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`IPR2016-00111
`Petition for Inter Partes Review
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
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`FRESENIUS KABI USA, LLC,
`Petitioner
`
`v.
`
`CEPHALON, INC.,
`Patent Owner
`
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`
`
`
`
`
`Case IPR2016-00111
`Patent No. 8,895,756
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`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,895,756
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.
`
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`IPR2016-00111
`Petition for Inter Partes Review
`
`
`TABLE OF CONTENTS
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`
`
`I. 
`
`II. 
`
`III. 
`
`INTRODUCTION AND BACKGROUND .................................................... 1 
`
`NOTICES, STATEMENTS AND PAYMENT OF FEES .............................. 4 
`
`A.  Real Party In Interest Under 37 C.F.R. § 42.8(b)(1) ............................... 4 
`B.  Related Matters Under 37 C.F.R. § 42.8(b)(2) ........................................ 5 
`C.  Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) ..................... 6 
`D.  Service Information Under 37 C.F.R. § 42.8(b)(4) ................................. 6 
`E.  Grounds for Standing Under 37 C.F.R. § 42.104(a) ................................ 6 
`F.  Fees Under 37 C.F.R. § 42.103 ................................................................ 6 
`IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R. § 42.104(B) ...... 7 
`
`A.  The Alleged Invention of the ’756 Patent ................................................ 9 
`B.  The Prosecution History of the ’756 Patent ........................................... 10 
`IV.  LEVEL OF ORDINARY SKILL IN THE ART ........................................... 12 
`
`V.  HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED
`UNDER 37 C.F.R. § 42.104(B)(3) ................................................................ 13 
`
`VI.  DETAILED EXPLANATION AND SUPPORTING EVIDENCE UNDER
`37 C.F.R. §§ 42.104(B)(4) AND (B)(5) ........................................................ 13 
`
`A.  Ground 1: Claims 1-4 Are Obvious Over the Ribomustin® Product
`Monograph in View Of Alexander or Sauerbier. .................................. 14 
`B.  Ground 2: Claims 1-4 Are Obvious Over the Ribomustin® Product
`Monograph in View Of Alexander or Sauerbier And Further in View of
`Teagarden. .............................................................................................. 26 
`C.  Ground 3: Claims 1-4 Are Obvious Over the Ribomustin® Product
`Monograph in View Of Alexander or Sauerbier and Teagarden and
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`IPR2016-00111
`Petition for Inter Partes Review
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`Further in View of DeLuca. ................................................................... 35 
`D.  Ground 4: Claims 1-4 Are Obvious Over Maas and the Ribomustin®
`Product Monograph in View Of Alexander or Sauerbier and Teagarden.
` ................................................................................................................ 46 
`VII.  PROPOSED GROUNDS 1-4 FOR UNPATENTABILITY ARE NOT
`CUMULATIVE. ............................................................................................ 56 
`
`VIII.  SECONDARY CONSIDERATIONS, EVEN IF CONSIDERED, FAIL TO
`OVERCOME THE EVIDENCE OF OBVIOUSNESS. ............................... 58 
`
`IX.  CONCLUSION .............................................................................................. 60 
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`IPR2016-00111
`Petition for Inter Partes Review
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`FEDERAL CASES
`AstraZeneca LP v. Breath Ltd.,
`603 F. App’x 999 (Fed. Cir. 2015) ..................................................................... 59
`
`Aventis Pharma S.A. v. Hospira, Inc.,
`743 F. Supp. 2d 305 (D. Del. 2010) .................................................................... 59
`
`Bayer Healthcare Pharmaceuticals, Inc. v. Watson Pharmaceuticals, Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 60
`
`Bayer Schering Pharma A.G. v. Barr Laboratories Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ...................................................................... 4, 19
`
`In re Bendamustine Consolidated Cases,
`Case No. 1:13-cv-2046 (D. Del. Dec. 19, 2013) .................................................. 5
`
`Cephalon, Inc. v. Apotex, Inc.,
`Case No. 1:15-cv-404 (D. Del. May 19, 2015) .................................................... 5
`
`Cephalon, Inc. v. Dr. Reddy’s Laboratories, Ltd.,
`Case No. 15-cv-00179 (D. Del.) ........................................................................... 5
`
`Cephalon, Inc. v. Nang Kuang Pharmaceutical Co., Ltd.,
`Case No. 1:14-cv-5180 (E.D.N.Y. Sept. 3, 2014) ................................................ 5
`
`Cephalon, Inc. v. Panacea Biotec, Ltd.,
`Case No. 1:15-cv-735 (D. Del. Aug. 25, 2015) .................................................... 5
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 58
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) ............................................................................ 59
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) ...................................................................... 3, 19
`
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`IPR2016-00111
`Petition for Inter Partes Review
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 58
`
`FEDERAL STATUTES
`
`35 U.S.C. § 102(a) ............................................................................................. 11, 12
`
`35 U.S.C. § 102(b) ..................................................................................................... 7
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`35 U.S.C. § 103 ................................................................................................ 7, 9, 56
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`35 U.S.C. §§ 311-19................................................................................................... 1
`
`35 U.S.C. § 311(b) ................................................................................................... 14
`
`35 U.S.C. §§ 315 ........................................................................................................ 4
`
`REGULATIONS
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`37 C.F.R. § 42.8(b)(1) ................................................................................................ 4
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`37 C.F.R. § 42.8(b)(2) ................................................................................................ 5
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`37 C.F.R. § 42.8(b)(3) ................................................................................................ 6
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`37 C.F.R. § 42.8(b)(4) ................................................................................................ 6
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`37 C.F.R. § 42.10(b) .................................................................................................. 6
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`37 C.F.R. §§ 42.22(a) and 42.104(b)(1)-(2) .............................................................. 7
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`37 C.F.R. § 42.63(e) ................................................................................................. 14
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`37 C.F.R. § 42.100(b) .............................................................................................. 13
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`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
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`37 C.F.R. § 42.103 ..................................................................................................... 6
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`37 C.F.R. § 42.104(a) ................................................................................................. 6
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`37 C.F.R. § 42.104(b) ................................................................................................ 7
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`37 C.F.R. § 42.104(b)(3) .......................................................................................... 13
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`IPR2016-00111
`Petition for Inter Partes Review
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`37 C.F.R. §§ 42.104(b)(4) and (b)(5) ...................................................................... 13
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`37 CFR § 1.111 ........................................................................................................ 11
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`37 CFR § 1.131 ........................................................................................................ 11
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`IPR2016-00111
`Petition for Inter Partes Review
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`PETITIONERS’ EXHIBIT LIST
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`Exhibit No.
`
`Description
`
`Exhibit 1001 U.S. Patent No. 8,895,756 (“the ’756 patent”)
`
`Exhibit 1002 Copy of Prosecution History for the U.S. Patent No. 8,895,756
`(downloaded from PAIR)
`
`Exhibit 1003
`
`Complaint filed in Cephalon, Inc. v. Dr. Reddy’s Labs., Ltd.,
`Case No. 15-cv-00179 (D. Del.) consolidated with Cephalon,
`Inc. v. Hetero Labs Ltd. v. Hetero USA, Inc., Case No. 13-cv-
`2046 (D. Del.)
`
`Exhibit 1004
`
`Institution Decision in Agila Specialties Inc. and Mylan Labs.
`Ltd. v. Cephalon, Inc., Paper No. 11, IPR2015-00503 (P.T.A.B.
`July 20, 2015).
`
`Exhibit 1005 The Ribomustin® Product Monograph, 2002 (“Ribomustin®
`Product Monograph”)
`
`Exhibit 1006 U.S. Patent No. 4,537,883 (“Alexander”)
`
`Exhibit 1007 U.S. Patent No. 5,204,335 (“Sauerbier”)
`
`Exhibit 1008
`
`Dirk L. Teagarden & David S. Baker, Practical Aspects of
`Lyophilization using Non-Aqueous Co-Solvent Systems, 15 EUR.
`J. PHARM. SCI. 115 (March 2002) (“Teagarden”)
`
`Exhibit 1009
`
`Birgit Maas et al., Stability of Bendamustine Hydrochloride in
`Infusions, 49 PHARMAZIE 775 (1994) (German language original
`and certified English translation) (“Maas”)
`
`
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`IPR2016-00111
`Petition for Inter Partes Review
`
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`Exhibit 1010 U.S. Patent No. 5,731,291 (“Sullivan”)
`
`Exhibit 1011
`
`P.P. DeLuca & J.C. Boylan, J.C., Chapter 5, Formulation of
`Small Volume Parenterals. in K.E. Avis, et al., eds.
`PHARMACEUTICAL DOSAGE FORMS: PARENTERAL MEDICATIONS,
`VOL. 1, New York: Marcel Dekker (1992) (“DeLuca”).
`
`Exhibit 1012 Declaration of Michael J. Akers, Ph.D. and Accompanying
`Exhibits
`
`Exhibit 1013
`
`Final Written Decision in Intri-Plex Techs., Inc. et al. v. Saint-
`Gobain Performance Plastics Rencol Ltd., Paper No. 83,
`IPR2014-00309 (P.T.A.B. March 23, 2015)
`
`Exhibit 1014 Copy of Prosecution History for U.S. Patent No. 8,436,190
`(downloaded from PAIR)
`
`
`
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`vii
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`IPR2016-00111
`Petition for Inter Partes Review
`
`
`Petitioner Fresenius Kabi USA, LLC (“Petitioner”) requests inter partes
`
`review of claims 1-4 (“the challenged claims”) of U.S. Patent No. 8,895,756 (“the
`
`’756 patent”) (Exh. 1001) pursuant to 35 U.S.C. §§ 311-19 and 37 C.F.R. § 42.100
`
`et seq.
`
`I.
`
`INTRODUCTION AND BACKGROUND
`
`The challenged claims of the ’756 patent should never have been issued. The
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`claims cover vials in which lyophilized pharmaceutical formulations of
`
`bendamustine hydrochloride—a nitrogen mustard compound that has been in the
`
`public domain for more than 50 years—are reconstituted. The claimed lyophilized
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`formulations contain bendamustine hydrochloride and mannitol, exactly the same
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`components of the prior art Ribomustin®, which was a lyophilized bendamustine
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`hydrochloride drug product sold in Germany since 1992 (and as Cytostasan® from
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`1971-1992). The primary difference between Ribomustin® and the ’756 patent
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`claims is the weight ratio of bendamustine hydrochloride to mannitol—1:1.2 in
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`Ribomustin® versus 1:1.7 (recited as 15:25.5) in the ’756 patent claims.
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`As discussed below, one of ordinary skill in the art seeking to obtain Food
`
`and Drug Administration (“FDA”) regulatory approval and market a lyophilized
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`bendamustine hydrochloride pharmaceutical product in the United States would
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`have been motivated to modernize the decades-old, foreign-sold Ribomustin® to
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`obtain a lyophilized formulation having more desirable cake characteristics. In
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`IPR2016-00111
`Petition for Inter Partes Review
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`particular, the slow reconstitution time of Ribomustin® was a known problem,
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`which the ’756 patent itself noted was “difficult,” “burdensome and time-
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`consuming for the healthcare professional,” and “increase[d] the potential for loss
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`of potency and impurity formation due to the hydrolysis of the product by water.”
`
`Exh. 1001, col. 2, ll. 29-37.
`
`The preparation of lyophilized formulations of other nitrogen mustards using
`
`a mannitol excipient was known. See Exhs. 1006 & 1007. Various non-aqueous co-
`
`solvent systems for preparing suitable prelyophilization solutions were known. See
`
`Exh. 1008. In particular, the tert-butanol / water co-solvent system was known to
`
`improve drug stability, increase the surface area of the lyophilized cake, reduce
`
`reconstitution time, and increase solubility allowing for higher drug concentrations.
`
`See Exh. 1008. With the advantages of a modified non-aqueous co-solvent system,
`
`one of ordinary skill in the art would have expected that obtaining a desirable
`
`lyophilized cake would involve altering the amount of mannitol from that of
`
`Ribomustin®.
`
`One of ordinary skill in the art thus would have been motivated to obtain a
`
`lyophilized formulation having a faster reconstitution time with a reasonable
`
`expectation of success. One of ordinary skill in the art would have tried varying the
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`amount of the mannitol excipient in Ribomustin® relative to that of bendamustine
`
`hydrochloride, and through routine optimization, would have arrived at a
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`IPR2016-00111
`Petition for Inter Partes Review
`
`lyophilized formulation having more desirable cake characteristics, particularly a
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`faster reconstitution time.
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`Another problem was the 50 mL vial size of the 100 mg Ribomustin®
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`product. See Exh. 1001, col. 2, ll. 13-14. One of ordinary skill in the art would
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`have been motivated to repackage Ribomustin® in a smaller vial—a 20 mL vial,
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`for example—to reduce the cost of goods by allowing for more vials to be
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`processed in a lyophilizer during each cycle. To maintain the same amount (100
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`mg) of bendamustine hydrochloride in a 20 mL vial, one of ordinary skill in the art
`
`would have modified the amount of mannitol to obtain a desirable lyophilized cake
`
`with the appropriate fill volume. One of ordinary skill in the art would have been
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`guided by known standards in the lyophilized pharmaceutical formulation art that
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`solid contents should be between about 5%-30% (optimally 10%-15%) and the fill
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`volume should not exceed about 50%. See Exh. 1011 at 0006.
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`Accordingly, one of ordinary skill in the art would have been able, through
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`routine optimization, to arrive at a lyophilized formulation of 100 mg (or 25 mg) of
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`bendamustine hydrochloride packaged in a 20 mL vial having desirable cake
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`characteristics, including a stable, non-brittle cake with a faster reconstitution time.
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`The resulting lyophilized formulation—with a weight ratio of bendamustine
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`hydrochloride to mannitol of 1:1.7 as claimed in the ’756 patent—therefore, is the
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`result of a finite number of predictable solutions. See In re Kubin, 561 F.3d 1351,
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`3
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`IPR2016-00111
`Petition for Inter Partes Review
`
`1360 (Fed. Cir. 2009); Bayer Schering Pharma A.G. v. Barr Labs. Inc., 575 F.3d
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`1341, 1347 (Fed. Cir. 2009). The fact that the claimed weight ratio was within the
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`ranges taught by the prior art for lyophilized formulations of other nitrogen
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`mustards using a mannitol excipient further supports this conclusion. See Exh.
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`1006, col. 7, ll. 18-22 (preferred drug to mannitol weight ratios between 1:0.5 and
`
`1:2.0); Exh. 1007, col. 3, ll. 26-33 (preferred drug to mannitol weight ratios
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`between 1:0.1 and 1:2.5).
`
`II. NOTICES, STATEMENTS AND PAYMENT OF FEES
`
`A. Real Party In Interest Under 37 C.F.R. § 42.8(b)(1)
`
`Fresenius Kabi USA, LLC is the real-party-in-interest. No unnamed entity is
`
`funding, controlling, or otherwise has an opportunity to control or direct this
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`Petition or Fresenius Kabi USA, LLC’s participation in any resulting IPR.
`
`Fresenius Kabi USA, LLC has numerous affiliated and/or related entities,
`
`including Fresenius Kabi USA, Inc., Fresenius Kabi Pharmaceuticals Holding,
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`Inc., Fresenius Kabi AG, and Fresenius SE & Co. KGaA. Fresenius Kabi USA,
`
`LLC is also contractual partners with Hetero Labs, Ltd. and Hetero USA, Inc. Out
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`of an abundance of caution, Fresenius Kabi USA, LLC identifies the foregoing
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`entities, each of which agrees to be estopped under the provisions of 35 U.S.C.
`
`§§ 315 and/or 325 as a result of any final written decision in the requested IPR to
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`the same extent as Fresenius Kabi USA, LLC, as real-parties-in-interest solely for
`
`
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`

`IPR2016-00111
`Petition for Inter Partes Review
`
`purposes of this Petition.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`
`Cephalon has asserted the ’756 patent in co-pending litigations captioned
`
`Cephalon, Inc. v. Dr. Reddy’s Labs., Ltd., Case No. 15-cv-00179 (D. Del.)
`
`consolidated with In re Bendamustine Consolidated Cases, Case No. 1:13-cv-2046
`
`(D. Del. Dec. 19, 2013) (“the Consolidated Bendamustine Action”), Cephalon, Inc.
`
`v. Apotex, Inc., Case No. 1:15-cv-404 (D. Del. May 19, 2015), Cephalon, Inc. v.
`
`Panacea Biotec, Ltd., Case No. 1:15-cv-735 (D. Del. Aug. 25, 2015), and
`
`Cephalon, Inc. v. Nang Kuang Pharm. Co., Ltd., Case No. 1:14-cv-5180 (E.D.N.Y.
`
`Sept. 3, 2014) (collectively, “the ’756 Bendamustine Actions”).
`
`Petitioner is not a party to any of the ’756 Bendamustine Actions, and
`
`Cephalon has never asserted the ’756 patent against Petitioner. Hetero Labs, Ltd.
`
`and Hetero USA, Inc., are parties to the Consolidated Bendamustine Action. A
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`Complaint asserting the ’756 patent against Hetero Labs, Ltd. and Hetero USA,
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`Inc. was served no earlier than February 23, 2015. Exh. 1003.
`
`On December 24, 2014, Agila Specialties f/k/a Strides Inc. and Mylan
`
`Laboratories Limited (collectively, “Mylan”) filed a petition for inter partes review
`
`of U.S. Patent No. 8,436,190 (“the ’190 patent”), from which the ’756 patent
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`claims priority. See IPR2015-00503. Trial in IPR2015-00503 was instituted by the
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`Board on July 20, 2015. Exh. 1004. On October 9, 2015, Mylan filed a petition for
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`5
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`IPR2016-00111
`Petition for Inter Partes Review
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`inter partes review of claims 1-23 of U.S. Patent No. 8,791,270, which also claims
`
`priority to the ’190 patent. This petition is pending. See IPR2016-0026.
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`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`Petitioner designates lead and back-up counsel as noted below. Powers of
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`attorney pursuant to 37 C.F.R. § 42.10(b) accompany this Petition.
`
`Lead Counsel
`
`Backup Counsel
`
`Lawrence Sung, Reg. No. 38,330
`
`Neal Seth, Reg. No. 67,075
`
`WILEY REIN LLP
`ATTN: Patent Administration
`1776 K Street, NW
`Washington, DC 20006 USA
`Phone: 202.719.7000 / Fax: 202.719.7049
`
`D.
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`
`Please address all correspondence to counsel at the address above. Petitioner
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`consents to electronic service by email at: lsung@wileyrein.com and
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`nseth@wileyrein.com.
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`E. Grounds for Standing Under 37 C.F.R. § 42.104(a)
`
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’756 patent is
`
`available for inter partes review, and that Petitioner is not barred or estopped from
`
`requesting inter partes review based on the grounds herein.
`
`F.
`
`Fees Under 37 C.F.R. § 42.103
`
`Petitioner concurrently submits fees of $23,000. If more fees are necessary
`6
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`

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`IPR2016-00111
`Petition for Inter Partes Review
`
`to accord this Petition a filing date, authorization is granted to charge the same to
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`Deposit Account No. 50-1129 with reference to Attorney Docket No. 86430.0023.
`
`III.
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`IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R. § 42.104(B)
`
`Petitioner requests cancellation of claims 1-4 of the ’756 patent as
`
`unpatentable under 35 U.S.C. § 103. This Petition, supported by the accompanying
`
`Declaration of Dr. Michael J. Akers (Exh. 1012), demonstrates that there is a
`
`reasonable likelihood that the challenged claims are not patentable and that
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`Petitioners will prevail with respect to at least one challenged claim.
`
`Pursuant to 37 C.F.R. §§ 42.22(a) and 42.104(b)(1)-(2), Petitioner’s
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`challenge is based on the following references, all of which are prior art pursuant
`
`to 35 U.S.C. § 102(b):
`
`1.
`
`Ribomustin® Product Monograph (Exhibit 1005), Ribosepharm
`
`GmbH, München, Germany, published in January 2002, and was available publicly
`
`in both print and electronic forms. The Ribomustin® Product Monograph is cited
`
`on the face of the ’756 patent, Exh. 1001, although it was not used during
`
`prosecution to substantively reject the claims.
`
`2.
`
`Alexander (Exhibit 1006), U.S. Patent No. 4,537,883, entitled
`
`“Lyophilized Cyclophosphamide,” issued on August 27, 1985. The ’756 patent
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`discloses Alexander in the specification (Background of the Invention), Exh. 1001,
`
`col. 2, l. 63, but the patent examiner did not rely upon this reference during
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`
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`IPR2016-00111
`Petition for Inter Partes Review
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`prosecution to substantively reject the claims.
`
`3.
`
`Sauerbier (Exhibit 1007), U.S. Patent No. 5,204,335, entitled
`
`“Ifosfamide Lyophilizate and Process for its Preparation,” issued on April 20,
`
`1993. The ’756 patent discloses Sauerbier in the specification (Background of the
`
`Invention), Exh. 1001, col. 2, ll. 66-67, but the patent examiner did not rely upon
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`this reference during prosecution to substantively reject the claims.
`
`4.
`
`Teagarden (Exhibit 1008), Practical Aspects of Lyophilization Using
`
`Non-Aqueous Co-Solvent Systems, 15 EUR. J. PHARM. SCI. 115, published in March
`
`2002. Teagarden was cited during the prosecution of the ’756 patent, but the patent
`
`examiner did not rely upon this reference during prosecution to substantively reject
`
`the claims.
`
`5. Maas (Exhibit 1009), Stability of Bendamustine Hydrochloride in
`
`Infusions, 49 PHARMAZIE 775, published in German in 1994. Maas is cited on the
`
`face of the ’756 patent, although it was not used during prosecution to
`
`substantively reject the claims.
`
`6.
`
`DeLuca (Exhibit 1011), Chapter 5, Formulation of Small Volume
`
`Parenterals, in K.E. Avis, et al., eds. PHARMACEUTICAL DOSAGE FORMS:
`
`PARENTERAL MEDICATIONS, VOL. 1, New York: Marcel Dekker (1992). DeLuca is
`
`cited on the face of the ’756 patent, Exh. 1001, although it was not used during
`
`prosecution to substantively reject the claims.
`
`
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`8
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`

`IPR2016-00111
`Petition for Inter Partes Review
`
`
`As explained in further detail below, Petitioner respectfully requests that the
`
`Board cancel claims 1-4 based on the following grounds of unpatentability:
`
`Ground 1: Claims 1-4 are invalid under 35 U.S.C. § 103 as obvious over
`
`Ribomustin® Product Monograph in view of Alexander or Sauerbier.
`
`Ground 2: Claims 1-4 are invalid under 35 U.S.C. § 103 as obvious over
`
`Ribomustin® Product Monograph in view of Alexander or Sauerbier and further in
`
`view of Teagarden.
`
`Ground 3: Claims 1-4 are invalid under 35 U.S.C. § 103 as obvious over
`
`Ribomustin® Product Monograph in view of Alexander or Sauerbier and
`
`Teagarden, and further in view of DeLuca.
`
`Ground 4: Claims 1-4 are invalid under 35 U.S.C. § 103 as obvious over
`
`Maas and the Ribomustin® Product Monograph in view of Alexander or Sauerbier,
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`Teagarden and DeLuca.
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`A. The Alleged Invention of the ’756 Patent
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`The application that matured into the ’756 patent was filed on December 19,
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`2012, and claims priority through a series of applications to a January 14, 2005
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`provisional application. Exh. 1001, col. 1, ll. 7-12. The ’756 patent is directed to
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`vials containing a reconstituted solution of bendamustine hydrochloride and
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`mannitol in a specific weight ratio. Exh. 1001, col. 35, ll. 13-25. The ’756 patent
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`admits that the nitrogen mustard bendamustine hydrochloride was synthesized in
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`1963 and has been commercially available outside of the United States since 1971
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`for the treatment of certain blood cancers. Exh. 1001, col. 1, ll. 60-67. Since 1992,
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`this product has been sold under the trade name Ribomustin®. Exh. 1001, col. 1, ll.
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`63-64.
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`The ’756 patent further admits that Ribomustin® was formulated as a
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`lyophilized powder with 100 mg of drug per 50 mL vial or 25 mg of drug per 20
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`mL vial to be reconstituted with 40 mL (for the 100 mg vial) or 10 mL (for the 25
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`mg vial) of sterile water for injection. Exh. 1001, col. 2, ll. 13-19. The ’756 patent
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`refers expressly to the Ribomustin® Product Monograph (Exh. 1005), see Exh.
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`1001, col. 2, ll. 53-56, which describes Ribomustin® as a lyophilized formulation
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`of bendamustine hydrochloride and mannitol, Exh. 1005 at 0055, §§ 3.2 & 3.3.
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`No dispute exists that Ribomustin® was a lyophilized formulation of
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`bendamustine hydrochloride and mannitol provided in a 25 mg vial or a 100 mg
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`vial for reconstitution, where the weight ratio of bendamustine hydrochloride to
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`mannitol was 1:1.2. The primary difference between the prior art and the ’756
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`patent, therefore, is the claimed weight ratio of bendamustine hydrochloride to
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`mannitol of 1:1.7.
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`B.
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`The Prosecution History of the ’756 Patent
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`On December 9, 2012, the applicants filed U.S. patent application Serial No.
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`13/719,409, asserting priority, inter alia, to U.S. provisional patent application
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`Serial No. 60/644,354 (filed on Jan. 14, 2005), and setting forth four claims.
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`Applicants received Track One Prioritized Examination.
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`On March 1, 2013, the USPTO issued a non-final Office Action rejecting all
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`pending claims. The patent examiner rejected Claims 1-4 under 35 U.S.C. § 102(a)
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`as anticipated by Kanekal et al., “SDX-105(TREANDA) Enhances the Tumor
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`Growth Inhibitory Effect of Rituximab in Daudi Lymphoma Xenografts,” Blood
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`(ASH Annual Meeting Abstracts), vol. 104 (2004). The patent examiner noted that
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`Kanekal teaches TREANDA and that TREANDA (according to the RxList in
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`2013) “is a lyophilized powder comprising either 25mg bendamustine and 42.5 mg
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`mannitol or 100mg bendamustine hydrochloride and 170mg mannitol to be
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`reconstituted in sterile water for injection.” Exh. 1002 at 0376 (Mar. 1, 2013).
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`On June 3, 2012, the applicants filed a Reply Pursuant to 37 CFR § 1.111
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`traversing the rejection and submitting a Declaration Pursuant to 37 CFR § 1.131
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`of co-inventor Jason E. Brittain. The Reply and the Brittain Declaration stated that
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`the claimed invention was reduced to practice before November 16, 2004, see Exh.
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`1002 at 0306 (Jun. 3, 2013); Brittain Decl., ¶ 11 (May 31, 2013), as evidenced by a
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`Formulation Development Report. The applicants also filed a terminal disclaimer
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`surrendering the terminal portion of the patent term beyond the expiry of U.S.
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`Patent No. 8,436,190 and co-pending, related patent application Serial No.
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`13/719,379.
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`On September 27, 2013, the USPTO issued a Notice of Allowance,
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`withdrawing the rejection of the pending claims under 35 U.S.C. § 102(a) in view
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`of the Kanekal reference based on the Brittain Declaration that the applicants
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`invented the claimed subject matter before the publication of the Kanekal
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`reference. The patent examiner further provided as reasons for allowance:
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`“While the prior art teaches a composition that maybe
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`reconstituted comprising bendamustine hydrochloride and
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`mannitol (third party prior art submission filed on 08/12/2013),
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`the instantly claimed ratio is not taught. Applicant however has
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`found unexpectedly that the instant ratio allows for the
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`maintenance of a well formed cake resistant to breakage during
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`handling (page 46, lines 17-27 of the instant specification).”
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`Exh. 1002 at 0012 (Oct. 24, 2014).
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`None of the claims of the ’756 patent, however, recite any limitations
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`concerning desirable lyophilized cake properties.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
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`A person of ordinary skill in the art is a hypothetical person presumed to be
`
`aware of all pertinent art. A person of ordinary skill in the art thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. A person of
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`ordinary skill in the art as of January 2005, the filing date of the ’756 patent, would
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`have a Ph.D. in pharmaceutics, pharmaceutical sciences, or a related field, with at
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`least three years of practical experience in the pharmaceutical formulation,
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`including the formulation of lyophilized products. See Exh. 1012, ¶ 22.
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`V. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED
`UNDER 37 C.F.R. § 42.104(B)(3)
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`A claim subject to inter partes review receives the “broadest reasonable
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`construction in light of the specification of the patent in which it appears.” 37
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`C.F.R. § 42.100(b). Throughout this Petition, Petitioner applies the broadest
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`reasonable construction of claim terms appropriate for these proceedings, including
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`claim terms for which a claim construction is not explicitly discussed.
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`Claim constructions appropriate for these proceedings may be different from
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`those appropriate in district courts. Thus, claim constructions relied upon in this
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`Petition do not necessarily reflect the claim constructions that Petitioner believes
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`should be adopted by a district court utilizing the Markman approach to claim
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`construction.
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`VI. DETAILED EXPLANATION AND SUPPORTING EVIDENCE
`UNDER 37 C.F.R. §§ 42.104(B)(4) AND (B)(5)
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`Pursuant to 37 C.F.R. §§ 42.104(b)(4) and (b)(5), Petitioner sets forth an
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`explanation below of why claims 1-4 are unpatentable under the statutory grounds
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`identified above, including the identification of where each element is found in the
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`prior art. The claim charts identify the supporting evidence relied upon to support
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`the challenge by exhibit number and set forth the relevance of the evidence to the
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`challenge raised, including an identification of those specific portions of the
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`evidence that support the challenge. An Exhibit List (see 37 C.F.R. § 42.63(e))
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`identifying the exhibits is also included, supra, at p. iv.
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`A. Ground 1: Claims 1-4 Are Obvious Over the Ribomustin®
`Product Monograph in View Of Alexander or Sauerbier.
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`No dispute exists that the Ribomustin® Product Monograph, Alexander, and
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`Sauerbier are relevant prior art to the ’756 patent claims. The ’756 patent lists all
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`three references in the Background of the Invention.1 See Exh. 1001, col. 2, ll. 53-
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`1 The Patent Trial and Appeal Board has held that Admitted Prior Art may
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`be considered in an inter partes review proceeding under 35 U.S.C. § 311(b). See
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`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol Ltd.,
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`IPR2014-00309, at 20-21 (P.T.A.B. 2014) (Exh. 1013). The Board further stated
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`that “even if Admitted Prior Art is not treated as a prior art reference per se for
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`purposes of Section 311(b), [the patent owner’s] admission nevertheless constitutes
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`background knowledge that may be imputed to a hypothetical person of ordinary
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`skill for purposes of an obviousness analysis.” Id. at 0021 n.8 (citing Randall Mfg.
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`v. Rea, 733 F.3d 1355, 1363 (Fed. Cir. 2013) for the proposition that non-applied
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`art should be considered as background information that could explain why an
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`ordinarily skilled artisan would have been motivated to combine or modify the
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`56 (Ribomustin® Product Monograph); Exh. 1001, col. 2, l. 63 (Alexander); Exh.
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`1001, col. 2, ll. 66-67 (Sauerbier). During the prosecution of the ’756 patent
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`application, however, the patent examiner did not rely upon any of these references
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`to substantively reject the claims.
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`No dispute exists that Ribomustin® is a lyophilized preparation of
`
`bendamustine hydrochloride and mannitol provided in a vial for reconstitution
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`prior to injection into human patients. The Ribomustin® Product Monograph and
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`the ’756 patent are in accord that Ribomustin® was formulated as a lyophilized
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`powder for injection with 100 mg of drug per 50 mL vial or 25 mg of drug per 20
`
`mL vial, and that Ribomustin® was reconstituted with 40 mL (for the 100 mg vial)
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`or 10 mL (for the 25 mg vial) of sterile water for injection. See Exh. 1005 at 0007-
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`0008, §§ 2.3-2.6; Exh. 1001 at col. 2, ll. 13-19.
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`The Ribomustin® Product Monograph thus teaches every aspect of claims
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`1-4 of the ’756 patent with the exception that in Ribomustin® the weight ratio of
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`bendamustine hydrochloride to mannitol is 1:1.2, whereas in the ’756 patent
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`claims,