UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`Taro Pharmaceuticals U.S.A., Inc.,
`
`v.
`
`Apotex Technologies, Inc.
`
`Patent No. 7,049,328 B2
`
`
`Title: USE FOR DEFERIPRONE
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 7,049,328 B2
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

` TABLE OF CONTENTS
`
`
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`PRELIMINARY STATEMENT ..................................................................... 1
`
`III. MANDATORY NOTICES ............................................................................. 2
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................. 2
`
`Related Matters (37 C.F.R. § 42.8(B)(2)) .......................................... 2
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) ........................... 2
`
`Service Information (37 C.F.R. § 42.8(b)(4)) ....................................... 3
`
`IV. CERTIFICATION OF GROUNDS FOR STANDING ............................. 3
`
`V.
`
`FEES ............................................................................................................... 3
`
`VI. SUMMARY OF THE ’328 PATENT AND PROSECUTION
`HISTORY ........................................................................................................ 3
`
`A.
`
`B.
`
`C.
`
`The Claims of the ’328 Patent ............................................................... 4
`
`Specification of the ’328 Patent ............................................................ 5
`
`Prosecution History of the ’328 Patent ................................................. 7
`
`VII. OVERVIEW OF CHALLENGE AND PRECISE RELIEF
`REQUESTED .................................................................................................. 9
`
`VIII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 11
`
`IX. BACKGROUND ON DEFERIPRONE AND IRON OVERLOAD ............ 12
`
`A.
`
`“Iron-Overload Conditions of the Heart” in Transfusion-Dependent
`Patients ................................................................................................ 12
`
`B.
`
`Iron Chelators Treat Iron-Overload Conditions .................................. 15
`
`1.
`
`Desferrioxamine ........................................................................ 15
`
`
`
`ii
`
`

`

`2.
`
`Deferiprone ............................................................................... 17
`
`X.
`
`CLAIM CONSTRUCTION .......................................................................... 19
`
`1.
`
`2.
`
`3.
`
`Preamble – Identification of “the Patient” ................................ 20
`
`Administration of a “Therapeutically Effective Amount” ........ 23
`
`Recitation of Intended Results .................................................. 24
`
`XI. GROUNDS 1–5: ANTICIPATION OF CLAIMS 1–11, 13–17, AND
`19 BY EACH OF MIMS 1998, HOFFBRAND 1998, OLIVIERI
`ABSTRACT 1995, AGARWAL 2000, AND OLIVIERI 1995 .................... 28
`
`A.
`
`B.
`
`C.
`
`The Intended Results Stated in Claims 1, 2, 4–10 and 19 Are Not
`Limiting, But Nonetheless Are Inherently Anticipated by the Primary
`References ........................................................................................... 29
`
`Ground 1: Anticipation by MIMS 1998 (Ex. 1009) ............................ 32
`
`Ground 2: Anticipation by Hoffbrand 1998 (Ex. 1007) ...................... 34
`
`D. Ground 3: Anticipation by Olivieri Abstract 1995 (Ex. 1010) ........... 36
`
`E.
`
`F.
`
`Ground 4: Anticipation by Agarwal 2000 (Ex. 1011) ........................ 39
`
`Ground 5: Anticipation by Olivieri 1995 (Ex. 1012) .......................... 42
`
`XII. GROUNDS 6–10: OBVIOUSNESS OF CLAIMS 1–17 AND 19
`OVER EACH OF MIMS 1998, HOFFBRAND 1998, OLIVIERI
`ABSTRACT 1995, AGARWAL 2000, AND OLIVIERI 1995 .................... 43
`
`A.
`
`B.
`
`The Claims of the ’328 Patent Are Prima Facie Obvious over Each of
`the Primary References in View of the Knowledge of a Person of
`Ordinary Skill in the Art ...................................................................... 44
`
`No Secondary Considerations Overcome the Prima Facie
`Obviousness of the Claims .................................................................. 51
`
`XIII. CONCLUSION .............................................................................................. 52
`
`
`
`
`
`
`
`
`
`iii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 49
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs.,
`246 F.3d 1368 (Fed. Cir. 2001) .............................................................. 26, 27, 30
`
`Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002) ............................................................................ 20
`
`In re Copaxone,
`Civil Action No. 14–1171-GMS, 2016 WL 873062 (D. Del. Mar.
`7, 2016) . ............................................................................................................. 25
`
`Cuozzo Speed Techs. LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 19
`
`In re Droge,
`695 F.3d 1334 (Fed. Cir. 2012) .......................................................................... 48
`
`Endo Pharm. Inc. v. Watson Labs., Inc.,
`No. 2:13-cv-192, 2014 WL 2859349 (E.D. Tex. Jun. 23, 2014) ........................ 25
`
`In re Huai-Hung Kao,
`639 F. 3d 1057 (Fed. Cir. 2011) ......................................................................... 50
`
`King Pharmaceuticals, Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .............................................................. 11, 31, 32
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 48
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 48
`
`Redline Detection, LLC v. Star Envirotech, Inc.,
`811 F.3d 435 (Fed. Cir. 2015) ............................................................................ 43
`iv
`
`
`
`

`

`Santarus, Inc. v. Par Pharmaceutical, Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 49
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 50
`
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 25
`
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) .......................................................................... 20
`
`Verdegaal Bros., Inc. v. Union Oil Co. of California,
`814 F. 2d 628 (Fed. Cir. 1987) ........................................................................... 30
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 50
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 40
`
`35 U.S.C. § 102(b) ................................................................................. 33, 34, 37, 42
`
`35 U.S.C. § 112 .......................................................................................................... 8
`
`35 U.S.C. § 112(d) ................................................................................................... 24
`
`35 U.S.C. § 314(a) ................................................................................................... 11
`
`Other Authorities
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 2
`
`37 C.F.R. § 42.8(B)(2) ............................................................................................... 2
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 2
`
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 3
`
`37 C.F.R. § 42.100(b) .............................................................................................. 19
`
`37 C.F.R. § 42.104(a) ................................................................................................. 3
`
`M.P.E.P § 608.01(i) ................................................................................................. 24
`v
`
`
`
`

`

`List of Exhibits for U.S. Patent No. 7,049,328 Petition for Inter Partes Review
`
`Exhibit No. Description
`U.S. Patent No. 7,049,328, Spino et al., Use for Deferiprone, issued
`1001
`on May 23, 2006 (“the ’328 Patent”)
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`
`
`Declaration of Jayesh Mehta, M.D. (“Mehta Dec.”)
`
`Curriculum Vitae of Jayesh Mehta, M.D.
`
`Prosecution History of U.S. Patent No. 7,049,328
`
`Olivieri et al., Reduction of Tissue Iron Stores and Normalization of
`Serum Ferritin During Treatment with the Oral Iron Chelator L1 in
`Thalassemia Intermedia, BLOOD, 79(10):2741–48, 1992 (“Olivieri
`1992”)
`
`Hoffbrand & Wonke, Iron Chelation Therapy, JOURNAL OF
`INTERNAL MEDICINE, 242 (Supplement 740): 37–41, 1997
`(“Hoffbrand 1997”)
`
`Hoffbrand et al., Long-Term Trial of Deferiprone in 51 Transfusion-
`Dependent Iron Overloaded Patients, BLOOD, 91(1):295–300, 1998
`(“Hoffbrand 1998”)
`
`U.S. Patent No. 5,922,761, Lai, Methods for In Vivo Reduction of
`Iron Levels and Compositions Useful Therefor, Issued on July 13,
`1999 (“Lai ’761”)
`
`Monthly Index of Medical Specialties, Vol. 18, No. 12, December
`1998 (“MIMS 1998”)
`
`Olivieri et al., First Prospective Randomized Trial of the Iron
`Chelators Deferiprone (L1) And Deferoxamine, Abstract 983:
`Hemoglobinopathies and Thalassemias II, 249a, PROGRAM OF THE
`37TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF
`HEMATOLOGY, December 1995 (“Olivieri Abstract 1995”)
`
`vi
`
`

`

`Exhibit No. Description
`Agarwal, Deferiprone (Kelfer): A Report of 22 Patients Who Have
`1011
`Taken it for over a Decade, 10TH INTERNATIONAL CONFERENCE ON
`ORAL CHELATORS IN THE TREATMENT OF THALASSEMIA AND OTHER
`DISEASES AND BIOMED MEETING, March 2000 (“Agarwal 2000”)
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`
`
`Olivieri et al., Iron-Chelation Therapy with Oral Deferiprone in
`Patients with Thalassemia Major, N. ENGL. J. MED., 332:918–22,
`1995 (“Olivieri 1995”)
`
`Intentionally Left Blank
`
`Olivieri et al., Survival in Medically Treated Patients with
`Homozygous β-Thalassemia, N. ENGL. J. MED., 331:547–78, 1994
`(“Olivieri 1994”)
`
`Nathan & Gunn, Thalassemia: The Consequences of Unbalanced
`Hemoglobin Synthesis, AMERICAN JOURNAL OF MEDICINE, 41:815–
`30, 1966 (“Nathan 1966”)
`
`Bannerman et al., Thalassemia Intermedia, with Iron Overload,
`Cardiac Failure, Diabetes Mellitus, Hypopituitarism and
`Porphyrinuia, AMERICAN JOURNAL OF MEDICINE, 476–86, 1967
`(“Bannerman 1967”)
`
`Barman Balfour & Foster, Deferiprone: A Review of its Clinical
`Potential in Iron Overload in β-Thalassemia Major and Other
`Transfusion-Dependent Diseases, DRUGS 58(3):553–78, 1999
`(“Barman Balfour 1999”)
`
`Barry et al., Long-Term Chelation Therapy in Thalassemia Major:
`Effect on Liver Iron Concentration, Liver Histology, and Clinical
`Progress, BMJ, 2:16–20, 1974 (“Barry 1974”)
`
`Kontoghiorghes, Oral Iron Chelation Is Here, BMJ, 303:1279–80,
`1991 (“Kontoghiorghes 1991”)
`
`Nathan, An Orally Active Iron Chelator, N. ENGL. J. MED.,
`332(14):953–54, 1995 (“Nathan 1995”)
`
`vii
`
`

`

`Exhibit No. Description
`GB 2 118 176, Pharmaceutically Active 3-Hydroxypyrid-2-and-4-
`1021
`ones, published on October 1983 (“Hider Patent”)
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`
`
`Diav-Citrin & Koren, Oral Iron Chelation with Deferiprone, NEW
`FRONTIERS IN PEDIATRIC DRUG THERAPY, 44(1):235–47, 1997
`(“Diav-Citrin 1997”)
`
`Prescribing Information for Ferriprox® (deferiprone) tablets, for
`oral use (Revised 10/2011) (“Deferiprone Label 2011”)
`
`Olson et al., Endomyocardial Biopsy in Hemochromatosis:
`Clinicopathologic Correlates in Six Cases, JACC, 13(1):116–20,
`1989 (“Olson 1989”)
`
`Kontoghiorghes et al., L1-Deferiprone Worldwide Update and New
`Strategies for Improving its Therapeutic Efficiency, 10TH
`INTERNATIONAL CONFERENCE ON ORAL CHELATORS IN THE
`TREATMENT OF THALASSEMIA AND OTHER DISEASES AND BIOMED
`MEETING, March 2000 (“Kontoghiorghes 2000”)
`
`Faa & Crisponi, Iron Chelating Agents in Clinical Practice,
`COORDINATION CHEMISTRY REVIEWS, 184:291–310, 1999 (“Faa
`1999”)
`
`Borgna-Pignatti, Survival and Disease Complications in
`Thalassemia Major, ANNALS NEW YORK ACADEMY OF SCIENCES,
`227–31, 1998 (“Borgna-Pignatti 1998”)
`
`McDonald, Deferoxamine and Diethylenetriaminepentaacetic Acid
`(DTPA) in Thalassemia, THE JOURNAL OF PEDIATRICS 69(4):563–
`71, 1966 (“McDonald 1966”)
`
`Cerami, Propper”Use of Desferrioxamine, N. ENGL. J. MED,
`294(26): 1456-57, 1976 (“Cerami 1976”)
`
`Matsui, Effective Iron Chelation /using the Oral Iron Chelator 1,2,-
`dimethyl-3-hydroxypyrid-4-one (L1), in Homozygous b-Thalassemia
`Major (HBT) Patients, Abstract P1-43, Clinical Pharmacology &
`Therapeutics, 53(2) (1993). (“Matsui”)
`
`viii
`
`

`

`Exhibit No. Description
`Mehta J. et al., Autoantibodies in Thalassaemia Major: Relationship
`1031
`with Oral Iron Chelator L1, J. ASSOC. PHYSICIANS INDIA,
`41(6):339–41, 1993
`
`Kratz, Normal Reference Laboratory Values, NEW ENGLAND
`JOURNAL OF MEDICINE, Vol. 339, No. 15, 1998 (“Kratz”)
`
`Mehta et al., Deaths in Patients Receiving Oral Iron Chelator L1,
`BR. J. HAEMATOL., 85:430–31, 1993
`
`Mehta et al., Deferiprone in Iron Overload, N. ENGL. J. MED.,
`333:597–99, 1995
`
`Mehta et al., Oral Iron Chelator L1 and Autoimmunity, BLOOD,
`81:1970–71, 1993
`
`1032
`
`1033
`
`1034
`
`1035
`
`
`
`
`
`ix
`
`

`

`I.
`
`INTRODUCTION
`Taro Pharmaceuticals USA, Inc. (“Taro” or “Petitioner”) petitions for inter
`
`partes review (“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42 et seq. of
`
`claims 1-17 and 19 of U.S. Patent 7,049,328 (Ex. 1001 (“the ʼ328 Patent”)).
`
`II.
`
`PRELIMINARY STATEMENT
`
`The ʼ328 Patent is directed to an old method of administering deferiprone to
`
`transfusion-dependent patients with iron overload. Deferiprone is an oral iron
`
`chelator that was first approved for use in treating iron overload diseases in India
`
`in 1995, years prior to the earliest filing date of the ʼ328 Patent. As explained in
`
`more detail below and as acknowledged in the patent specification, every element
`
`of the claims, including the target patient population, the oral dosage amount of 75
`
`mg/kg per day, and the goal of treating iron overload and related heart conditions,
`
`was explicitly disclosed in many prior art references.
`
`According to the specification, prosecution history, and statements the
`
`Patent Owner made during an opposition to the European counterpart to the ʼ328
`
`Patent, the alleged inventive aspect of the claimed method is the discovery that
`
`deferiprone preferentially reduces iron in the heart. According to the Patent
`
`Owner, deferiprone targets iron found in the heart in preference to iron found in
`
`other organs, such as the liver. Regardless of the merits of this alleged discovery,
`
`the claimed methods are identical to previously known methods of administering
`
`

`

`deferiprone, including the target patient population (transfusion-dependent
`
`patients), the dosage form and amount (oral, at least 75 mg/kg per day), and the
`
`goal of the treatment (to treat iron-overload conditions, including overload
`
`conditions of the heart). Claims drawn to a newly discovered benefit of an old
`
`method are not patentable. Therefore, the claims of the ʼ328 Patent are anticipated
`
`and rendered obvious by each of many prior art references, including the five
`
`representative references selected by Petitioner and its expert, and discussed in
`
`detail below.
`
`III. MANDATORY NOTICES
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`The real parties-in-interest are Taro, Taro Pharmaceutical Industries, Ltd.,
`
`and Sun Pharmaceuticals, Ltd.
`
`B. Related Matters (37 C.F.R. § 42.8(B)(2))
`The ’328 Patent is at issue in ApoPharma Inc. v. Taro Pharmaceutical
`
`Industries, Ltd., No. 2:16-cv-00528, currently pending in the District Court for the
`
`Eastern District of Texas – Marshall Division. Taro Pharmaceutical Industries Ltd.
`
`was served with a complaint in that case on June 2, 2016.
`
`C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`Lead counsel is Huiya Wu, Reg. No. 44,411. Backup counsel are Robert V.
`
`Cerwinski (to seek pro hac vice admission) and Sarah Fink, Reg. No. 64,886. All
`
`counsel are with Goodwin Procter LLP at 620 Eighth Avenue, New York, NY
`2
`
`
`
`

`

`10018, tel. 212-813-8800, fax 212-355-3333. Email addresses for counsel are
`
`hwu@goodwinlaw.com, rcerwinski@goodwinlaw.com, and
`
`sfink@goodwinlaw.com.
`
`Service Information (37 C.F.R. § 42.8(b)(4))
`
`D.
`Please direct all correspondence to counsel at the contact information above.
`
`Petitioner consents to service by electronic mail at hwu@goodwinlaw.com,
`
`rcerwinski@goodwinlaw.com, and sfink@goodwinlaw.com.
`
`IV. CERTIFICATION OF GROUNDS FOR STANDING
`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the patent for
`
`which review is sought is available for inter partes review and that Petitioner is not
`
`barred or estopped from requesting an inter partes review challenging the patent
`
`claims on the grounds identified in this petition.
`
`V.
`
`FEES
`
`The Commissioner is hereby authorized to charge all fees due in connection
`
`with this matter to Attorney Deposit Account 506989.
`
`VI. SUMMARY OF THE ’328 PATENT AND PROSECUTION HISTORY
`The ’328 Patent (Ex. 1001) issued on May 23, 2006, from Application Ser.
`
`No. 10/311,814 (“the ’814 application”), which entered the U.S. national stage on
`
`April 4, 2003, and claims priority to a foreign application that was filed on June
`
`30, 2000. The earliest possible priority date associated with the ’328 Patent is June
`
`30, 2000.
`
`
`
`3
`
`

`

`A. The Claims of the ’328 Patent
`The ’328 Patent has 20 claims. Claims 1–10 are each independent, and
`
`claims 11–20 are each multiply dependent on claims 1–10. The claims are
`
`generally drawn to a method of treating a transfusion-dependent patient who has an
`
`iron overload condition comprising administering an effective amount of
`
`deferiprone. The claims also include recitations of alleged intended results of
`
`treatment with deferiprone, such as the reduction of iron in the heart or the
`
`preferential reduction of iron in the heart as compared to iron in other parts of the
`
`body.1
`
`The dependent claims further specify the mode of administration of
`
`deferiprone (claims 11, 16, and 17), that deferiprone is in a dosage form with
`
`excipients (claim 12), the dosage amount (claims 13, 14, and 15), and the property
`
`1 Petitioner and its expert Dr. Mehta offer no opinion as to the merits of the alleged
`
`intended results or discovery of the cardio-selectivity of deferiprone that is
`
`suggested in the patent. It is Petitioner’s position that the behavior of deferiprone
`
`in the human body as set forth in the ’328 Patent is identical to the behavior of
`
`deferiprone in the human body prior to the filing of the ’328 Patent, and there is no
`
`patentable invention here. Any and all references to the “discovery” described in
`
`the ’328 Patent should be understood to mean the alleged “discovery” disclosed
`
`therein.
`
`
`
`4
`
`

`

`that deferiprone is more cardio-selective in its reduction of iron than another iron
`
`chelator, desferrioxamine (claim 19).
`
`Specification of the ’328 Patent
`
`B.
`The ’328 Patent is directed to a “method of treating iron induced cardiac
`
`disease in a patient with iron overload, such as in thalassemia patients or the like
`
`comprising administering to the patient a therapeutically effective amount of
`
`deferiprone.” (Ex. 1001 (’328 Patent) at Abstract.) The patent discloses that
`
`patients with thalassemia must be treated with regular transfusions of red blood
`
`cells, and that the transfusions create “a wide-spread iron overload in the patient.”
`
`(Id. at col. 1, ll. 27–29.) This iron overload may cause toxic degenerative changes
`
`in organs, in particular, to the heart. (Id.)
`
`The patent states that iron overload has been treated with two iron chelators
`
`known in the art. Iron overload is most often treated with desferrioxamine, which
`
`must be subcutaneously infused daily with the use of an infusion pump for a period
`
`of 8–12 hours, as long as the patient continues to receive regular blood
`
`transfusions. (Id. at col. 1, ll. 52–62; col. 2, ll. 26–30.) Alternatively, “another
`
`iron chelator, deferiprone by oral administration,” has “been used successfully for
`
`removal of iron in thalassemia patients.” (Id. at col. 1, ll. 63–65.)
`
`Thalassemia patients who receive regular transfusions generally die from
`
`heart failure in their teens “if iron overload is not treated.” (Id. at col. 2, ll. 9–13.)
`
`
`
`5
`
`

`

`Treatment with desferrioxamine often prolongs life only through age 30, with
`
`many treated patients still dying prematurely from heart failure. (Id.) The
`
`specification states that the high rate of premature death despite treatment with
`
`desferrioxamine is because “patients do not take adequate amounts of the
`
`injectable chelator,” and notes that patient compliance is poor with the difficult
`
`treatment regimen. (Id. at col. 2, ll. 26–34.) The specification further
`
`hypothesizes, without providing a basis, that while desferrioxamine “removes iron
`
`from the liver and possibly the blood, its effects on the heart are secondary, not
`
`specific for this organ.” (Id. at col. 2, ll. 18–26.) Further, according to the
`
`specification, “[i]t has thus become evident that lowering of the total body iron
`
`alone is insufficient to protect against iron-induced heart damage.” (Id. at col. 2, ll.
`
`53–55.) The patent states that there is therefore a “long felt need to improve the
`
`life expectancy” of these patients. (Id. at col. 2, ll. 55–60.)
`
`The patent then provides a list of 62 prior art references, characterizes them
`
`as “technical literature which discusses the clinical use of chelating agents in
`
`conditions of chronic iron overload” (id. at col. 2, l. 63–col. 6, l. 56), and further
`
`states, “[t]here are more than 250 articles in the peer-reviewed literature which
`
`refer to deferiprone and 48 of these (at the time of writing) present data on the use
`
`of deferiprone in patients with iron overload.” (Id. at col. 6, ll. 57–60.)
`
`
`
`6
`
`

`

`According to the patent, 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
`
`load.” (Id. at col. 7, ll. 6–10.)
`
`The “Summary of the Invention” section provides the patentees’ description
`
`of the alleged invention in the ’328 Patent: “Applicants have now discovered that
`
`the use of deferiprone in effective amounts as an iron chelating agent for patients
`
`suffering from an iron overload condition … provides for unexpected
`
`prevention/stabilization/reduction of the risk of heart disease such as heart failure
`
`and iron-induced cardiac complications.” (Id. at col. 9, l. 60–col. 10, l. 1.)
`
`Prosecution History of the ’328 Patent
`
`C.
`The ’814 application entered the U.S. national stage on April 4, 2004, and
`
`was filed with a preliminary amendment. The patent was allowed following
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`several rounds of rejections by the examiner, each of which was met with a
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`response and amendment, and two examiner interviews. The examiner rejected the
`
`pending claims as anticipated by or obvious over Olivieri 19922 (Ex. 1005),
`
`
`2 Olivieri et al., Reduction of Tissue Iron Stores and Normalization of Serum
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`Ferritin During Treatment with the Oral Iron Chelator L1 in Thalassemia
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`Intermedia, BLOOD, 79(10):2741–48, 1992 (“Olivieri 1992,” Ex. 1005).
`
`
`
`7
`
`

`

`Hoffbrand 19973 (Ex. 1006), Hoffbrand 19984 (Ex. 1007), and Lai ’7615 (Ex.
`
`1008). The examiner also made rejections based on indefiniteness and lack of
`
`enablement under 35 U.S.C. § 112.
`
`In an Office Action Response dated July 30, 2004, the applicants provided
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`“the Examiner with further general discussion and perspective information.” (Ex.
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`1004 (Response to Office Action, July 30, 20046) at 9.) This “general discussion”
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`largely mirrors the discussion of the prior art provided in the patent specification
`
`and discussed above. Applicants argued that Olivieri 1992, Hoffbrand 1997, and
`
`Hoffbrand 1998, are not anticipatory and do not render the claims obvious, inter
`
`alia, because they do not disclose the cardio-protective effect of deferiprone.
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`Applicants purported to differentiate the alleged invention from the prior art
`
`identified in the patent specification as follows: “However, in Applicant’s opinion
`
`
`3 Hoffbrand & Wonke, Iron Chelation Therapy, JOURNAL OF INTERNAL MEDICINE,
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`242 (Supplement 740): 37–41, 1997 (“Hoffbrand 1997,” Ex. 1006).
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`4 Hoffbrand et al., Long-Term Trial of Deferiprone in 51 Transfusion-Dependent
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`Iron Overloaded Patients, BLOOD, 91(1):295–300, 1998 (“Hoffbrand 1998,” Ex.
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`1007).
`
`5 U.S. Patent No. 5,922,761, Lai, Methods for In Vivo Reduction of Iron Levels and
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`Compositions Useful Therefor, issued on July 13, 1999 (“Lai ’761,” Ex. 1008).
`
`6 Prosecution History, U.S. Patent Application No. 10/311,814.
`8
`
`
`
`

`

`there is no literature that demonstrates that deferiprone has a greater cardio
`
`protective effect than desferrioxamine or that it might have activity beyond its
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`general ability to reduce the total body iron load, and benefit to heart function.”
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`(Id. at 19–20.) Applicants made similar statements throughout the prosecution
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`history.
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`The application was allowed on December 23, 2005.
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`VII. OVERVIEW OF CHALLENGE AND PRECISE RELIEF
`REQUESTED
`
`In Grounds 1-5, Petitioner challenges claims 1–11, 13–17 and 19 of the ’328
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`Patent as anticipated by each of MIMS 19987 (Ex. 1009), Hoffbrand 1998 (Ex.
`
`1007), Olivieri Abstract 1995 (Ex. 1010), Agarwal 20008 (Ex. 1011), and Olivieri
`
`
`7 Monthly Index of Medical Specialties, Vol. 18, No. 12, December 1998 (“MIMS
`
`1998,” Ex. 1009).
`
`8 Agarwal, Deferiprone (Kelfer): A Report of 22 Patients Who Have Taken It for
`
`over a Decade, 10TH INTERNATIONAL CONFERENCE ON ORAL CHELATORS IN THE
`
`TREATMENT OF THALASSEMIA AND OTHER DISEASES AND BIOMED MEETING, March
`
`2000 (“Agarwal 2000,” Ex. 1010).
`
`
`
`9
`
`

`

`19959 (Ex. 1012) (collectively, “the Primary References”).
`
`In Grounds 6–10, Petitioner challenges claims 1–17 and 19 of the ’328
`
`Patent as obvious over each of the Primary References in view of the knowledge of
`
`a person of ordinary skill in the art.
`
`Petitioner’s challenge to the claims of the ’328 patent are based on the
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`bedrock principle that a patent may not be supported by a mere discovery of an
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`alleged new benefit of an old process, when that process was used in the same way
`
`and for the same reason as disclosed in the prior art. See, e.g., King
`
`Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1276 (Fed. Cir. 2010),
`
`discussed in detail infra.
`
`This petition is supported by the Expert Declaration of Dr. Jayesh
`
`Mehta, M.D. (Ex. 1002.) Dr. Mehta is Professor of Medicine and Director
`
`of the Hematopoietic Stem Cell Transplant Program at the Northwestern
`
`University Feinberg School of Medicine. He has extensive experience
`
`treating thalassemia patients for iron overload using chelators including
`
`those described in the ’328 Patent. In particular, he has administered
`
`deferiprone to thalassemia patients as early as 1989.
`
`9 Olivieri et al., Iron-Chelation Therapy with Oral Deferiprone in Patients with
`
`Thalassemia Major, N. ENGL. J. MED., 332:918–22, 1995 (“Olivieri 1995,” Ex.
`
`1011).
`
`
`
`10
`
`

`

`The petition and supporting declaration show that there is at least a
`
`reasonable likelihood that Petitioner will prevail with respect to at least one of the
`
`challenged claims. See 35 U.S.C. § 314(a). Petitioner respectfully requests that
`
`the Board institute IPR and find claims 1–17 and 19 unpatentable.
`
`VIII. LEVEL OF ORDINARY SKILL IN THE ART
`As Dr. Mehta explains, as of June 2000, the priority date of the ’328 Patent,
`
`physicians had been treating iron overload in blood-transfusion-dependent patients
`
`with iron chelators for decades. The art of treating iron overload using iron
`
`chelators was very mature, and the level of ordinary skill in the art was relatively
`
`high in 2000. A person of ordinary skill in the art would have had an M.D. and
`
`several years of clinical work experience in hematology, and would have had
`
`research, clinical, and/or testing experience with iron chelators to treat iron
`
`overload in the body, including iron overload of the heart. The skilled person
`
`would have been familiar with blood disorders such as thalassemia or
`
`hemochromatosis10, including their causes and treatments. (Ex. 1002 (Mehta Dec.)
`
`at ¶ 41.)
`
`
`10 Hemochromatosis is a genetic disorder which causes the body to load too much
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`iron. (Ex. 1002 (Mehta Dec.) at ¶ 41.)
`
`
`
`11
`
`

`

`IX. BACKGROUND ON DEFERIPRONE AND IRON OVERLOAD
`As conceded by the Patent Owner, at least 250 articles discuss the use of
`
`deferiprone as an orally administered iron chelator by transfusion-dependent
`
`patients in order to reduce iron overload, and 48 of these articles provide data on
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`this use. (Ex. 1001 (’328 Patent) at col. 6, ll. 57–61.) The patent specification also
`
`says that deferiprone was “commonly” administered at a dose of 75 mg/kg per day.
`
`(Id. at col. 7, ll. 2–3.) Indeed, the prior art shows that deferiprone is an old drug,
`
`was known at the time that the patent was filed, and was “commonly” used to treat
`
`transfusion-dependent patients in order to reduce iron overload. Petitioner further
`
`agrees with Patent Owner that “a general review of the literature reveals that
`
`deferiprone is effective in removing iron from patients who are iron loaded.” (Id.
`
`at col. 9, ll. 34–36.)
`
`A.
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`“Iron-Overload Conditions of the Heart” in Transfusion-
`Dependent Patients
`
`Thalassemia is a type of anemia, a disorder in which a person’s blood cells
`
`are not able to hold and transport oxygen sufficiently to the body tissues. ((Ex.
`
`1002 (Mehta Dec.) at ¶ 27; Ex. 1001 (’328 Patent) at col. 1, ll. 27–32.) Left
`
`untreated, a patient with thalassemia has a life expectancy of less than 20–30 years.
`
`
`
`12
`
`

`

`(Ex. 1002 (Mehta Dec.) at ¶ 26; Ex. 1014 (Olivieri 199411) at 574; Ex. 1001 (’328
`
`Patent) at col. 2, ll. 16–17.) A regimen of regular blood transfusions is effective at
`
`treating thalassemia. (Ex. 1002 (Mehta Dec.) at ¶ 27.) This treatment has been
`
`known and used since at least the 1960s. (Ex. 1015 (Nathan 196612) at 828; Ex.
`
`1001 (’328 Patent) at col. 1, ll. 27–29.) A thalassemia patient is therefore
`
`characterized as “transfusion-dependent.” The ’328 Patent recognizes that
`
`thalassemia causes a patient to be transfusion-dependent, and its claims are drawn
`
`to treating a “transfusion dependent patient.”13
`
`
`11 Olivieri et al., Survival in Medically Treated Patients with Homozygous β-
`
`Thalassemia, N. ENGL. J. MED., 331:547–78, 1994 (“Olivieri 1994,” Ex. 1014.)
`
`12 Nathan & Gunn, Thalassemia: The Consequences of Unbalanced Hemoglobin
`
`Synthesis, AMERICAN JOURNAL OF MEDICINE, 41:815–30, 1966 (“Nathan 1966,”
`
`Ex. 1015.)
`
`13 Two sub-types of thalassemia are described in the literature. Patients with
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`“Thalassemia Major” are always transfusion dependent, while patients with
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`“Thalassemia Intermedia” may or may not be transfusion dependent. See
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`Bannerman et al., Thalassemia Intermedia, with Iron Overload, Cardiac Failure,
`
`Diabetes Mellitus, Hypopituitarism and Porphyrinuia, AMERICAN JOURNAL OF
`
`MEDICINE, 476–86, 1967 (“Bannerman 1967,” Ex. 1016