, a diagnosis of NYHA Class I-II heart disease, or a more serious
`
`cardiomyopathy such as NYHA Class III-IV heart disease. (See Ex. 2026 at ¶ 11.)
`
`Petitioner’s analysis of the prior art refers to “an iron overload condition of
`
`the heart” as “i.e., a condition on the spectrum of cardiac disease due to iron
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`overload.” (Pet. at 33, 35, 38, 41, 43.) Taro’s expert, Dr. Mehta, states that a
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`patient with an “iron overload condition of the heart” includes a patient “with a
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`broad spectrum of cardiac disease, including patients with only mild cardiac
`
`dysfunction due to iron overload and patients with severe congestive heart failure.”
`
`(Ex. 1002 at ¶ 60.) Indeed, Dr. Mehta agrees that the word “condition” requires
`
`dysfunction of the heart to actually be present, with cardiomyopathy representing
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`an “extreme” iron overload condition of the heart. (See Ex. 1002 at ¶ 60; Ex. 2024
`
`at 124:21 – 125:25.) Dr. Mehta also testified that, in the case of claims 4, 5, and
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`10, if the results recited in part three of these claims are ignored (as the Board has
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`construed these claims), then they require the blood transfusion-dependent patient
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`to already have heart disease. (Ex. 2024 at 80:2 to 81:21, 82:10 to 83:22.)
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`For these reasons, the Board should construe a patient with “an iron overload
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`condition of the heart” as a patient having iron-induced cardiac disease.
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`B.
`
`The “Claimed Results” Would be Understood by a POSA to
`Define Whether the Methods of Treatment of Claims 1, 2, and 4-
`10 are Successfully Achieved
`Apotex and Taro dispute the constructions of the following claim terms:
`
`Claim Term
`“therapeutically effective
`
`Apotex’s Proposed
`Construction
`An amount of deferiprone
`
`Taro’s Proposed
`Construction
`An amount of
`
`amount of deferiprone”
`
`that produces the claimed
`
`deferiprone that causes
`
`(claims 1, 2, and 4-10)
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`result.
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`adequate chelation.
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`The “claimed result”
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`Limiting as defining the
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`None—not limitations
`
`(claims 1, 2, 4-10, and 19)
`
`successful practice of the
`
`because merely an
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`claimed methods.
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`intended result.
`
`
`
`Claims 1, 2 and 4-10 require administering deferiprone to provide specific
`
`results in specific blood transfusion-dependent patients. (See Ex. 1001 at col. 27,
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`l. 3 – col. 28, l. 13.) Petitioner erroneously asserts that the required results do not
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`have patentable weight because they do not alter the steps of the method, and are
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`thus non-limiting. (Pet. at 24-26.) To the contrary, the results required by claims
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`1, 2, 4-10, and 19 are properly construed as limitations under a “broadest
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`reasonable construction” of these claims because the results define inventive
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`aspects of the claim methods, and reflect the successful practice of the claimed
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`methods. (37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct
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`2131, 2144-214