UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`Taro Pharmaceuticals U.S.A., Inc.
`Petitioner,
`v.
`
`Apotex Technologies, Inc.
`Patent Owner
`
`
`
`Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`
`
`
`Inter Partes Review No. IPR2017-01446
`
`
`PETITIONER’S REPLY
`
`
`
`i
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`Taro Pharmaceuticals U.S.A., Inc.
`Petitioner,
`v.
`
`Apotex Technologies, Inc.
`Patent Owner
`
`
`
`Patent No. 7,049,328 B2
`
`Title: USE FOR DEFERIPRONE
`
`
`
`Inter Partes Review No. IPR2017-01446
`
`
`PETITIONER’S REPLY
`
`
`
`i
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`B.
`
`C.
`
`
`I.
`INTRODUCTION ............................................................................................. 1
`II. CLAIM CONSTRUCTION ............................................................................... 2
`A.
`The Claims Require a “Therapeutically Effective Amount of
`Deferiprone” and 75 mg/kg/day Meets This Limitation ....................... 3
`Some Claims Are Drawn to Treating Iron Loading in the Heart;
`Some Claims Are Drawn to Treating Cardiac Disease ......................... 4
`Because the Intended Results Are Not Limiting, the Claims Do
`Not Require “Successful Practice” of the Claimed Methods ................ 5
`1.
`Claim Differentiation Does Not Transform the Intended
`Results into Limitations .............................................................. 6
`The Successful Achievement of the Claimed Results Is Not
`Relevant to Patentability ............................................................. 8
`III. THE CLAIMS ARE ANTICIPATED BY THE PRIOR ART ...................... 10
`A. Olivieri Abstract 1995 Anticipates the Challenged Claims ................ 11
`B.
`Olivieri 1995 Anticipates the Challenged Claims. .............................. 14
`C.
`Hoffbrand 1998 Anticipates the Challenged Claims .......................... 16
`IV. THE CLAIMS ARE OBVIOUS OVER THE PRIOR ART .......................... 19
`A.
`The Prior Art Does Not Teach Away from Treating Iron-Induced
`Cardiac Disease with Deferiprone....................................................... 21
`The Other Secondary Considerations Do Not Support
`Patentability ......................................................................................... 23
`
`2.
`
`B.
`
`
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`
`
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`
`ii
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`
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .................................................................... 2, 7, 8
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2013) ............................................................................ 24
`
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .......................................................................... 19
`
`Constant v. Advanced Micro-Devices, Inc.,
`848 F.2d 1560 (Fed. Cir. 1988) .......................................................................... 12
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 24
`
`King Pharms., Inc. v. Eon Labs., Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) ............................................................................ 8
`
`Wi-Lan USA, Inc. v. Apple Inc.,
`830 F.3d 1374 (Fed. Cir. 2016) ............................................................................ 6
`
`
`
`iii
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`
`
`Cardiac health was of central importance to doctors treating blood-
`
`transfusion-dependent patients. Cardiac disease was the main cause of death for
`
`these patients prior to the introduction of chelation therapy; it was a concern when
`
`patients were treated with the original iron chelator, deferoxamine, and continued
`
`to be a concern with deferiprone. Doctors understood that cardiac iron was the
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`culprit, and the prior art studied this issue. For example, the ’328 patent cites Dr.
`
`Olivieri’s early work, which recognized that “deferiprone induced reduction of iron
`
`in the liver and the heart.” (Ex. 1001, 7:47–54.) Doctors, including Dr. Olivieri
`
`and Dr. Hoffbrand, administered deferiprone to blood-transfusion-dependent
`
`patients in order to reduce iron overload, which they understood would reduce their
`
`cardiac iron, which would in turn improve heart function and treat cardiac disease.
`
`Patent Owner (“PO”) defends its patent by claiming that the named
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`inventors came up with a “new use” for the admittedly old drug deferiprone. But
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`the prior art not only taught the administration of 75 mg/kg/day deferiprone to
`
`blood-transfusion-dependent patients, it also taught administering that amount of
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`deferiprone to such patients (i) with cardiac iron overload and (ii) with iron-
`
`induced cardiac disease, (iii) with positive results. “Newly discovered results of
`
`known processes directed to the same purpose are not patentable, because such
`
`1
`
`
`
`
`
`results are inherent.” Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F-3d
`
`1368,1376 (Fed. Cir. 2001). Because the claimed methods of treatment are
`
`directed to the same patient populations with the same drug in the same amount as
`
`in the prior art, the Board should find that the claims are unpatentable and cancel
`
`the challenged claims.
`
`II.
`
`CLAIM CONSTRUCTION
`
`All of the claims are directed to treating blood-transfusion-dependent
`
`patients by administering a therapeutically effective amount of deferiprone. The
`
`preambles identify the method and the type of patient; the independent claims (and
`
`claim 19) each recite an intended result:
`
`treating iron
`induced cardiac
`
`experiencing an iron to stabilize/reduce iron
`overload condition
`accumulation in the heart
`
`disease
`
`of the heart
`
`treating iron
`loading in the
`heart
`
`experiencing an iron to reduce further iron overload in
`overload condition
`the heart
`of the heart
`
`the heart
`
`stabilizing iron
`induced heart
`
`having iron
`overload
`
`to treat the iron burden in the
`heart
`
`disease
`
`reducing the
`iron burden in
`
`having iron
`overload
`
`to reduce the iron burden of the
`heart
`
`
`
`treating iron
`induced heart
`
`having an iron
`overload condition
`
`disease
`
`of the heart
`
`treating iron
`loading in the
`heart
`
`having an iron
`overload condition
`
`of the heart
`
`to reduce the iron stores in the
`
`heart in preference to general iron
`stores in the body, such as found
`in the liver
`
`to chelate the iron stores in the
`
`heart in preference to general iron
`stores in the body, such as found
`in the liver
`
`treating iron
`loading in the
`heart
`
`having an iron
`overload condition
`
`of the heart
`
`to reduce the iron stores in the
`
`heart in preference to general iron
`stores organs/tissue in the body,
`such as found in the liver
`
`treatment of
`
`iron induced
`
`having an iron
`overload condition
`
`for the direct reduction/removal
`
`of intracellular iron stores in the
`
`heart disease
`
`of the heart
`
`heart
`
`
`
`p—i C
`
`reduce the
`
`with an iron
`
`occurrence of
`
`overload condition
`
`iron-induced
`
`cardiac disease
`
`p—i \O
`
`dependent on claims 1, 2, 3, 4, 5, 6, 7,
`8,9or10
`
`wherein deferiprone’s efficacy is
`cardio preferential when
`compared with its ability to lower
`total iron stores in the body
`
`wherein deferiprone has a cardio
`preferred!selective function when
`compared to desferrioxamine or
`other alternative chelating agents
`utilized in patients suffering iron
`overload
`
`A.
`
`The Claims Require a “Therapeutically Effective Amount of
`Deferiprone” and 75 mg/kg/day Meets This Limitation
`
`The Board correctly found that 75 mg/kg/day of deferiprone “necessarily
`
`constitutes a value that is a ‘therapeutically effective amount’ as recited in claims
`
`3
`
`
`
`1, 2, and 4-10.” (Decision on Institution (“DI”), 7.) PO readily acknowledged this
`
`finding. (POR, 15.) The only study reported in the ’328 patent used a fixed dose
`
`of 75 mg/kg/day of deferiprone. (See Ex. 1001, 15:28–30.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Accordingly, there is no
`
`dispute that, for the claimed patient populations, 75 mg/kg/day of deferiprone
`
`constitutes a “therapeutically effective amount” of deferiprone. (Ex. 1060 ¶¶7–15.)
`
`B.
`
`Some Claims Are Drawn to Treating Iron Loading in the Heart;
`Some Claims Are Drawn to Treating Cardiac Disease
`
`Claims 2, 7, and 8 are directed to a method of treating patients with “an iron
`
`overload condition of the heart.” PO reads “iron overload condition of the heart”
`
`narrowly to mean “iron-induced cardiac disease” (POR, 11–13), but that reading is
`
`not supported by the record. The patent specification consistently discusses the
`
`prevention, treatment, or reversal of heart disease in “a patient having an iron
`
`overload condition of the heart.” (See Ex. 1001, cols. 11–12.) To prevent heart
`
`disease in such a patient, that patient cannot already have heart disease. Thus, a
`
`patient having an “iron overload condition of the heart” may, on the one hand,
`4
`
`
`
`
`
`simply have iron burden in the heart (and not cardiac disease), and, on the other
`
`hand, have a condition on the spectrum of cardiac disease due to iron overload.
`
`(Ex. 1060 ¶¶5–6.) Claims 2, 7, and 8, directed to treating “iron loading in the
`
`heart,” are thus directed to patients who have iron loading, but do not necessarily
`
`have iron-induced cardiac disease. Claims 1, 6, and 9, also directed to patients
`
`with an iron overload condition of the heart, are drawn to a method of treating
`
`iron-induced cardiac disease.
`
`Independent claims 4, 5, and 10 do not include the term “iron overload
`
`condition of the heart.” Of these, only claim 4 is directed to treating “heart
`
`disease,” while claims 5 and 10 are directed to patients who have iron burden, but
`
`do not necessarily have iron-induced cardiac disease.
`
`C. Because the Intended Results Are Not Limiting, the Claims Do
`Not Require “Successful Practice” of the Claimed Methods
`
`The Board correctly found that the claim language reciting intended results
`
`is not limiting. (DI, 9.) PO revisits this issue and argues that the claims require the
`
`“successful practice” of the claimed methods. (POR, 22.) However, the
`
`requirement that every individual patient achieves the intended results and is thus
`
`successfully treated is not supported by the specification.
`
`The specification contains a single example describing a retrospective study
`
`of treating blood-transfusion-dependent patients—some of whom had cardiac
`
`disease—with either 75 mg/kg/day of deferiprone or 20–60 mg/kg/day of
`5
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`
`
`
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`deferoxamine, to examine the development and progression of cardiac disease.
`
`Although 75 mg/kg/day of deferiprone was generally successful, a worsening of
`
`cardiac function was observed in two patients taking deferiprone. (See Ex. 1001,
`
`21:7–10.) PO’s proposed construction, requiring that each patient successfully
`
`achieve the claimed intended result, is not supported by the specification and thus
`
`cannot be part of the claimed invention. (Ex. 1060 ¶¶7–15.)
`
`PO relies on claim differentiation and the prosecution history to attempt to
`
`transform the intended results into limitations. Both arguments fail.
`
`1.
`
`Claim Differentiation Does Not Transform the Intended
`Results into Limitations
`
`Claim differentiation is “a guide, not a rigid rule.” Wi-Lan USA, Inc. v.
`
`Apple Inc., 830 F.3d 1374, 1391 (Fed. Cir. 2016). “Claim differentiation cannot
`
`‘overcome . . . a contrary construction dictated by the written description or
`
`prosecution history.’” Id.
`
`Each of the independent claims (and claim 19) contains intended results
`
`setting forth alleged behavior of deferiprone in the body, e.g. reduction of iron in
`
`the heart or preferential removal of iron from the heart. But this is not an aspect of
`
`the method over which either an administering physician or a patient has any
`
`control.
`
`
`
`
`
`
`
`6
`
`
`
`
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` These intended results describe the inherent
`
`
`
`behavior of deferiprone in the body and cannot be limiting. See Bristol-Myers, 246
`
`F.3d at 1376 (finding that “reduced hematologic toxicity” is not limiting because it
`
`“does not result in a manipulative difference in the steps of the claim”).
`
`The different words used in the preambles of the claims may indicate two
`
`overlapping groups of patients (patients with cardiac iron overload, and the subset
`
`of those patients who have cardiac disease), but despite this difference in wording,
`
`the claimed methods are all directed to the same purpose: treating blood-
`
`transfusion-dependent patients with deferiprone so that the patients do not
`
`succumb to iron-induced cardiac disease. While PO takes the position that the
`
`claimed results are different and therefore, they must be limiting, neither PO nor its
`
`experts have explained how the steps of the claims differ from one another. The
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`claims themselves do not readily provide any clear differences among the claimed
`
`methods, and the specification does not set forth different steps based on the
`
`allegedly different intended results. Indeed, PO’s expert Dr. Coates struggled at
`
`his deposition to articulate the alleged different meanings of the various claims.
`
`For example, Dr. Coates testified that claims “1 and 4, to me, appear to say the
`
`same thing, except for one implies that you’re making things better, and the other
`
`7
`
`
`
`
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`implies you’re at least keeping them the same.” (Ex. 1058, 159:13–18, 144:25–
`
`164:25; see also Ex. 1060 ¶¶16–18.)
`
`2.
`
`The Successful Achievement of the Claimed Results Is Not
`Relevant to Patentability
`
`PO points to the intrinsic record and argues that since the patent itself admits
`
`that the method of using deferiprone to treat blood-transfusion-dependent patients
`
`is in the prior art, patentability requires the claimed results to be limiting. PO also
`
`points to the prosecution history and notes that “prior art and enablement rejections
`
`. . . were overcome by citing to the specific results required by” the claims. (POR,
`
`16.)
`
`This evidence fails in the face of the law that a claim to an inherent result of
`
`an old process is not patentable. See, e.g., King Pharms., Inc. v. Eon Labs., Inc.,
`
`616 F.3d 1267, 1275 (Fed. Cir. 2010); Bristol-Myers, 246 F.3d at 1376. While
`
`claim terms in general should be construed to preserve the claims’ validity, that
`
`doctrine holds only when the terms “impart patentability” and “distinguish [the]
`
`claims over the prior art.” Bristol-Myers, 246 F.3d at 1377. Here, the intended
`
`results are not patentable, as the method of treating iron overload in the heart and
`
`the ensuing cardiac disease is the same as that described in the prior art.
`
`PO argues that the ’328 patent is directed to a new use for deferiprone, not a
`
`new result of an old method: “prior to the invention, deferiprone had not been
`
`given to a patient having an iron overload condition of the heart to treat or reduce
`
`8
`
`
`
`
`
`cardiac iron.” (POR, 20–21.) PO mischaracterizes the prior art which explicitly
`
`teaches the use of deferiprone to treat transfusion-dependent patients who have
`
`iron overload and cardiac disease. (DI, 35.) Because the intended results cannot
`
`“impart patentability,” they should not be treated as limitations.
`
`Other evidence also compels the conclusion that the claimed results are not
`
`limiting. PO’s proffered construction regarding successful treatment requires “a
`
`reduction in cardiac iron” and a POSA to “rely on [the claimed] results to
`
`determine whether the claimed methods of treatment are successfully practiced.”
`
`(POR, 40, 15.) This construction conflicts with PO’s other assertion that “it was
`
`not until 2000 that cardiac MRI T2* was capable of quantitatively assessing
`
`cardiac iron levels.”1 (Id., 32.) PO’s expert Dr. Pennell confirmed that MRI T2*
`
`was first presented to the public in December 2000, months after the priority date
`
`of the ’328 patent, June 30, 2000. (Ex. 2003 ¶26; Ex. 1059, 40:5–7.) Since it is
`
`axiomatic that the claims of a patent must be understood from the viewpoint of a
`
`POSA as of the filing date of the patent, PO’s construction requiring measuring a
`
`reduction in cardiac iron cannot be correct because, according to PO, measuring
`
`cardiac iron was not possible until after the filing date.
`
`1 PO made this assertion to “prove” that the prior art did not inevitably disclose
`
`treatment of patients with iron-induced cardiac disease. This contention is
`
`addressed further in the section on anticipation.
`
`9
`
`
`
`
`
`III. THE CLAIMS ARE ANTICIPATED BY THE PRIOR ART
`
`The Board applied the correct construction of the challenged claims and
`
`correctly determined that Hoffbrand 1998, Olivieri 1995, and Olivieri Abstract
`
`1995 each anticipate challenged claims 1–11, 13–17, and 19. PO does not
`
`meaningfully dispute that each of the Primary References anticipates the claims
`
`under the Board’s construction.
`
`Each of the Primary References discloses the administration of 75
`
`mg/kg/day deferiprone, i.e., “a therapeutically effective amount,” to blood-
`
`transfusion-dependent patients to treat “iron-induced cardiac disease” or “iron
`
`loading in the heart.” (Petition, 23.) These references also each anticipate the
`
`claims even under PO’s erroneous, narrower claim construction under which the
`
`results are limiting.
`
`PO argues that the prior art does not anticipate because it does not explicitly
`
`state that patients’ cardiac disease was iron-induced. (POR, 23–24.) However, the
`
`sole example in the ’328 patent also does not explicitly state that patients’ cardiac
`
`disease was iron-induced. (Ex. 1060 ¶14.) Patients in the patent study were
`
`diagnosed with iron-induced cardiac disease simply because they were iron
`
`overloaded, as evidenced by serum ferritin and liver iron concentrations and had
`
`symptoms of cardiac disease. (See Ex. 1001, 10:10–14.) As Dr. Coates testified,
`
`this is how hematologists diagnosed iron-induced cardiac disease as of 2000. (Ex.
`
`10
`
`
`
`
`
`1058, 32:16–34:7.) The prior art uses the same assessments—elevated body iron
`
`levels simultaneous with cardiac disease—to diagnose iron-induced cardiac disease
`
`(Ex. 1060 ¶¶13–14).
`
`A. Olivieri Abstract 1995 Anticipates the Challenged Claims
`
`Olivieri Abstract 1995 taught that the administration of 75 mg/kg/day of
`
`deferiprone to patients with cardiac iron overload reduces cardiac iron in blood-
`
`transfusion-dependent patients. (Petition, 36–39.) Olivieri Abstract 1995
`
`measured cardiac iron by MRI T2 relaxation time (“TRT”). The abstract reports
`
`that the initial TRT measurements were nearly all below the “normal” threshold of
`
`32 msec. (Id.) At the end of the study, at least some of the patients had TRT
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`levels in the “normal” range. (Id.)
`
`PO argues that Olivieri Abstract 1995 cannot anticipate because TRT as
`
`measured by Dr. Olivieri, is not a reliable indicator of the concentration of iron in
`
`the heart. Instead, according to PO, only a related technique, T2* relaxation time,
`
`can reliably measure iron in the heart. (See POR, 32.) This is incorrect. T2 and
`
`T2* are closely related MRI techniques, and both are understood to measure
`
`cardiac iron.
`
`
`
`).
`
`The prior art and post art demonstrate that TRT is reliable. For example, a
`
`1996 paper confirmed a linear relationship between cardiac MRI TRT and cardiac
`
`11
`
`
`
`
`
`iron concentration. (Ex. 1062, 162–63; see also Ex. 1055, 118.) Indeed, as of the
`
`priority date, multiple groups used MRI TRT to measure heart iron concentration.
`
`(Ex. 1059, 173:14–22.)
`
`
`
`POSAs in fact relied on the data in Olivieri Abstract 1995. The patent itself
`
`cites Olivieri Abstract 1995 for the proposition that “deferiprone can remove iron
`
`from the iron-overloaded heart,” and that “an increase of the T2 relaxation time” as
`
`was “consistent with a reduction in cardiac iron.”2 (Ex. 1001, 23:66–24:13.) A
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`publication by Dr. Pennell described T2* results as “consistent” with that of
`
`Olivieri Abstract 1995 in which “deferiprone (75 mg/kg/d) resulted in a significant
`
`increase in T2 relaxation time.” (Ex. 1057, 3743.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2 The patentees’ characterization of Olivieri Abstract 1995 is binding for
`
`anticipation purposes. Constant v. Advanced Micro-Devices, Inc., 848 F.2d 1560,
`
`1570 (Fed. Cir. 1988) (“A statement in the patent that something is in the prior art
`
`is binding on the applicant and patentee for determinations of anticipation
`
`and obviousness.”).
`
`12
`
`
`
`
`
`Thus, TRT relaxation time, as used in Olivieri Abstract 1995, is and was a
`
`reliable measure of cardiac iron concentration, and a POSA would have understood
`
`from Dr. Olivieri’s TRT data that 75 mg/kg/day deferiprone was effective to
`
`reduce cardiac iron. (Ex. 1060 ¶¶19–28.) Olivieri Abstract 1995 therefore
`
`expressly anticipates claims 2, 5, 7, 8, and 10 (and all of the dependent claims)
`
`which are directed to methods of treating iron overload of the heart.
`
`A POSA would have also understood that patients with abnormal TRT
`
`relaxation times of 23.9±6.4 msec suffered from iron-induced cardiac disease (Ex.
`
`1060 ¶¶21-27) and that reducing cardiac iron would in turn improve heart function
`
`in blood-transfusion-dependent patients, thereby treating cardiac disease.
`
`
`
`
`
`
`
`
`
` Accordingly, Olivieri
`
`Abstract 1995 expressly anticipates claims 1, 4, 6, and 9, which are directed to
`
`methods of treating cardiac disease.
`
`To the extent that the challenged claims require “successful treatment,”
`
`Olivieri Abstract 1995 expressly confirms successful reduction of cardiac iron, as
`
`measured by an increase in TRT from abnormal to “normal” values. (Ex. 1010,
`
`12.) It also contrasted this improvement in TRT with that for deferoxamine:
`
`13
`
`
`
`
`
`“Initial TRT in [deferoxamine]-treated [patients] [21.4±7.9msec] remains
`
`unchanged [21.7±6.9msec, p>0.67].” (Id.) Thus, even under PO’s narrow
`
`construction of the claims, Olivieri Abstract 1995 expressly meets the intended
`
`results of claims 1, 2, 4, and 5 (treating iron burden in the heart) and those of
`
`claims 6, 7, 8, 9, 10 and 19 (preferential treatment of cardiac iron) (and the
`
`dependent claims).
`
`B. Olivieri 1995 Anticipates the Challenged Claims.
`
`Olivieri 1995 discloses the treatment with 75 mg/kg/day deferiprone of
`
`blood-transfusion-dependent patients whose long-term high SF and LIC values
`
`were understood to represent of iron overload of the heart. (Ex. 1012, Fig. 1
`
`(showing two patients whose LIC values declined but remained above 80 μmol/g
`
`wet weight over the course of treatment), Fig. 2 (showing two patients whose SF
`
`values declined but remained above 5000 μg/L over the course of treatment).)
`
`These measurements were taken regularly. (Ex. 1060 ¶¶30–32.) During his
`
`deposition, Dr. Pennell conceded that a POSA would have understood that these
`
`thresholds of SF and LIC were “surrogates for cardiac iron.” (Ex. 1059 132:7–11).
`
`Thus a POSA would have understood that at least the patients of Figs. 1 and 2
`
`noted above had iron overload of the heart and that 75 mg/kg/day deferiprone was
`
`effective to reduce that overload, as reflected in their declining LIC and SF
`
`measurements. Further, a POSA would have understood that at least some patients
`
`14
`
`
`
`
`
`described in Olivieri 1995 had cardiac disease because the reference states that
`
`some patients had “complications” with iron overload. A POSA would have
`
`known that the most common complication of iron overload is iron-induced
`
`cardiac disease. (Ex. 1060 ¶33; Petition, 42–43.)
`
`PO contends that Olivieri 1995 does not anticipate because “it was clinically
`
`and statistically shown that neither SF [serum ferritin] nor LIC [liver iron
`
`concentration] correlate with cardiac iron levels or cardiac health in TM patients.”
`
`(POR, 3, 29, 39.)
`
`
`
`
`
`
`
`
`
`
`
` And, Noetzli 2008, a reference that PO relies on to challenge the link
`
`between liver and heart iron, actually confirms that “[h]igh hepatic iron
`
`concentration (HIC)3 is associated with cardiac iron overload.” (Ex. 2006,
`
`Abstract.)
`
`
`3 “Hepatic iron concentration” is a synonym for liver iron concentration. (Ex.
`
`1001, 2:39–40.)
`
`15
`
`
`
`
`
`More significantly, PO’s contention does not square with how a POSA
`
`would have understood Olivieri 1995 as of the priority date. A POSA would have
`
`understood that the patients in Olivieri 1995 had cardiac iron overload and iron-
`
`induced cardiac disease. (Ex. 1060 ¶36; Ex. 1058, 32:16–34:7.) Accordingly,
`
`Olivieri 1995 anticipates claims 2, 5, 7, 8, and 10 (and the dependent claims),
`
`directed to treatment of cardiac iron overload and anticipates claims 1, 4, 6, and 9,
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`directed to treatment of iron-induced cardiac disease (and the dependent claims).
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`Finally, Olivieri 1995 discloses successful treatment: “[o]ral deferiprone
`
`induces sustained decreases in body iron to concentrations compatible with the
`
`avoidance of complications from iron overload.” (Ex. 1012, Abstract, Figs. 1–2
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`(showing decreases in SF and LIC); Ex. 1060 ¶¶35–36.) Thus Olivieri 1995
`
`expressly anticipates the results recited in claims 1, 2, 4, and 5 (reduction of
`
`cardiac iron) and inherently anticipates the results recited in claims 6, 7, 8, 9, 10,
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`and 10 (preferential reduction of cardiac iron) because the activity of deferiprone
`
`did not change between the publication of the prior art and the time that the patent
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`was filed. (Ex. 1060 ¶¶29–36.)
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`C. Hoffbrand 1998 Anticipates the Challenged Claims
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`Hoffbrand 1998 describes the treatment of fifty-one “iron-overloaded
`
`regularly transfused” patients with 75 mg/kg/day of deferiprone. (Ex. 1007, 295.)
`
`These patients’ cardiac disease was annually monitored via MUGA (multigated
`
`16
`
`
`
`
`
`acquisition) scan, a reliable measure of cardiac disease. (See id., 296–97; Ex. 1060
`
`¶37; Ex. 2022, 685; Ex. 1058, 44:10–15; Ex. 2027, 101.).)
`
`Hoffbrand 1998 expressly discloses that four patients in the study died from
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`“cardiac disease induced by iron overload.” (Ex. 1007, 299 (emphasis added).)
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`Dr. Coates opined that the authors’ diagnosis of iron-induced cardiac disease for
`
`these patients was correct: “In my opinion, a POSA viewing Hoffbrand 1998
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`would have no reason to doubt the authors’ conclusion that four patient deaths
`
`were due to iron induced CHF.” (Ex. 2035 ¶26.)
`
`Three of these patients, (1) a 23-year-old male, (2) a 24-year-old female, and
`
`(3) a 30-year-old male, were administered 75 mg/kg/day deferiprone, for 26, 19,
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`and 24 months, respectively. (Ex. 1007, 296.) Each of these patients had iron-
`
`induced cardiac disease, as evidenced by their MUGA results:
`
`(1) LVEF of 55% at rest and 40% on cold stress and, two years later, 54% at
`
`rest and 42% on cold stress;
`
`(2): LVEF of 48% at rest and 40% on cold stress and, one year later, 46% at
`
`rest and 40% on cold stress;
`
`(3) “moderately severe cardiomyopathy,” with an initial LVEF of 51% at
`
`rest falling to 43% on stress and, two years later, 49% at rest falling to 41%.
`
`A LVEF measurement of less than 56% indicates cardiac dysfunction and
`
`disease, and therefore a POSA would have understood from these results that these
`
`17
`
`
`
`
`
`patients had iron-induced cardiac disease, and that 75 mg/kg/day deferiprone was
`
`effective in treating heart disease in these patients for much of the time that they
`
`were treated with deferiprone. (Ex. 1058, 196:11–197:10; see also Ex. 1060 ¶¶38–
`
`40.) Absent chelation and stabilization with deferiprone, these patients, with
`
`diagnosed heart disease, would have died much sooner. (Ex. 1060 ¶¶38–41; Ex.
`
`1058, 197:16–198:6.) A POSA would also have understood that these patients
`
`necessarily and inevitably had iron overload of the heart, which caused the heart
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`disease, and that the stabilization of the heart disease was the result of removing
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`cardiac iron from these continuously transfused patients. (Ex. 1060 ¶¶38–41.)
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`Aside for the patients who died of heart failure after long-term successful
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`treatment with deferiprone, Hoffbrand 1998 also discloses other patients with iron
`
`overload of the heart, as determined by SF and/or LIC measurements. (Ex. 1007,
`
`Fig. 1 (showing, inter alia, a patient having serum ferritin values over 6000 μg/L
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`over a period of almost 50 months).), 297 (“10 patients had a liver iron content
`
`above 15.0 mg/g dry weight, i.e., falling within the range that has been associated
`
`with cardiac disease”).)
`
`Hoffbrand 1998 also discloses additional evidence of successful treatments.
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`For example, it discloses that 26 patients who were regularly transfused over an
`
`average of 39.4 months saw “no overall change in iron stores” and “no significant
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`changes” in cardiac function, despite the constant influx of iron, thereby
`
`18
`
`
`
`
`
`demonstrating successful stabilization of iron load in the heart and cardiac disease.
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`(Ex. 1007, Abstract; Ex. 1007, 298 (“Deferiprone, therefore, has been effective in
`
`these patients at balancing iron input from blood transfusions by iron excretion in
`
`the urine.”); see also Ex. 1058, 93:20–94:1, 196:7–198:18 (Dr. Coates’s admission
`
`that Dr. Hoffbrand’s patients were successfully treated).)
`
`Thus, Hoffbrand 1998 expressly anticipates claims 2, 5, 7, 8, and 10 (and the
`
`dependent claims) directed to methods of treating cardiac iron overload, and
`
`anticipates claims 1, 4, 6, and 9 (and the dependent claims), directed to methods of
`
`treating iron-induced cardiac disease. Because the treatment was expressly
`
`disclosed to be successful, Hoffbrand 1998 expressly anticipates the results
`
`claimed in claims 1, 2, 4, and 5 and inherently anticipates the results claimed in
`
`claims 6, 7, 8, 9, 10, and 19. (Ex. 1060 ¶¶37–43.)
`
`IV. THE CLAIMS ARE OBVIOUS OVER THE PRIOR ART
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`PO’s procedural arguments regarding Petitioner’s obviousness analysis are
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`incorrect, and beside the point. Petitioner presented a complete analysis, including
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`an examination of all the Graham factors (see Petition, 43–49), and in any event,
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`since “anticipation is the epitome of obviousness,” the claims are obvious even if
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`they are also anticipated because there are no differences between them and the
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`prior art. Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983).
`
`19
`
`
`
`
`
`To the extent that the Board now finds that, as PO argues, the prior art does
`
`not anticipate the use of deferiprone to treat iron overload of the heart or iron-
`
`induced cardiac disease, the record establishes that this use was obvious.
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`The Primary References all report the treatment of iron overloaded patients,
`
`and their cardiac issues: Olivieri Abstract 1995 measured cardiac iron; Olivieri
`
`1995 measured on SF and LIC levels associated with cardiac iron; Hoffbrand 1998
`
`assessed cardiac function via MUGA scans annually. These assessments
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`underscored the POSA’s recognition that cardiac disease in iron overloaded
`
`patients was iron-induced, and could be effectively treated with deferiprone, which
`
`would chelate iron in the body, including the heart. In view of the overwhelming
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`prior art teaching the safety and efficacy of deferiprone, a POSA would have been
`
`motivated to use deferiprone to treat the most severe complication afflicting iron
`
`overloaded patients—cardiac disease—and would have had a reasonable
`
`expectation of success. (Ex. 1001, 6:57–64 (“There 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.
`
`The vast majority of these references demonstrate the safety and efficacy of this
`
`drug in treating such patients, particularly those with thalassemia major.”); see Ex.
`
`1002 ¶49.) Indeed, Dr. Olivieri, Dr. Hoffbrand, and many others were motivated
`
`to treat iron overloaded patients with deferiprone and reported on their success in
`
`20
`
`
`
`
`
`treating cardiac iron and cardiac disease, as discussed infra. Thus, the prior art
`
`renders the claims obvious.
`
`PO alleges secondary considerations of nonobviousness: (1) teaching away,
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`(2) unexpected results, (3) long-felt need, and (4) praise of others. None of these
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`considerations render the challenged claims nonobvious.
`
`A. The Prior Art Does Not Teach Away from Treating Iron-Induced
`Cardiac Disease with Deferiprone.
`
`PO asserts that the prior art taught that deferiprone was not effective and
`
`toxic to the heart. (POR, 56.) This assertion should be rejected, particularly in
`
`view of patentee’s binding admission that the “vast majority” of prior art
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`“demonstrate the safety and efficacy of this drug deferiprone.” (Ex. 1001, 6:57–
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`64.)
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`Although PO now contends that Olivieri’s subsequent work teaches away
`
`from the claimed metho
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