Paper No. 7
`February 5, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`FRESENIUS KABI USA, LLC
`Petitioner,
`
`v.
`
`CEPHALON, INC.
`Patent Owner.
`
`_____________
`
`Case IPR2016-00098
`Patent No. 8,791,270 B2
`
`_____________________
`
`CEPHALON, INC.’S PRELIMINARY PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`February 5, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`FRESENIUS KABI USA, LLC
`Petitioner,
`
`v.
`
`CEPHALON, INC.
`Patent Owner.
`
`_____________
`
`Case IPR2016-00098
`Patent No. 8,791,270 B2
`
`_____________________
`
`CEPHALON, INC.’S PRELIMINARY PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION .........................................................................................1
`
`BACKGROUND............................................................................................6
`The Inventors Identified a Problem Not Recognized in the Art ...........6
`A.
`The Inventions of the ’270 Patent .........................................................9
`B.
`FDA Approval and Market Response.................................................10
`C.
`The ANDA Filing by Petitioner’s Contractual Partner.......................11
`D.
`
`III. PETITIONER’S PROPOSED CLAIM CONSTRUCTIONS
`AND DEFINITION OF AN ORDINARY ARTISAN..............................11
`
`IV. THE PETITION FAILS TO MAKE THE SHOWING
`REQUIRED UNDER 35 U.S.C. § 314(a)...................................................12
`Ground 1: Petitioner Has Not Demonstrated a Reasonable
`A.
`Likelihood that It Would Prove that Claims 1-20 Are Obvious
`over Maas and Teagarden. ..................................................................12
`1.
`Petitioner Fails to Establish That an Ordinary Artisan
`Would Have Targeted the Claimed Degradant Profiles
`with a Reasonable Likelihood of Success.................................13
`Petitioner’s Post-Hoc Estimates of Bendamustine
`Degradants in Maas are Unreliable...........................................17
`Petitioner Dramatically Overstates Teagarden’s Teaching ......26
`Claim-by-Claim Analysis .........................................................32
`a.
`Claim 1............................................................................32
`b.
`Claim 2............................................................................34
`c.
`Claims 3-12, 14-18 and 20 .............................................34
`d.
`Claims 13 and 19 ............................................................38
`
`3.
`4.
`
`2.
`
`i
`
`
`
`Page
`
`B.
`
`C.
`
`D.
`
`E.
`
`Ground 1 (Petitioner’s Alternate Argument): Petitioner Has
`Not Demonstrated that Table 13 of the ’270 Patent Reflects the
`Inherent Characteristics of the Ribomustin Tested by Maas or
`that Claims 1-20 Are Obvious over Table 13 and Teagarden. ...........40
`1.
`Claim 1......................................................................................40
`2.
`Claims 2-20...............................................................................46
`Ground 2: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Will Prove that Claims 13 and 19 Are
`Obvious over Maas, Teagarden and Gust. ..........................................47
`Ground 3: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Will Prove that Claims 20-23 Are Obvious
`over Maas, Teagarden and the Ribomustin Product Monograph. ......50
`Ground 4: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Will Prove that Claims 1-23 Are Obvious
`over Allegedly Admitted Prior Art in View of Teagarden. ................51
`
`V.
`
`PETITIONER’S GROUNDS ARE REDUNDANT AND
`VIOLATE THE BOARD’S RULES..........................................................55
`
`VI. CONCLUSION ............................................................................................59
`
`ii
`
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Agila Specialties Inc. v. Cephalon, Inc.,
`IPR2015-00503, Paper 10 (PTAB July 20, 2015)..............................................17
`
`Agila Specialties Inc. v. Cephalon, Inc.,
`IPR2016-00026, Paper 3 (PTAB Oct. 9, 2014)..................................................11
`
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................44
`
`Cadence Pharm. Inc. v. Exela PharmSci Inc.,
`780 F.3d 1364 (Fed. Cir. 2015) ..........................................................................29
`
`Ex Parte Fyke,
`2015 WL 4126808 (PTAB June 22, 2015).........................................................53
`
`Illumina, Inc. v. Tr. of Columbia Univ.,
`IPR2012-0006, Paper 43 (PTAB May 10, 2013) ...............................................56
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ..........................................................................35
`
`Intri-Plex Techs. Inc. v. Saint-Gobain Performance Plastics Rencol Ltd.,
`IPR2014-00309, Paper 83 (PTAB Mar. 23, 2014).............................................53
`
`Kingbright Elecs. Co. Ltd. v. Cree, Inc.,
`IPR2015-00746, Paper 8 (PTAB Aug. 20, 2015)...............................................52
`
`Liberty Mutual Ins. Co. v. Progressive Casualty Ins. Co.,
`CBM2012-0003, Paper 7 (PTAB Oct. 25, 2012) ...............................................56
`
`Medtronic, Inc. v. NuVasive, Inc.,
`IPR2014-00487, Paper 8 (PTAB Sept. 11, 2014)...............................................58
`
`Oracle Corp. v. Clouding IP, LLC,
`IPR2013-00075, Paper 15 (PTAB June 13, 2013) .......................................55, 56
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ..........................................................................45
`iii
`
`
`
`Page(s)
`
`Reading & Bates Constr. Co. v. Baker Energy Res. Corp.,
`748 F.2d 645 (Fed. Cir. 1984) ............................................................................54
`
`Riverwood Int’l Corp. v. R.A. Jones & Co., Inc.,
`324 F.3d 1346 (Fed. Cir. 2003) ....................................................................53, 54
`
`Scaltech Inc. v. Retec/Tetra, LLC,
`178 F.3d 1378 (Fed. Cir. 1999) ..........................................................................44
`
`Statutes
`
`35 U.S.C. § 102....................................................................................................5, 51
`
`35 U.S.C. § 102(b) ...................................................................................................52
`
`35 U.S.C. § 103....................................................................................................5, 51
`
`35 U.S.C. § 311(b) ...............................................................................................6, 52
`
`35 U.S.C. § 325(d) ...................................................................................................58
`
`Other Authorities
`
`37 C.F.R. § 42.1(b) ............................................................................................55, 56
`
`37 C.F.R. § 42.104(b)(4)......................................................................................6, 52
`
`37 C.F.R. § 42.108(b) ..............................................................................................55
`
`iv
`
`
`
`PATENT OWNER’S LIST OF EXHIBITS
`
`EXHIBIT
`
`DESCRIPTION
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`TREANDA® Prescribing Information
`
`“Treanda New Drug Application for the Treatment of
`Chronic Lymphocytic Leukemia Granted Priority
`Review Status by FDA,” Drugs.com (December 3,
`2007)
`Kanti R. Rai, et al., “Fludarabine Compared with
`Chlorambucil as Primary Therapy for Chronic
`Lymphocytic Leukemia,” 343(24) New Eng. J. Med.
`1752 (December 14, 2000)
`M. J. Keating, et al., “Long-Term Follow-up of
`Patients with Chronic Lymphocytic Leukemia (CLL)
`Receiving Fludarabine Regimens as Initial Therapy,”
`92 Blood 1165 (August 15, 1998)
`Guillaume Dighiero, et al., “Chlorambucil in Indolent
`Chronic Lymphocytic Leukemia,” 338 New Eng. J.
`Med. 1506 (May 21, 1998)
`The French Cooperative Group on Chronic
`Lymphocytic Leukemia, “Comparison of Fludarabine,
`Cyclophosphamide / Doxorubicin / Prednisone, and
`Cyclophosphamide / Doxorubicin / Vincristine /
`Prednisone in Advanced Forms of Chronic
`Lymphocytic Leukemia: Preliminary Results of a
`Controlled Clinical Trial,” 20 Seminarsin Oncology 21
`(October 1993)
`Suzanne Demko, et al., “FDA Drug Approval
`Summary: Alemtuzumab as Single-Agent Treatment
`for B-Cell Chronic Lymphocytic Leukemia,” 13 The
`Oncologist 167 (2008)
`A. J. Davies, et al., “Tositumomab and Iodine I 131
`Tositumomab for Recurrent Indolent and Transformed
`B-Cell Non-Hodgkin’s Lymphoma,” 22 J. Clin. Oncol.
`1469 (April 15, 2004)
`
`v
`
`
`
`EXHIBIT
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`DESCRIPTION
`
`Samuel A. Jacobs, et al., “Phase II Trial of Short-
`Course CHOP-R Followed by 90Y-ibritumomab
`Tiuexetan and Extended Rituximab in Previously
`Untreated Follicular Lymphoma,” 14(21) Clin. Cancer
`Res. 7088 (November, 1, 2008)
`Richard I. Fisher, et al., “Comparison of a Standard
`Regimen (CHOP) with Three Intensive Chemotherapy
`Regimens for Advanced Non-Hodgkin’s Lymphoma,”
`328(14) New Eng. J. Med. 1002 (April 8, 1993)
`Peter McLaughlin, et al., “Fludarabine, Mitoxantrone,
`and Dexamethasone: An Effective New Regimen for
`Indolent Lymphoma,” 14 J. Clin. Oncol. 1262 (April
`1996)
`File History of U.S. Patent No. 8,609,863
`
`“FDA Approves Treanda,” Drugs.com (March 20,
`2008)
`“Cephalon Receives FDA Approval for Treanda to
`Treat Patients with Relapsed Indolent Non-Hodgkin’s
`Lymphoma,” Drugs.com (October 31, 2008)
`Brad S. Kahl, et al., “Bendamustine Is Effective
`Therapy in Patients with Rituximab-Refractory,
`Indolent B-cell Non-Hodgkin Lymphoma: Results
`From a Multicenter Study,” Cancer 106 (January 1,
`2010)
`K. Sue Robinson, et al., “Phase II Multicenter Study of
`Bendamustine Plus Rituximab in Patients with
`Relapsed Indolent B-Cell and Mantle Cell Non-
`Hodgkin’s Lymphoma,” 26 J. Clin. Oncol. 4473
`(September 20, 2008)
`Wolfgang U. Knauf, et al., “Phase III Randomized
`Study of Bendamustine Compared with Chlorambucil
`in Previously Untreated Patients with Chronic
`Lymphocytic Leukemia,” 27 J. Clin. Oncol. 4278
`(September 10, 2009)
`
`vi
`
`
`
`EXHIBIT
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`DESCRIPTION
`
`Wolfgang U. Knauf, et al., “Bendamustine Compared
`with Chlorambucil in Previously Untreated Patients
`with Chronic Lymphocytic Leukaemia: Updated
`Results of a Randomized Phase III Trial,” 159 Brit. J.
`Hematology 67 (August 4, 2012)
`Norbert Niederle, et al., “Bendamustine Compared to
`Fludarabine as Second-Line Treatment in Chronic
`Lymphocytic Leukemia,” 92 Ann. Hematology 653
`(January 23, 2013)
`Teva Pharmaceutical Industries Limited, Form 20-F,
`2014
`Teva Pharmaceutical Industries Limited, Form 20-F,
`2011
`Cephalon, Inc., Form 10-K, 2010
`
`Cephalon, Inc., Form 10-K, 2009
`
`Cephalon, Inc., Form 10-K, 2008
`
`Alternate Copy of Birgit Maas et al., Stability of
`Bendamustine Hydrochloride in Infusions, 49
`PHARMAZIE 775 (1994) produced in Fresenius Kabi
`USA, LLC v. Cephalon, Inc., IPR2016-00111, Ex.
`1009 (PTAB Nov. 2, 2015)
`Alternate Copy of Birgit Maas et al., Stability of
`Bendamustine Hydrochloride in Infusions, 49
`PHARMAZIE 775 (1994) produced in, Agila
`Specialties Inc. v. Cephalon, Inc., IPR2015-00503, Ex.
`1010 (PTAB Dec. 24, 2014)
`
`Thissen Laboratories, Batch 02K27 Certificate of
`Analysis
`Thissen Laboratories, Batch 03C08 Certificate of
`Analysis
`Thissen Laboratories, Batch 03H08 Certificate of
`Analysis
`
`vii
`
`
`
`EXHIBIT
`
`DESCRIPTION
`
`2030
`
`2031
`
`Thissen Laboratories, Batch 03H07 Certificate of
`Analysis
`Cephalon, Inc.’s Preliminary Patent Owner Response
`Pursuant to 37 C.F.R. § 42.107, IPR2016-00026,
`Paper 12 (PTAB Jan. 20, 2016)
`
`viii
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`I.
`
`INTRODUCTION
`
`Patent Owner Cephalon Inc.’s (“Cephalon’s”) U.S. Patent No. 8,791,270 B2
`
`(“the ’270 Patent”) claims life-saving pharmaceutical compositions of
`
`bendamustine used to treat cancers such as indolent B-cell non-Hodgkin’s
`
`lymphoma (“NHL”) and chronic lymphocytic leukemia (“CLL”). (Ex. 2001, 1).
`
`The inventors named on the ’270 Patent discovered that although
`
`bendamustine had been sold for many years in Germany, the product suffered from
`
`high impurity levels — owing to the recognized degradation of bendamustine in
`
`water — which would have precluded FDA approval for sale in the United States.
`
`The inventors devised new methods of manufacturing a bendamustine product that
`
`increased its stability, reduced the degradants and allowed for FDA approval.
`
`As detailed below, the Petition is predicated entirely on prior art that was
`
`before the Examiner during prosecution and Petitioner fails to demonstrate a
`
`reasonable likelihood that it would prevail in invalidating any of the claims of the
`
`’270 patent. In Ground 1, Petitioner asserts that Claims 1-20 of the ’270 Patent are
`
`obvious in view of two prior art publications: B. Maas, et al., Stability of
`
`Bendamustine Hydrochloride in Infusions, Pharmazie 49 (1994), 775-77 (“Maas”)
`
`1
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`(Ex. 1004)1 and D. Teagarden, et al., Practical aspects of lyophilization using non-
`
`aqueous co-solvent systems, 15 Eur. J. Phar. Sci. 115 (2002) (“Teagarden”) (Ex.
`
`1005). Maas concerns the stability of Ribomustin, the bendamustine product
`
`manufactured in Germany. Teagarden discusses lyophilizing compounds that are
`
`unstable in water.
`
`Although Maas considered the degradation of bendamustine, as Petitioner
`
`concedes, Maas lacked the specific degradant data — such as the amount of the
`
`degradant denominated HP1 — that is key to the claims of the ’270 Patent.
`
`Petitioners propose two alternative approaches to remedy that critical shortcoming.
`
`Neither has merit.
`
`In Ground 1, Petitioner first argues that an ordinary artisan would have been
`
`able to calculate peak area and thus determine area percent bendamustine for HP1
`
`by calculating the area under a small peak in a chromatogram that appears in Maas:
`
`1 The title shown here is a translation. The article was published in German and is
`
`entitled Stabilität von Bendamustinhydrochlorid in Infusionslösungen.
`
`2
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`(Ex. 1004, 2 (emphasis added); see also Ex. 1017, ¶ 70). As shown above, though,
`
`the first peak in the Maas chromatogram, when enlarged for purposes of detailed
`
`analysis, is quite blurry. Petitioner uses this low-resolution image to produce a
`
`dozen different estimates of the HP1 found by Maas. The twelve estimates include
`
`six attempts to count the pixels under the peak, four attempts to use the integrator
`
`tool built into commercial software (USCAN-IT), and two attempts at importing
`
`the USCAN-IT data into Microsoft Excel to sum the total area across a peak. (Ex.
`
`1017, ¶¶ 63-68). It is telling that the estimates offered by the Petitioner differ
`
`significantly from one another and Petitioner’s declarant is silent as to the lack of
`
`consistency.
`
`3
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`In the alternative, Petitioner posits that the degradant data missing from
`
`Maas can be found in Table 13 of the ’270 Patent which data was supposedly
`
`inherent in the Ribomustin tested by Maas. But the data in Table 13 reflects the
`
`degradant content of lyophilized (freeze-dried) Ribomustin powder and does not
`
`reflect the degradant content of the reconstituted and admixed Ribomustin product
`
`that Maas tested. Moreover, the Ribomustin described in Table 13 and Maas’s
`
`Ribomustin were from different manufacturers. Hence, the data upon which
`
`Petitioners rely does not reflect degradant content that would need to be inherent
`
`— i.e., “necessarily present” — in the reconstituted bendamustine formulation
`
`discussed in Maas in order for Petitioner’s alternative argument to succeed. Again,
`
`it is noteworthy that the numbers arrived at by Petitioner via its alternative
`
`approaches are inconsistent.
`
`Petitioner postulates that in light of its conclusions (albeit inconsistent
`
`conclusions) as to the degradant content of the Ribomustin analyzed by Maas, the
`
`specific degradant limitations of the claims of the ’270 Patent would have been
`
`obvious in light of Maas in combination with Teagarden. Teagarden is a review
`
`article that points, inter alia, to an unpublished finding that lyophilization of a
`
`compound known as trecetilide fumarate from a solution containing water and
`
`tertiary butanol (“TBA”) reduced in solution degradation of the trecetilide
`4
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`fumarate by “a factor of approximately 4-5.” (Ex. 1005, 118). Petitioner argues
`
`that lyophilizing bendamustine from a water/TBA solution would likewise reduce
`
`degradation by “a factor of approximately 4-5.” However, Petitioner fails to
`
`support the far-fetched notion that a person of ordinary skill in the art would
`
`conclude that the use of TBA in a pre-lyophilization solution would have identical
`
`impacts on both trecetilide fumarate and bendamustine. The two compounds have
`
`vastly different structures and necessarily degrade through different chemical
`
`pathways to yield different degradants.
`
`In each of Grounds 2 and 3, Petitioner relies on Maas, Teagarden and a third
`
`reference. Yet, the additional cited art provides none of the information missing
`
`from the references cited in Ground 1. Consequently, Grounds 2 and 3 fail as well.
`
`In Ground 4, Petitioner asserts that “[t]he admitted prior art in the ’270
`
`Patent in combination with Teagarden render all limitations in claims 1-23
`
`obvious.” (Pet. 53). Petitioner contends that “Ribomustin and its associated
`
`description — including Table 13 — should be treated as ‘admitted prior art.’”
`
`(Pet. 55). Petitioner does not and cannot demonstrate, however, that the Patent
`
`Owner admitted in the ’270 Patent or during prosecution that the Ribomustin
`
`product sold outside of the United States was statutory prior art under 35 U.S.C.
`
`§§ 102, 103. The Ribomustin product itself is neither a patent nor a printed
`5
`
`
`
`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`publication upon which Congress authorized institution of inter partes review. 35
`
`U.S.C. § 311(b); see also 37 C.F.R. § 42.104(b)(4). Nor does Petitioner dispute
`
`that the experimental data reported in Table 13 was the work of the applicants for
`
`the ’270 Patent, who never said that the process for making Ribomustin in
`
`Germany (about which they learned pursuant to a license agreement) was public
`
`information that would have been known to persons of ordinary skill in the art.
`
`Even assuming that the data of Table 13 are independently available as
`
`admitted prior art, Petitioner relies, in Ground 4, on a subset of the arguments
`
`raised in its alternative to Ground 1 and thus Ground 4 fails for the same reasons.
`
`Accordingly, as provided in further detail below, Petitioner has not
`
`demonstrated a reasonable likelihood that it would prevail in invalidating any of
`
`the claims of the ’270 Patent and thus the Board should deny the Petition without
`
`institution.
`
`II.
`
`BACKGROUND
`
`A.
`
`The Inventors Identified a Problem Not Recognized in the Art
`
`Bendamustine was initially synthesized in 1963 in the East German
`
`Democratic Republic. (Ex. 1001, 2:1-2). Beginning in 1971, the drug was
`
`available in East Germany as Cytostasan®; it was later manufactured in re-unified
`
`Germany as Ribomustin®. (Id. at 2:2-5). Neither Cytostasan nor Ribomustin was
`
`6
`
`
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`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`ever approved by the U.S. Food and Drug Administration (“FDA”) and, before the
`
`invention of the ’270 Patent, bendamustine was unavailable to patients in the
`
`United States. (Ex. 2002, 1).
`
`Clinical studies performed both before and after the inventors’ 2005
`
`provisional patent application filing showed that the treatments for NHL and CLL
`
`then available, though they elicited some response, did not improve survival and
`
`presented a risk of serious side effects in an already compromised patient
`
`population. (Ex. 2003, 1750; Ex. 2004, 1160; Ex. 2005, 1506; Ex. 2006, 21-23;
`
`Ex. 2007, 167; Ex. 2008, 1469; Ex. 2009, 7090; Ex. 2010, 1004; Ex. 2011, 1262).
`
`Thus, there was a recognized need for an effective pharmaceutical treatment.
`
`Based on the information publicly available at the time, Ribomustin, as
`
`formulated, appeared to be a viable candidate for FDA approval. Although
`
`bendamustine was known to degrade in the presence of water, the published
`
`product information indicated that the lyophilized Ribomustin product could be
`
`reconstituted in water relatively quickly such that the product would not degrade to
`
`the point that it was unusable. (See Ex. 1007, 9 (reconstitution “usually takes 5 to
`
`10 minutes”)). Researchers concluded that reconstituted Ribomustin was suitable
`
`for infusion into patients. (See Ex. 1004, 6 (“Likewise for the recommended
`
`administration as a short infusion over 30 min, no stability problems are expected,
`7
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`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`since these bendamustine preparations have a stability of 9 h at room temperature.”
`
`(Emphasis added))).
`
`In 2003, Salmedix, Inc. (“Salmedix”), a small pharmaceutical company
`
`(later acquired by Patent Owner), evaluated Ribomustin for purposes of seeking
`
`FDA approval to sell it in the United States. (Ex. 1001, 5:39-59). Salmedix
`
`licensed confidential information from Fujisawa Deutschland regarding the process
`
`for manufacturing Ribomustin and visited the German manufacturing facilities.
`
`Salmedix determined that the FDA would not approve Ribomustin as then
`
`formulated and that “an alternative to the Ribomustine formulation of
`
`Bendamustine HCl” was needed. (Ex. 2012, 52).2 Salmedix was concerned that,
`
`by modern FDA standards, the degradant levels in Ribomustin were too high. (Ex.
`
`1001, 20:47-61). In addition, in practice, reconstituting the lyophilized drug took
`
`significantly longer (“may take 30-45 minutes”) than the publicly available product
`
`information indicated. (Id. at 33:20-24). The inventors realized that besides being
`
`burdensome for healthcare professionals tasked with reconstituting the Ribomustin
`
`for infusion, the unexpectedly slow reconstitution process increased the potential
`
`2 The ’270 patent and Salmedix also referred to Ribomustin as “Ribomustine.”
`
`8
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`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`for loss of potency and for degradant formation due to the hydrolysis of
`
`bendamustine in water. (Id. at 2:40-49).
`
`The inventors of the ’270 Patent thus identified “a need for lyophilized
`
`formulations of bendamustine that are easier to reconstitute and which have a
`
`better impurity profile than the current lyophilate (lyophilized powder)
`
`formulations of bendamustine.” (Id. at 2:50-53).
`
`B.
`
`The Inventions of the ’270 Patent
`
`Salmedix undertook an extensive research and development program aimed
`
`at creating a bendamustine formulation that would satisfy FDA standards. (Ex.
`
`2012, 52-72). In an effort to develop a formulation that was easier to reconstitute
`
`and had “a better impurity profile than Ribomustin” (Ex. 1001, 2:50-53), the
`
`inventors conducted a multi-faceted inquiry, balancing interrelated factors such as
`
`chemical reactivity, solubility, physical properties, and compatibility with various
`
`excipients. (Id. at 2:26-35:67). The inventors discovered that alcohols had a
`
`“unique” and “unexpected” effect on bendamustine stability and were “useful in
`
`manufacturing bendamustine with fewer impurities since an aqueous solution can
`
`be used while maintaining the stability of the bendamustine.” (Id. at 31:57-32:3).
`
`They found TBA “to be the best stabilizer of the six alcohols tested.” (Id. at 31:62-
`
`63, FIGS. 2-4). Ultimately, the inventors succeeded in achieving unexpectedly
`
`9
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`IPR2016-00098
`Patent Owner’s Preliminary Response
`
`improved bendamustine-containing pharmaceutical compositions with
`
`substantially lower degradant levels as compared to Ribomustin. (Id. at 20:43-
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`25:34; FIGS. 2-4).
`
`C.
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`FDA Approval and Market Response
`
`In 2007, the FDA granted “priority review” status to Cephalon’s New Drug
`
`Application for Treanda® for injection, a lyophilized bendamustine product which
`
`embodies the claimed inventions of the ’270 Patent, meaning that the drug would
`
`potentially provide significant improvements in the safety or effectiveness of the
`
`treatment of serious conditions when compared to standard applications. (Ex.
`
`2002, 1). The FDA approved Treanda for injection in 2008. (Ex. 2013, 1; Ex.
`
`2014, 1).
`
`Researchers hailed Cephalon’s invention as a significant advance over prior
`
`chemotherapy drugs and Treanda for injection quickly became a commercial
`
`success. (Ex. 2015, 106; Ex. 2016, 4473; Ex. 2017, 4378; Ex. 2018, 67; Ex. 2019,
`
`653). Since launch in 2008, Treanda for injection has generated over $3 billion in
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`sales in the United States. (Ex. 2020, 61; Ex. 2021, 64; Ex. 2022, 47; Ex. 2023,
`
`62; Ex. 2024, 65).3
`
`D.
`
`The ANDA Filing by Petitioner’s Contractual Partner
`
`Petitioner is a contractual partner with Hetero Labs, Ltd. and Hetero USA,
`
`Inc., which are seeking FDA approval to sell a generic version of Treanda for
`
`injection in the United States, using the same pharmaceutical formulation with the
`
`same specific degradant profiles claimed in the ’270 Patent, prior to the expiration
`
`of the patents covering Treanda. (Ex. 1002, ¶¶ 35-38).
`
`III. PETITIONER’S PROPOSED CLAIM CONSTRUCTIONS AND
`DEFINITION OF AN ORDINARY ARTISAN
`Even accepting, arguendo, Petitioner’s proposed claim constructions and
`
`definition of a person of ordinary skill in the art, the Board should conclude that
`
`Petitioner has failed to establish a reasonable likelihood that it would prevail in
`
`showing the unpatentability of Claims 1-23 of the ’270 Patent if a review were
`
`instituted. Nonetheless, Patent Owner shows below (Section IV.B.1) that
`
`Petitioner’s proposed construction of “pharmaceutical composition that has been
`
`3 Patent Owner reserves the right to address secondary indicia of non-obviousness
`
`in detail in the event the Board decides to institute.
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`reconstituted,” as recited in Claims 1-6 and 9-13, conflicts with how the term
`
`“reconstituted” is used throughout the specification of the ’270 Patent.
`
`It is worth noting that, in some respects, Petitioner’s proposed claim
`
`constructions are different from the claim constructions proposed by Petitioners
`
`Agila Specialties Inc. and Mylan Laboratories Limited in IPR2016-00026, which
`
`also pertains to the ’270 Patent. Agila Specialties Inc. v. Cephalon, Inc., IPR2016-
`
`00026, Paper 3 at 11-12 (PTAB Oct. 9, 2014).
`
`Patent Owner reserves the right to address Petitioner’s other claim
`
`construction proposals and Petitioner’s definition of one of ordinary skill in the art
`
`in the event that the Board institutes an inter partes review.
`
`IV. THE PETITION FAILS TO MAKE THE SHOWING REQUIRED
`UNDER 35 U.S.C. § 314(a)
`
`Petitioner has failed to demonstrate a reasonable likelihood that it would
`
`prevail regarding even one of the claims of the ’270 Patent.
`
`A.
`
`Ground 1: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-20 Are Obvious
`over Maas and Teagarden.
`
`Petitioner asserts in Ground 1 that Claims 1-20 of the ’270 Patent are invalid
`
`as obvious in light of Maas together with Teagarden. The Examiner considered
`
`both Maas and Teagarden during prosecution. (Ex. 1003, 316, 319). As explained
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`below, Maas and Teagarden do not make obvious a Ribomustin formulation
`
`having the degradant profiles recited in the claims.
`
`1.
`
`Petitioner Fails to Establish That an Ordinary Artisan
`Would Have Targeted the Claimed Degradant Profiles with
`a Reasonable Likelihood of Success.
`
`The challenged claims of the ’270 patent recite specific limits for the
`
`amounts of one or more degradants of bendamustine that may be present in the
`
`claimed pharmaceutical compositions. Although Maas includes an HPLC
`
`chromatogram analyzing the German Ribomustin product, with peaks that the
`
`authors identify as bendamustine and presumably HP1, Petitioner concedes that
`
`“Maas does not provide peak area data for these peaks.” (Pet. 30). Nor does
`
`Teagarden provide information regarding the quantities of any of the degradants
`
`found in Ribomustin. In fact, Teagarden does not even mention Ribomustin or
`
`bendamustine.
`
`Nonetheless, Petitioner asserts that “one of skill in the art would have been
`
`motivated to improve the stability of Ribomustin” and would have had “a
`
`reasonable expectation that degradant levels reported in Maas could be reduced by
`
`applying the teachings of Teagarden.” (Pet. 25, 27). Petitioner attributes that
`
`supposed motivation to improve upon Ribomustin to the fact that, according to
`
`Petitioner, the “Maas chromatogram reflects significant degradation ‘immediately
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`after dilution.’” (Id. at 26). Petitioner also states that “the instability issues
`
`reported in Maas would constrain the flexibility for manufacturing operations and
`
`the use of bendamustine solutions in clinical practice.” (Id.) However, Petitioner
`
`does not find support in any passage in Maas for this statement. Maas never
`
`suggests that bendamustine degradants were present at levels that warranted
`
`concern.
`
`Although Petitioner’s declarant, Dr. Bernard Olsen, refers to the “instability
`
`of bendamustine in aqueous solutions described by Maas” (Ex. 1017, ¶ 50), he
`
`ignores entirely Maas’s conclusion that bendamustine’s instability in water was not
`
`a problem that needed solving. (Ex. 1004, 6 (“for the recommended administration
`
`as a short infusion over 30 min, no stability problems are expected” (emphasis
`
`added)). According to Maas, Ribomustin’s “stability times ensure unproblematic
`
`storage and application in clinical practice.” (Id. at 4).
`
`The concerns about bendamustine instability conjured by Petitioner contrast
`
`starkly with the rosy depiction of Ribomustin that appears elsewhere in the
`
`Petition. Indeed, Petitioner states that “Maas teaches that Ribomustin is ‘an
`
`effective chemotherapeutic drug in the treatment of malignant diseases,’ and the
`
`‘270 patent teaches that Ribomustin was administered to patients for years.” (Pet.
`
`46 (internal citation omitted); see also id. at 29 (“Ribomustin is suitable for
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`administration to humans, and was, in fact, administered to humans over a long
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`period of time.”)).
`
`Petitioner further suggests that an ordinary artisan would have been
`
`motivated to reduce the degradants in Maas “to comply with FDA guidelines
`
`concerning impurities.” (Pet. 26). Yet, Petitioner fails to relate the FDA guidelines
`
`to Maas’s findings or to the degradant limits recited in the claims of the ’270
`
`Patent. Nor does Petitioner show that at the time of the invention a person of
`
`ordinary skill in the art would have been aware of the degradant profile of
`
`Ribomustin and in a position to determine whether improvement was needed.
`
`Even accepting, arguendo, Petitioner’s conclusory assertion that a person of
`
`ordinary skill in the art would have been motivated to reduce the degradant levels
`
`in Ribomustin, Petitioner does not demonstrate that the person of ordinary skill
`
`would have had reason to target the specific degradant limits claimed in the ’270
`
`Patent and a reasonable expectation of satisfying them. (See, e.g., Pet. 5
`
`(“lowering impurities”); id. at 26 (“to improve Maas”); id. (“lower the
`
`degradants”); id. (“further refinement to the stability profile”); id. (“improve the
`
`stability”); id. at 27 (“degradant levels reported in Maas could be reduced”)
`
`(emphasis added in all)). Petitioner’s declarants never state that an ordinary artisan
`
`would have targeted the claimed degradant profiles. (See, e.g., Ex. 1013, ¶ 38
`15
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`(“lowering degradant levels”); id., ¶ 40 (“lowering degradant levels”); id., ¶ 45
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`(“reducing these degradants”); id., ¶ 47 (“reduce the degradants”); id., ¶ 52
`
`(“reducing bendamustine hydrochloride degradant levels”); Ex. 1017, ¶ 51
`
`(“further improve this stability”); id., ¶ 52 (“improve these stability issues”); id.,
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`¶ 53 (“lower degradant levels”) (emphasis added in all)).
`
`The same sort of hindsight argument advanced here by Petitioner was
`
`rejected in IPR2015-00503, where the Board declined to institute review of Claims
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`2, 3, 5, 6, 8 and 9 of related U.S. Patent No. 8,436,190 (“’190 Patent”).4 Even
`
`though the Board made a preliminary finding there (on a less extensive factual
`
`record than is presented here) that an ordinary artisan would have been motivated
`
`to improve the stability of Ribomustin, the petitioners in that proceeding failed to
`
`demonstrate that an ordinary artisan would have targeted the specific properties of
`
`the compositions of Claims 2 and 3 of the ’190 Patent. As the Board stated in
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`instituting a review of the ’190 Patent as to certain claims but not
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