Paper No. ____
`Filed: October 9, 2015
`
`
`Filed on behalf of: Agila Specialties Inc. and Mylan Laboratories Limited
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Nicole W. Stafford
`WILSON SONSINI GOODRICH & ROSATI
`701 Fifth Avenue
`Suite 5100
`Seattle, WA 98104-7036
`Tel.: 206-883-2542
`Fax: 206-883-2699
`Email: sparmelee@wsgr.com
`Email: mrosato@wsgr.com
`Email: nstafford@wsgr.com
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`AGILA SPECIALTIES INC. and MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`v.
`
`CEPHALON, INC.,
`Patent Owner.
`
`_____________________________
`
`IPR2016-00026
`Patent No. 8,791,270
`_____________________________
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,791,270
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION .............................................................................................. 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Brief Overview of the ’270 Patent....................................................... 1
`
`Brief Overview of the Prosecution History ......................................... 3
`
`Brief Overview of the Scope and Content of the Prior Art .................. 5
`
`Brief Overview of the Level of Skill in the Art ................................... 7
`
`II.
`
`GROUNDS FOR STANDING ............................................................................... 8
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ............................................ 9
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED .............................................................................................. 11
`
`V.
`
`STATEMENT OF NON-REDUNDANCY ............................................................. 12
`
`VI. CLAIM CONSTRUCTION ................................................................................ 13
`
`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO JANUARY 14, 2005 .......... 16
`
`VIII. OVERVIEW OF DIFFERENCES BETWEEN THE ASSERTED PRIOR ART AND
`THE CLAIMS ................................................................................................. 20
`
`IX. DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................... 22
`
`A.
`
`[Ground 1] Claims 1, 2, 7-10, 13-16, 19, and 20 are Anticipated
`Under 35 U.S.C. § 102(b) By Maas .................................................. 22
`
`i.
`
`ii.
`
`Claim 1 ................................................................................... 23
`
`Claim 2 ................................................................................... 25
`
`iii. Claims 7 and 8 ........................................................................ 26
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`iv.
`
`v.
`
`Claims 9, 14, and 15 ............................................................... 27
`
`Claims 10 and 16 .................................................................... 27
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`-i-
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`

`
`
`Claims 13 and 19 .................................................................... 28
`
`vi.
`
`vii. Claim 20 ................................................................................. 29
`
`B.
`
`[Ground 2] Claims 1-20 are Obvious Under 35 U.S.C. § 103
`Over Maas and Teagarden ................................................................ 33
`
`i.
`
`ii.
`
`Claim 1 ................................................................................... 34
`
`Claim 2 ................................................................................... 37
`
`iii. Claims 3, 4, 5, and 6 ............................................................... 38
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`iv.
`
`v.
`
`vi.
`
`Claims 7 and 8 ........................................................................ 40
`
`Claims 9, 14, and 15 ............................................................... 41
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`Claims 10, 11, 12, 16, 17, and 18 ............................................ 42
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`vii. Claims 13 and 19 .................................................................... 43
`
`viii. Claim 20 ................................................................................. 45
`
`C.
`
`D.
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`[Ground 3] Claims 13 and 19 are Obvious Under 35 U.S.C.
`§ 103 Over Maas, Teagarden, and Gust ............................................ 52
`
`[Ground 4] Claims 20-23 are Obvious Under 35 U.S.C. § 103
`Over Maas, Teagarden, and the Rote Liste 2003 ............................... 55
`
`X.
`
`CONCLUSION ............................................................................................... 58
`
`XI. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ...................... 59
`
`XII. APPENDIX – LIST OF EXHIBITS...................................................................... 60
`
`
`
`
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`-ii-
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`

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`
`
`I.
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Agila Specialties Inc. and
`
`Mylan Laboratories Limited, (collectively referred to herein as “Petitioner”)
`
`request review of United States Patent No. 8,791,270 to Brittain et al. (hereinafter
`
`“the ’270 patent,” Ex. 1001) that issued on July 29, 2014, and is currently assigned
`
`to Cephalon, Inc. (“Patent Owner”). This Petition demonstrates there is a
`
`reasonable likelihood that claims 1-23 of the ’270 patent are unpatentable based on
`
`a preponderance of the evidence for failing to distinguish over prior art. Thus,
`
`claims 1-23 of the ’270 patent should be found unpatentable by the Patent Trial
`
`and Appeal Board and canceled.
`
`A. Brief Overview of the ’270 Patent
`
`The ’270 patent is entitled “Bendamustine Pharmaceutical Compositions.”
`
`The ’270 patent, with an earliest claimed priority date of January 14, 2005, is
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`directed to pharmaceutical compositions of the drug bendamustine hydrochloride
`
`containing specified amounts of degradants, and methods of treatment using said
`
`pharmaceutical compositions. Claims 1, 3-6, 10-12, and 16-18 recite compositions
`
`containing specified amounts of HP1 (monohydroxy bendamustine). Ex. 1001, col.
`
`36, ll. 2-18, 22-38, 51-62, col. 37, ll. 19-28. Claims 7 and 8 recite compositions
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`containing specified amounts of bendamustine hydrochloride degradants. Id. at col.
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`36, ll. 39-46. Claims 13 and 19 recite compositions containing specified amounts
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`of bendamustine ethyl ester. Id. at col. 36, l. 63-col. 37, l. 13, col. 38, ll. 1-17.
`
`Claims 1 and 9 specify that the composition “has been reconstituted from a
`
`1
`
`

`
`
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`lyophilized preparation.” Id. at col. 36, ll. 2-18, 47-49. Claims 2 and 10-13 further
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`recite that the composition contains specified amounts “at time zero after
`
`reconstitution.” Id. at col. 36, ll. 19-21, 51-67, col. 37, ll. 1-13. Claims 14 and 15
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`recite that the pharmaceutical composition is a lyophilized composition. Id. at col.
`
`37, ll. 14-18. Claim 20 recites a method of treating cancer, comprising
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`administering the pharmaceutical composition of bendamustine hydrochloride
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`recited in claim 7 to a patient. Id. at col. 38, ll. 18-20. Claims 21-23 depend from
`
`claim 20 and recite specific types of cancer. Id. at col. 38, ll. 21-28.
`
`The Background of the Invention of the ʼ270 patent explains that
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`bendamustine is a nitrogen mustard compound. Ex. 1001, col. 1, ll. 51-55. It was
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`initially synthesized in 1963 in East Germany and marketed from 1971 to 1992 as
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`a treatment for chronic lymphocytic leukemia and other cancers under the trade
`
`name Cytostasan®. Id. at col. 2, ll. 1-8; see also, Ex. 1002, ¶¶ 23-24. After 1992, it
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`was marketed in unified Germany under the trade name Ribomustin®. Ex. 1001,
`
`col. 2, ll. 4-5; see also, Ex. 1002, ¶¶ 23-24. Ribomustin® was a lyophilized
`
`(freeze-dried) composition of bendamustine hydrochloride and mannitol. Ex. 1001,
`
`col. 2, ll. 12-15.
`
`Tertiary butanol is also known as tertiary-butyl alcohol, tert-butyl alcohol, t-
`
`butyl alcohol, tert-butanol, and t-butanol; these interchangeable names are
`
`collectively referred to in the ʼ270 patent and here as “TBA.” Ex. 1001, col. 5, ll.
`
`36-38. During cycles of freeze-drying, which are known as the process of
`
`lyophilization, co-solvents, such as TBA, are substantially removed by
`
`-2-
`
`

`
`
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`sublimation, yielding a dry powder of bendamustine hydrochloride and mannitol.
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`Id. at col. 16, ll. 54-56.
`
`B.
`
`Brief Overview of the Prosecution History
`
`Application No. 13/969,724 (the ʼ724 application) was filed on August 19,
`
`2013 (Ex. 1004 at 0253), and issued on July 29, 2014, as the ʼ270 patent (id. at
`
`0010). The ʼ724 application was granted fast track status on September 24, 2013.
`
`Id. at 0248. The ʼ724 application was filed as a continuation of U.S. Patent No.
`
`8,436,190 (hereinafter “the ʼ190 patent,” subject to IPR proceeding IPR2015-
`
`00503, instituted July 20, 2015).
`
`Other applications filed as continuations of the ʼ190 patent include
`
`application 13/719,409 (now U.S. Patent No. 8,895,756) and 13/719,379 (now U.S.
`
`Patent No. 8,609,863, hereinafter “the ’863 patent”). During prosecution of the
`
`’863 patent, the applicant filed a Declaration via 37 C.F.R. § 1.131. Ex. 1019 at
`
`0048-50. Filed with the Rule 131 Declaration was an internal company document,
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`titled “Formulation Development Report for SDX-105 (Bendamustine HCl) for
`
`Injection.” Id. at 0052-72. The company document, though heavily redacted,
`
`acknowledged that “TBA is a commonly used co-solvent for lyophilization.” Id. at
`
`0061 (citing to Dirk L. Teagarden & David S. Baker, Practical aspects of
`
`lyophilization using non-aqueous co-solvent systems, 15 EUR. J. PHARM. SCI. 115
`
`(2002) (hereinafter “Teagarden,” Ex. 1008)). Teagarden is relied on in Grounds 2-
`
`4 of this petition.
`
`Although there is no record in the prosecution history of the applicant
`
`arguing unexpected or surprising results relating to the claimed subject matter, the
`
`-3-
`
`

`
`
`
`examiner’s Reasons For Allowance stated:
`
`[T]he prior art teaches a formulation of bendamustine and mannitol to
`be lyophilized. The prior art also teach a combination of mannitol,
`tertiary-butyl alcohol, water, and an anti-neoplastic agent can be
`lyophilized. The prior art suggests using a combination of mannitol
`and tertiary-butyl alcohol with bendamustine to produce a formulation
`to be lyophilized. However, Applicant has unexpectedly found that
`the addition of a solvent stabilizes the formulation such that
`bendamustine degradation is negligible (no more than 0.5% formation
`of bendamustine ethyl ester).
`
`Ex. 1004 at 0024.
`
`The reasons for allowance provided by the examiner are only directly
`
`applicable to claims 13 and 19 of the ’270 patent, as only these claims recite
`
`limitations to the amount of bendamustine ethyl ester in a composition. As
`
`discussed below, however, applicant’s own test data presented in the ʼ270 patent
`
`for Ribomustin® showed that bendamustine ethyl ester was already present at
`
`levels of not more than about 0.5% (area percent of bendamustine). Ex. 1001, col.
`
`30, ll. 35-45; see also, Ex. 1002 ¶¶ 28-31. Moreover, as discussed below, the use
`
`of the tert-butyl alcohol (TBA) as a solvent to stabilize drug formulations and
`
`prevent degradation prior to lyophilization was well known in the art, and, thus its
`
`effects on minimizing bendamustine hydrochloride degradation, particularly to the
`
`ethyl ester form, would have been entirely expected. See, Ex. 1002, ¶¶ 26-27.
`
`-4-
`
`

`
`
`
`C. Brief Overview of the Scope and Content of the Prior Art
`
`Birgit Maas et al., Stability of Bendamustine Hydrochloride in Infusions, 49
`
`PHARMAZIE 775 (1994) (hereinafter “Maas,” Ex. 1007), discussed below, describes
`
`Ribomustin® as a lyophilized substance. Ex. 1007 at 0004; see also, Ex. 1002, ¶
`
`72. Maas is prior art to the claims of the ʼ270 patent under 35 U.S.C. § 102(b). Ex.
`
`1002, ¶ 70. Maas describes degradation products in reconstituted aqueous
`
`solutions of bendamustine hydrochloride prepared from vials of lyophilized
`
`Ribomustin®. Maas discloses, “[b]endamustine is very unstable in an aqueous
`
`solution.” Ex. 1007 at 0004. Maas identified degradation products, including
`
`monohydroxy bendamustine and dihydroxy bendamustine. Ex.1007 at 0004; see
`
`also, Ex. 1002, ¶¶ 72-75. Monohydroxy bendamustine is identified as the
`
`degradant “HP1” in the ʼ270 patent. Ex. 1001, col. 21, ll. 3-19.
`
`The instability of injectable drugs in water necessitates preparation of a
`
`freeze-dried pharmaceutical product to remove water and inhibit degradation.
`
`Teagarden teaches “[m]ost freeze-dried products are developed as this dosage form
`
`in order to circumvent poor stability.” Ex. 1006 at 117; see also, Ex. 1002, ¶ 78.
`
`Teagarden describes the use of organic/water co-solvent systems, including
`
`TBA/water, for preparing pre-lyophilization drug solutions, particularly for water-
`
`unstable drugs. Ex. 1006 at 115; see also, Ex. 1002, ¶¶ 77, 79. Teagarden is prior
`
`art to the claims of the ʼ270 patent under 35 U.S.C. § 102(b). Id. at ¶ 76.
`
`Teagarden teaches substantial improvements in drug stability obtained by
`
`using TBA/water solutions to formulate water-unstable drugs, and states that this
`
`improved stability would be expected to be observed for many different drug
`
`-5-
`
`

`
`
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`products. Ex. 1006 at 117-18; see also, Ex. 1002, ¶¶ 80-82. As noted above,
`
`bendamustine was known to be highly unstable in water. See, e.g., Ex. 1007 at
`
`0004; Ex. 1013 at 489. Teagarden expressly teaches that TBA/water is more
`
`extensively evaluated than other co-solvent solutions, is easier to use, and yields
`
`better lyophilized cakes. Ex. 1006 at 131; see also, Ex. 1002, ¶ 79.
`
`R. Gust et al., Investigations on the Stability of Bendamustin, a Cytostatic
`
`Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization
`
`of Reference Substances, 128 Monatsheft für Chemie 291 (1997) (hereinafter
`
`“Gust,” Ex. 1008) describes characterizing bendamustine derivatives, including
`
`bendamustine degradants that were known to be present in compositions of
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`bendamustine. Ex. 1008 at 292; see also, Ex. 1002, ¶¶ 86, 88-90. In particular,
`
`Gust teaches that bendamustine ethyl ester, referred to by Gust as the
`
`“dichloroester” form, is a precursor in the synthesis of bendamustine that is present
`
`in samples of crude bendamustine. Ex. 1008 at 292-93, 298; see also, Ex. 1002, ¶¶
`
`87-88, 90. Gust also teaches that bendamustine ethyl ester is synthesized from
`
`bendamustine “by esterification in ethanolic HCl.” Ex. 1008 at 293, 299; see also,
`
`Ex. 1002 ¶ 89. Gust is prior art to the claims of the ʼ270 patent under 35 U.S.C. §
`
`102(b). Ex. 1002 ¶ 85.
`
`The Rote Liste 2003 (Ex. 1005), a German equivalent to the Physicians’
`
`Desk Reference, describes the Ribomustin® pharmaceutical product as an injection
`
`vial containing bendamustine hydrochloride, and provides treatment indications for
`
`the drug, including indications for treating various specific cancers. Ex. 1005 at
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`-6-
`
`

`
`
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`0003; see also, Ex. 1002, ¶¶ 24, 84. The Rote Liste 2003 is prior art to the claims
`
`of the ʼ270 patent under 35 U.S.C. § 102(b). Ex. 1002, ¶ 83.
`
`D. Brief Overview of the Level of Skill in the Art
`
`A person of ordinary skill in the art in the relevant field as of January 14,
`
`2005, would likely have some combination of the following skills and experience:
`
`(a) experience with drug lyophilization; (b) experience designing and preparing
`
`liquid drug formulations; (c) experience designing and preparing formulations of
`
`drugs that are unstable in water; and (d) the ability to understand work presented or
`
`published by others in the field. Ex. 1002, ¶ 47. Typically this person would have
`
`an advanced degree (e.g., a Ph.D.) in pharmaceutics, pharmaceutical chemistry,
`
`medicinal chemistry, or a related field, or would have less education but
`
`considerable professional experience in one or more of these fields. Id. at ¶ 46.
`
`Petitionerʼs expert, Dr. Samuel Yalkowsky, is a tenured Professor of
`
`Pharmaceutical Sciences at The University of Arizona, Tucson, Arizona, where
`
`he has been a member of the faculty since 1982. Ex. 1002, ¶ 1; see also, Ex.
`
`1003. Dr. Yalkowsky received his Ph.D. in Pharmaceutical Chemistry in 1969
`
`from the University of Michigan, after which he became a research scientist at the
`
`Upjohn Company in their Pharmaceutical Research Unit. Ex. 1002, ¶¶ 1-2; see
`
`also, Ex. 1003. While at Upjohn he developed the marketed formulations of
`
`Xanax® and Halcion® tablets, and worked on a Xanax® injectable formulation.
`
`Ex. 1002, ¶ 3; see also, Ex. 1003. His research interests lie in the relationship
`
`between chemical structure and physiochemical properties, especially the
`
`solubility of organic compounds, and solubilization in aqueous media. Ex. 1002,
`
`-7-
`13-
`
`

`
`
`
`¶ 4. He also has experience with pharmaceutical formulations, including the use
`
`of organic co-solvents in drug formulations and optimization of formulations for
`
`freeze-drying (lyophilization) of pharmaceuticals. Id. Using this expertise Dr.
`
`Yalkowsky has developed novel dosage forms of highly water-insoluble drugs.
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`Id. at ¶ 5.
`
`Dr. Yalkowsky has authored or co-authored over two-hundred and sixty
`
`peer-reviewed scientific articles, and two of his publications have been awarded
`
`the Ebert Prize for best scientific paper in the Journal of Pharmaceutical Sciences.
`
`Ex. 1002, ¶ 7; see also, Ex. 1003. He has authored, co-authored, or edited eight
`
`books dealing with solubility and solubilization of drugs, and contributed to more
`
`than 40 symposia, conferences, and short courses. Ex. 1002, ¶¶ 7-8; see also, Ex.
`
`1003. His work has led to numerous awards, honors, and research grants. Ex.
`
`1002, ¶¶ 6, 9; see also, Ex. 1003. Dr. Yalkowsky is well qualified as an expert,
`
`possessing the necessary scientific, technical, and other specialized knowledge as
`
`of January 2005 in order to assist in an understanding of the evidence presented
`
`herein, as well as possessing the ability to address pertinent background art and
`
`common knowledge in the art at the relevant time. See Ex. 1003.
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’270 patent is
`
`available for Inter Partes Review, and Petitioner is not barred or estopped from
`
`requesting Inter Partes Review of the ’270 patent on the grounds identified.
`
`
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`-8-
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`

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`
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`Agila Specialties Inc. f/k/a Strides Inc. and Mylan Laboratories Limited are
`
`the Petitioner in this matter. Mylan Laboratories Limited is a manufacturing
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`subsidiary of Mylan Inc., and Mylan Inc. is a wholly owned subsidiary of Mylan
`
`N.V. Petitioner identifies Mylan N.V. as a real party-in-interest out of an
`
`abundance of caution, due to a pending issue in IPR2015-01069 (an unrelated
`
`proceeding), wherein the petitioner in that proceeding has opposed an allegation
`
`that Mylan N.V. should have been identified as a real party-in-interest. (Paper 12).
`
`Petitioner’s identification of Mylan N.V. as a real party-in-interest in the instant
`
`proceeding in no way constitutes an admission that Mylan N.V. is or was a real
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`party-in-interest in any other IPR proceeding.
`
`Related Matters (37 C.F.R. § 42.8(b)(2))
`
`Petitioner filed a Petition for Inter Partes Review in IPR2015-00503 of the
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`ʼ190 patent, from which the ʼ270 patent claims priority. Trial was instituted by the
`
`Board in IPR2015-00503 on July 20, 2015. The ʼ270 patent also claims priority
`
`from U.S. Patent No. 8,461,350 and from U.S. Provisional Patent Application No.
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`60/644,354, filed January 14, 2005. Ex. 1001, col. 1, ll. 8-15. Other patents in this
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`family of which Petitioner is aware and which claim priority from U.S. Provisional
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`Patent Application No. 60/644,354 and the ʼ190 patent are U.S. Patent No.
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`8,895,756 and U.S. Patent No. 8,609,863.
`
`
`
`Petitioner and a number of other entities are involved in litigation over the
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`’270 patent and related patents in the action styled In Re: Bendamustine
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`-9-
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`

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`
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`Consolidated Cases, No. No. 1:13-cv-02046 (GMS), filed by Cephalon, Inc. in the
`
`District of Delaware. A complaint asserting the ’270 patent against Petitioner was
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`served no earlier than October 9, 2014 in the action styled Cephalon, Inc. v. Agila
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`Specialties Inc., et al., No. 1:14-cv-01237 (GMS) filed by Cephalon, Inc. in the
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`District of Delaware. Ex. 1020. On November 24, 2014, several Delaware matters
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`were consolidated into the single case styled In Re: Bendamustine Cases, Civil
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`Action No. 13-cv-2046 (GMS), including the action styled Cephalon, Inc. v. Agila
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`Specialties Inc., et al., No. 1:14-cv-01237 (GMS). Additional cases were
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`consolidated into In Re: Bendamustine Consolidated Cases on April 8, 2015.
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`
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`To Petitioner’s knowledge, the ’270 patent is also at issue in Cephalon, Inc.
`
`v. Apotex, Inc., Civil Action No. 15-cv-00404 (D. Del. May 19, 2015); Cephalon
`
`Inc. v. Panacea Biotec, Ltd., Civil Action No. 15-cv-00735 (D. Del. Aug. 25,
`
`2015); and Cephalon, Inc. v. Nang Kuang Pharmaceutical Co., Ltd., Civil Action
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`No. 14-cv-05180 (E.D.N.Y. Sept. 3, 2014).
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
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`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
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`Back-up Counsel: Michael T. Rosato (Reg. No. 52,182); Nicole Stafford
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`(Reg. No. 43,929)
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`Service Information – 37 C.F.R. § 42.8(b)(4)
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`Petitioner hereby consents to electronic service.
`Lead Counsel
`Back-up Counsel
`
`Steven W. Parmelee
`
`sparmelee@wsgr.com
`
`Michael T. Rosato
`
`mrosato@wsgr.com
`
`-10-
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`

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`
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`WILSON SONSINI GOODRICH & ROSATI,
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`WILSON SONSINI GOODRICH & ROSATI,
`
`701 Fifth Avenue, Suite 5100
`
`701 Fifth Avenue, Suite 5100
`
`Seattle, WA 98104-7036
`
`Seattle, WA 98104-7036
`
`Tel.: 206-883-2542
`
`
`
`
`
`Tel.: 206-883-2529
`
`
`
`
`
`Fax: 206-883-2699
`
`Fax: 206-883-2699
`
`
`
`Nicole W. Stafford
`
`nstafford@wsgr.com
`
`WILSON SONSINI GOODRICH & ROSATI,
`
`900 South Capital of Texas Highway,
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`Las Cimas IV, 5th Floor
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`Austin, TX 78746-5546
`
`Tel.: 512-338-5400
`
`
`
`
`
`Fax: 512-338-5499
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED
`
`Petitioner requests review of claims 1-23 of the ’270 patent under 35 U.S.C.
`
`§ 311 and AIA § 6. Petitioner challenges claims 1-23 of the ʼ270 patent on the
`
`grounds that each of the claims should be canceled as unpatentable as follows:
`
`Ground
`
`Claims
`
`Description
`
`1
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`1, 2, 7-10,
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`13-16, 19-20
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`Anticipated under §102(b) by Maas
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`-11-
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`

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`
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`2
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`3
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`4
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`1-20
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`13, 19
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`20-23
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`Obvious under §103 over Maas and Teagarden
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`Obvious under §103 over Maas, Teagarden, and Gust
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`Obvious under §103 over Maas, Teagarden, and the
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`Rote Liste 2003
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`V.
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`STATEMENT OF NON-REDUNDANCY
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`Each of the four Grounds raised in this Petition is meaningfully distinct:
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`1.
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`Ground 1 presents anticipation of claims 1, 2, 7-10, 13-16, 19, and 20
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`based on the description by Maas in 1994 of Ribomustin®, a pharmaceutical
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`composition comprising bendamustine hydrochloride. The claims anticipated by
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`Maas are drawn to pharmaceutical compositions and methods of treatment that fail
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`to distinguish over the disclosure by Maas of Ribomustin® and its stated use in
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`methods of cancer treatment.
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`2.
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`Ground 2 differs from Ground 1 in asserting obviousness of claims 1-
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`20 based on the combination of Maas and Teagarden. Maas teaches that
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`bendamustine hydrochloride is very unstable in water, describes reconstituting the
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`lyophilized Ribomustin® preparation, and identifies bendamustine hydrochloride
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`degradants present in the reconstituted pharmaceutical composition, which is
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`intended for use in a method of treating cancer. Teagarden teaches the use of a
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`TBA/water solution to reduce degradation of water unstable drugs prior to
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`lyophilization, and expressly states that the stabilizing effect of TBA/water would
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`be expected for other water-unstable drugs.
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`3.
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`Ground 3 presents obviousness of claims 13 and 19, based on a
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`combination of Maas, Teagarden, and Gust. Gust adds to the combination
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`presented in Ground 2 by explicitly teaching that bendamustine ethyl ester
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`(referred to in Gust as “dichloroester”) is an impurity that is present in samples of
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`crude bendamustine and is formed by esterification of bendamustine in the
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`presence of ethanol.
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`4.
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`Ground 4 presents obviousness of method of treatment claims 20-23,
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`based on a combination of Maas, Teagarden, and the Rote Liste 2003. The Rote
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`Liste 2003 adds to the combination presented in Ground 2 by explicitly teaching
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`that Ribomustin® is intended for injection as a treatment for Non-Hodgkin’s
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`lymphoma, chronic lymphocytic leukemia and other malignancies, as recited in
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`these dependent claims 20-23.
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`VI. CLAIM CONSTRUCTION
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`A claim subject to Inter Partes Review receives the broadest reasonable
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`construction or interpretation in light of the specification of the patent in which it
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`appears because, among other reasons, the patent owner has an opportunity to
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`amend the claims. 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 778
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`F.3d 1271, 1279-82 (Fed. Cir. 2015). A few terms that warrant discussion are
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`identified and discussed below.
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`1. “lyophilized preparation” and “lyophilized composition”
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`The term “lyophilized preparation” appears in claims 1, 2, and 9 of the ’270
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`patent. The term “lyophilized composition” appears in claims 14 and 15 of the
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`’270 patent. The specification of the ’270 patent defines “lyophilized powder” or
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`“lyophilized preparation” as “solid material obtained by lyophilization, i.e., freeze-
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`drying of an aqueous solution.” Ex. 1001, col. 9, ll. 21-23. The terms “lyophilized
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`preparation” and “lyophilized composition” should be given the same meaning in
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`light of the specification: “any solid material obtained by lyophilization, i.e.,
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`freeze-drying of an aqueous solution.” Ex. 1002, ¶ 50.
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`2. “pharmaceutical composition”
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`The term “pharmaceutical composition” appears in claims 1-20 of the ’270
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`patent. The term “pharmaceutical composition” is not defined in the specification
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`of the ’270 patent, and should be given its plain and ordinary meaning of “a
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`composition intended for use as a pharmaceutical.” Ex. 1002, ¶ 50.
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`3. “area percent of bendamustine”
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`The term “area percent of bendamustine” appears in claims 1, 3-8, 10-13,
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`and 16-19 of the ’270 patent. According to the specification of the ’270 patent,
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`“area percent of bendamustine” means “the amount of a specified degradant, e.g.,
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`HP1, relative to the amount of bendamustine as determined, e.g., by HPLC.” Ex.
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`1001, col. 12, ll. 10-12. In light of the ’270 patent specification, the broadest
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`reasonable construction of “area percent of bendamustine” is “the amount of a
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`specified degradant relative to the amount of bendamustine expressed as a
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`percent.” Ex. 1002, ¶ 50.
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`4. “bendamustine degradants”
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`The term “bendamustine degradants” appears in claims 7 and 8 of the ’270
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`patent. Bendamustine degradants described in the specification of the ’270 patent
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`are: monohydroxy bendamustine (HP1), bendamustine dimer (BM1 Dimer),
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`bendamustine ethyl ester (BM1EE), and BM1DCE. Ex. 1001, col. 21, l. 3-col. 22,
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`l. 10, col. 30, ll. 35-45. Thus, in light of the specification, the term “bendamustine
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`degradants” means “monohydroxy bendamustine (HP1), bendamustine dimer
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`(BM1 Dimer), bendamustine ethyl ester (BM1EE), BM1DCE, or a combination
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`thereof.” Ex. 1002, ¶ 50.
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`5. “time zero after reconstitution”
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`The term “time zero after reconstitution” appears in claims 2 and 10-13 of
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`the ’270 patent. The term “time zero after reconstitution” is not defined in the
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`specification of the ’270 patent. The specification of the patent provides amounts
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`of degradants measured at a “Hold Time” of “0 hours,” “3 hours,” “6 hours,” or
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`“24 hours” in solution. See, e.g., Ex. 1001, col. 21, ll. 20-29. The ’270 patent
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`specification therefore provides time in units of hours. Thus, in light of the
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`specification, the term “time zero after reconstitution” should mean “30 minutes or
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`less after reconstitution.” Ex. 1002, ¶ 50.
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`6. “about”
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`The term “about” appears in claims 1, 8, 10-13, and 16-19 of the ’270
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`patent, in reference to amounts of bendamustine degradants, expressed as “area
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`percent of bendamustine” in a “pharmaceutical composition.” To determine the
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`range encompassed by the term “about,” one must consider the context of the term
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`as it is used in the claims and the specification. Ortho-McNeil Pharm., Inc. v.
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`Caraco Pharm. Labs., Ltd. at 476 F.3d 1321, 1326 (Fed. Cir. 2007). In view of the
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`’270 patent specification, the term “about” accommodates for variability typical to
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`the analytical methods employed. Ex. 1002, ¶ 49. The ’270 patent acknowledges
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`
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`“slight variability” between different HPLC methods (Ex. 1001, col. 25, ll. 32-34),
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`identifies variability in the amount of degradant observed across batches of a
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`composition (id. at col. 30, ll. 35-45), and shows variability of the baseline within
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`single HPLC runs (id. at fig. 6). Variability can be due to, e.g., sample preparation,
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`column temperature, flow rate, and integration protocols, as well as variability
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`between different HPLC methods (id. at col. 25, ll. 32-34), and across samples or
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`batches (id. at col. 30, ll. 35-45), sources that are well known to persons of
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`ordinary skill familiar with HPLC. Ex. 1002, ¶ 49. In the context of the ’270
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`patent, one of ordinary skill in the art would accommodate for each of these
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`sources of variability in determining the broadest reasonable interpretation of the
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`term “about.” Id. Thus, in the context of the claims and specification of the ’270
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`patent, one of ordinary skill in the art would construe the claim term “about 0.9%
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`(area percent of bendamustine)” to include “0.96% (area percent of
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`bendamustine),” an amount differing by only 0.06%. Id. This amount of
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`variability would reasonably be expected in HPLC analysis of pharmaceutical
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`compositions as described in the ’270 patent specification, and thus falls within the
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`scope of the term “about,” as recited in the ’270 patent claims. Id.
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`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO JANUARY 14, 2005
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`Bendamustine, a nitrogen mustard compound, was developed in East
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`Germany in 1963 (Ex. 1010 at 782), with clinical use beginning there in 1969 (Ex.
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`1011 at 639), and, later, in unified Germany. Ex. 1002, ¶ 52. It was available as a
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`dry, lyophilized pharmaceutical preparation in vials containing 25 mg
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`bendamustine, with mannitol as an excipient, and was marketed under the brand
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`
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`names Cytostasan® (Ex. 1010 at 782; see also, Ex. 1002, ¶ 52) and Ribomustin®.
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`At the time of a review article in 2001, bendamustine hydrochloride (Ribomustin®)
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`was approved for use in Germany for treatment of Hodgkin’s disease, Non-
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`Hodgkin’s lymphoma, multiple myeloma, chronic lymphocytic leukemia, and
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`breast cancer. Ex. 1012 at 637; see also, Ex. 1002, ¶ 53.
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`The specific formulation of Ribomustin® that was marketed in Germany is
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`described in the Ribomustin® Product Monograph. Ex. 1014 at 1; see also, Ex.
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`1002, ¶¶ 54-55. The Ribomustin® Product Monograph was disclosed by the
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`applicant during prosecution as having a publication date of January 2002. Ex.
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`1004 at 0041, 0233. The Ribomustin® Product Monograph is also cited in the
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`Background of the Invention of the ’270 patent. Ex. 1001, col. 2, l. 66-col. 3, l. 2.
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`The Ribomustin® Product Monograph describes Ribomustin® as a lyophilized
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`pharmaceutical composition of bendamustine hydrochloride intended for
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`reconstitution prior to injection (Ex. 1014 at 57, sec. 11), and further describes uses
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`of Ribomustin® and contraindications, dosages, and other product information. Ex.
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`1014 at 8-9, 57, sec. 11; see also, Ex. 1002, ¶¶ 54-55.
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`Bendamustine itself was long known to be water-soluble, yet unstable in
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`aqueous environments. Scasnar et al., Radiochemical Assay of Stability of C-
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`Cytostasan Solutions During Preparation and Storage, 121 J. RADIOANAL. NUCL.
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`CHEM. 489, 489 (1988) (hereinafter “Scasnar,” Ex. 1013), referring to a 1971
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`publication, notes that “the drug degrades spontaneously in water solutions
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`yielding two hydrolysis products, monohydroxy-cytostasan and
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`dihydroxycytostasan.” Ex. 1013 at 489; see also, Ex. 1002, ¶ 56. Cytostasan® was
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`-17-
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`the pharmaceutical trade name for bendamustine used in the former German
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`Democratic Republic, as acknowledged in the Backgro