Tria1s@uspt0. gov
`571-272-7822
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`Paper No. 10
`Entered: July 20, 2015
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`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.
`
`Case IPR2015-00503
`
`Patent 8,436,190 B2
`
`Before LINDA M. GAUDETTE, JACQUELINE WRIGHT BONILLA, and
`ZHENYU YANG, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`DECISION
`
`Institution of Inter Partes Review
`
`37 C.F.R. § 42.108
`
`FRESENIUS KABI 1012-OOO1
`
`
`571-272-7822
`
`Paper No. 10
`Entered: July 20, 2015
`
`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.
`
`Case IPR2015-00503
`
`Patent 8,436,190 B2
`
`Before LINDA M. GAUDETTE, JACQUELINE WRIGHT BONILLA, and
`ZHENYU YANG, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`DECISION
`
`Institution of Inter Partes Review
`
`37 C.F.R. § 42.108
`
`FRESENIUS KABI 1012-OOO1
`
`
`
`IPR20l5-00503
`
`Patent 8,436,190 B2
`
`INTRODUCTION
`
`Agila Specialties Inc. and Mylan Laboratories Limited (collectively,
`
`“Petitioner”) filed a Petition for an inter partes review of claims l—9 of U.S.
`
`Patent No. 8,436,190 B2 (“the ’l9O patent,” Ex. 1001). Paper 4 (“Pet”).
`
`Cephalon, Inc. (“Patent Owner”) timely filed a Preliminary Response. Paper
`
`9 (“Prelim Resp”). We have jurisdiction under 35 U.S.C. § 314.
`
`For the reasons provided below, we determine Petitioner has satisfied
`
`the threshold requirement set forth in 35 U.S.C. § 3 l4(a). Because
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`Petitioner has established a reasonable likelihood that it would prevail in
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`showing the unpatentability of claims 1, 4, and 7, we institute an inter partes
`
`review of these claims. Petitioner, however, has not established a reasonable
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`likelihood that it would prevail in showing the unpatentability of claims 2, 3,
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`5, 6, 8, and 9. Therefore, we deny the Petition regarding the challenges to
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`those claims.
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`Related Proceedings
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`According to the parties, Patent Owner previously asserted the ’ 190
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`patent against Petitioner in Cephalon, Inc. v. Agila Specialties Inc. , Case
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`No. l:l3-cv-02080 (D. Del). Pet. 14, Paper 6, 2. Patent Owner also
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`asserted the ’l9O patent against several other entities in cases filed in district
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`courts. Pet. 14-15; Paper 6, 1-3.
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`The ’I90 Patent
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`The ’ 190 patent is directed to stable phannaceutical compositions of
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`nitrogen mustards, in particular, lyophilized bendamustine, which can be
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`2
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`FRESENIUS KABI 1012-OOO2
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`IPR2015-00503
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`used to treat Various disease states, especially neoplastic diseases and
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`autoimmune diseases. Ex. 1001, 2:66—3:3. According to the ’190 patent,
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`“the term ‘lyophilized powder’ or ‘lyophilized preparation’ refers to any
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`solid material obtained by lyophilization, i.e., freeze-drying of an aqueous
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`solution.” Id. at 9:1—3.
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`Bendamustine was first synthesized in East Germany in 1963. Id. at
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`1:50-51. At the time of the ’ 190 patent invention, bendamustine was
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`marketed in Germany under the name Ribomustin® to treat chronic
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`lymphocytic leukemia, Hodgkin’s disease, non-Hodgl<in’s lymphoma,
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`multiple myeloma, and breast cancer. Id. at 1:53—5 7.
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`The ’ 190 patent discloses stable pharmaceutical compositions
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`prepared from bendamustine, in particular, “formulations for the
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`lyophilization of bendamustine HCl.” Id. at 12:7—10. According to the ’ 190
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`patent, the lyophilized powder obtained from such formulations is more
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`easily reconstituted and has a better impurity profile than Ribomustin®. Id.
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`at 12: 1 0-1 6.
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`Illustrative Claim
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`Among the challenged claims, claim 1 is the sole independent claim.
`
`It reads:
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`A pharmaceutical composition comprising bendamustine
`1.
`or bendamustine hydrochloride, mannitol, tertiary-butyl alcohol
`and water.
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`FRESENIUS KABI 1012-OOO3
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`IPR2015-00503
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`Patent 8,436,190 B2
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`Assertea’ Grounds of Unpatentability
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`Petitioner asserts the following grounds of unpatentability:
`
`Claims
`1-9
`1-9
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`7-9
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`Basis
`§ 103
`§ 103
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`§ 103
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`References
`The Rote Listel and Teagardenz
`The Rote Liste, Teagarden, and
`Nuij en3
`The Rote Liste, Teagarden, Nuijen,
`and Gust4
`
`4, 5, 7, and 8
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`§ 102
`
`The Rote Liste
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`Patent Owner asserts January 14, 2005 as the priority date of the ’ 190
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`patent. Prelim. Resp. 13. According to Petitioner, all asserted references are
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`prior art under 35 U.S.C. § 102(b). Pet. 4-7.
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`In support of its patentability challenge, Petitioner relies on the
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`Declaration of Dr. Raj Suryanarayanan. Ex. 1002.
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`1 The Rote Liste 1996 (Ex. 1006, “the Rote Liste”).
`2 Teagarden and Baker, Practical Aspects ofLyophilization Using Non-
`Aqueous Co—Solvent Systems, 15 EUR. J. PHARM. SCI. 115-33 (2002)
`(Ex. 1007, “Teagarden”).
`3 Nuijen et al., Pharmaceutical Development ofa Parenteral Lyophilizea’
`Formulation ofthe Novel Antitumor Agent/lplia’ine, 54 PDA J. PHARM SCI.
`& TECH. 193-208 (2000) (Ex. 1008, “Nuijen”).
`4 Gust and Krauser, Investigations on the Stability ofBendamustin, a
`Cytostatic Agent of the Nitrogen Mustard Type, 1. Synthesis, Isolation, and
`Characterization ofReference Substances, 128 CHEMICAL MONTHLY 291-
`99 (1997) (Ex_ 1009, “Gust”).
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`4
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`ANALYSIS
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`Claim Construction
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`In an inter partes review, the Board interprets a claim term in an
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`unexpired patent according to its broadest reasonable construction in light of
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`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b).
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`Under that standard, and absent any special definitions, we assign claim
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`terms their ordinary and customary meaning, as would be understood by one
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`of ordinary skill in the art at the time of the invention, in the context of the
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`entire patent disclosure. In re Translogic Tech., Inc, 504 F.3d 1249, 1257
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`(Fed. Cir. 2007).
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`Petitioner requests that we construe the term “made from.” Pet. 18-
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`19. The term “made from” appears in claim 4, which reads, “[a] lyophilized
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`pharmaceutical composition made from the pharmaceutical composition
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`according to claim 1.” Petitioner argues that claim 4 and claims dependent
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`therefrom are directed to lyophilized products, made from the process of
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`lyophilizing the pharmaceutical composition of claim 1. Id. at 18. Thus,
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`Petitioner asserts the term means “made from the process of lyophilizing.”
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`Id. Patent Owner disagrees. Prelim. Resp. 19. According to Patent Owner,
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`the plain language of the claim indicates that “made from” refers to the
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`composition of claim 1, and not the process of lyophilizing. Id. We agree
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`with Petitioner that claim 4 and claims dependent therefrom are product-by-
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`process claims.
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`A product-by-process claim is “one in which the product is defined at
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`least in part in terms of the method or process by which it is made.” Bonito
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`Boats, Inc. V. Thunder Craft Boats, Inc, 489 U.S. 141, 158 n. (1989). Claim
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`5
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`4 recites a pharmaceutical composition made from the composition of claim
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`1. It specifies that the pharmaceutical composition is “lyophilized” In other
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`words, the pharmaceutical composition of claim 4 is defined in part by the
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`lyophilization process. Thus, we adopt Petitioner’s proposed construction
`
`and interpret the term “made from” to mean “made from the process of
`
`lyophilizing.”
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`Petitioner also proposes to construe the terms “lyophilized,” “said
`77 CC
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`pharmaceutical composition,
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`containing not more than about 0.5%,” and
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`“about” Pet. 17-21. Patent Owner states that these terms “need no
`
`construction to determine whether to institute the proceeding.” Prelim.
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`Resp. 19. We agree with Patent Owner, and thus, decline to construe these
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`terms expressly for purposes of this Decision.
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`Prior Art Disclosures
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`Patentability Analysis
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`The Rote Liste discloses a dry substance and specifies that “1 Vial
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`with 55 mg of dry substance contains: bendamustine HCl 25 mg. Other
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`components: mannitol.” Ex. 1006, 8.
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`Teagarden teaches that using non-aqueous co-solvent systems in
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`freeze-drying pharmaceutical products has numerous advantages, including
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`“increased pre-dried bulk solution or dried product stability.” Ex. 1007, 115.
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`Specifically, according to Teagarden, the tert-butanol [TBA]/water
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`combination “possesses a high Vapor pressure, freezes completely in most
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`commercial freeze-dryers, readily sublimes during primary drying, can
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`increase sublimation rates, and has low toxicity.” Id. In contrast, other co-
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`6
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`solvent systems do not freeze completely in commercial freeze-dryers, are
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`more difficult to use, and often result in unacceptable freeze-dried cakes. Id.
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`In addition, Teagarden teaches that the TBA/water co-solvent system
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`“significantly reduced” the degradation rate of certain water unstable drugs.
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`Ex.1007,117-18.
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`Nuij en teaches formulating 500 mg/mL solution of aplidine in 40%
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`(V/V) TBA containing 25 mg/mL D-mannitol. EX. 1008, 193. Aplidine is an
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`antitumor agent. Id. Nuij en’s data show that aplidine lyophilized from this
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`formulation is stable for at least 1 year when stored at 2-8°C in the dark. Id.
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`Gust teaches the synthesis, isolation, and characterization of
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`bendamustine and its derivatives. Ex. 1009, 291-99. According to Gust,
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`bendamustine is synthesized by cleaving dichloroester5 with HCl, whereas
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`dichloroester can be formed by esterification of bendamustine in ethanolic
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`HCl. Id. at 292-93. Gust also teaches that dichloroester is present in crude
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`bendamustine samples. Id. at 298.
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`35 U.S.C.
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`325 d
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`Patent Owner asks us to deny the Petition under 35 U.S.C. § 325(d).
`
`Prelim. Resp. 21-24. According to Patent Owner, during prosecution of the
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`’190 patent, the examiner allowed the challenged claims despite having
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`knowledge of prior art with essentially the same teachings as those in the
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`references asserted here. Id. at 21-23.
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`5 According to Dr. Suryanarayanan, dichloroester in Gust is the same as
`bendamustine ethylester in the ’190 patent. Ex. 1002 11 54.
`7
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`The statute allows, but does not require, the Director to deny a petition
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`if “the same or substantially the same prior art or arguments previously were
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`presented to the Office.” 35 U.S.C. § 325(d). Here, even if we were to
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`agree with Patent Owner that the prior art before the examiner and those
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`asserted in the Petition might be considered “substantially the same prior
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`art” under § 325 (d), we decline to exercise our discretion to deny the
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`Petition on this basis in this case.
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`Obviousness over the Rote Liste and Teagarden
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`Petitioner asserts that claims 1-9 would have been obvious over the
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`Rote Liste and Teagarden. Pet. 21-34. Based on the current record, we
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`determine that Petitioner has shown a reasonable likelihood that it would
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`prevail in this assertion with regard to claims 1, 4, and 7, but not claims 2, 3,
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`5, 6, 8, and 9.
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`Claim 1
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`Citing the Declaration of Dr. Suryanarayanan, Petitioner argues that
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`one of ordinary skill in the art would have understood bendamustine HCl in
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`the Rote Liste as resulting from the lyophilization of a liquid solution. Pet.
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`22 (citing Ex. 1002 11 69). Petitioner refers to the prosecution history of the
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`’190 patent, in which the applicants stated that “[p]rior to the [’ 190 patent]
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`invention, bendamustine was historically lyophilized from a solution of
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`ethanol, water, mannitol, and bendamustine.” Id. (citing Ex. 1005, 367). At
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`the time of the ’ 190 patent invention, Petitioner asserts, it was known that
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`bendamustine, a nitrogen mustard compound, is highly reactive and unstable
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`in aqueous solutions. Id. (citing Ex. 1009, 292, Ex. 1010,6 4). Petitioner
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`contends that Teagarden teaches using TBA to improve the stability of
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`unstable drugs in solution.
`
`Id. at 23 (citing Ex. 1007, 117). Thus, according
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`to Petitioner, a skilled artisan, concerned with the instability of
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`bendamustine, would have looked to Teagarden to address the problem. Id.
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`at 24.
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`Petitioner also points to Teagarden for describing using TBA/water in
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`five drug formulations. Id. (citing Ex. 1007, 117-18). According to
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`Petitioner, the TBA/water co-solvent system improves the stability of those
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`water unstable drugs. Id. at 25 (citing Ex. 1007, 117 (reporting that the first-
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`order degradation rate of alprostadil in 20% v/v TBA/water “was
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`significantly reduced”), 118 (reporting that using TBA slowed solution state
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`degradation of trecetilide fumarate “by a factor of approximately 4—5”)).
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`Thus, Petitioner argues, one of ordinary skill in the art would have had a
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`reasonable expectation of success in arriving at the composition of claim 1
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`based on the combined teachings of the Rote Liste and Teagarden. Id. at 24.
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`Patent Owner contends that Petitioner combines the Rote Liste and
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`Teagarden through hindsight reasoning. Prelim. Resp. 24. According to
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`Patent Owner, even though bendamustine compositions, such as
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`Ribomustin®, had been marketed in Germany for more than forty years,
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`only the inventors of the ’ 190 patent set out to create a lyophilized
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`formulation that is easier to reconstitute and has a better impurity profile. Id.
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`6 Maas et al., Stability ofBendamustine Hydrochloride in Infusion Solutions,
`49 PHARMAZIE 775-77 (1994) (Ex. 1010, “Maas”).
`9
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`at 24. Patent Owner asserts that none of the references cited in the Petition
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`“identified any problem with [the then] existing bendamustine/mannitol
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`compositions.” Id. at 25. And even if any problems associated with
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`bendamustine had been identified, Patent Owner further argues, the possible
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`approaches to solving those problems “were not known or finite,” Petitioner
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`does not present any evidence to show that TBA would have solved those
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`problems, and the TBA solution was not predictable. Id. at 26-29. We
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`disagree.
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`Patent Owner’s arguments are based on the premise that at the time of
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`the invention, only the inventors of the ’ 190 patent identified a need for
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`lyophilized formulations of bendamustine that would be “easier to
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`reconstitute” and would have “a better impurity profile” than the then-
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`available lyophilized powder of bendamustine. Id. at 10, 24 (both citing EX.
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`1001, 2:29-32). The law, however, “does not require that the references be
`
`combined for the reasons contemplated by the inventor.” In re Beattie, 974
`
`F.2d 1309, 1312 (Fed. Cir. 1992). Indeed,
`
`[T]he problem motivating the patentee may be only one of
`many addressed by the patent’s subject matter. The question is
`not whether the combination was obvious to the patentee but
`whether the combination was obvious to a person with ordinary
`skill in the art. Under the correct analysis, any need or problem
`known in the field of endeavor at the time of invention and
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`addressed by the patent can provide a reason for combining the
`elements in the manner claimed.
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`KSR Int’! CO. V. Teleflex Inc, 550 U.S. 398, 420 (2007).
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`Such is the case here. Petitioner contends that a skilled artisan “would
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`have been aware as a matter of basic knowledge that bendamustine is a
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`nitrogen mustard compound and thus highly reactive and unstable in
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`aqueous solutions.” Pet. 22. Petitioner’s argument is supported by evidence
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`before us at this time. For example, Maas teaches that bendamustine “is
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`very unstable in an aqueous solution.” Ex. 1010, 4. It explained that “[d]ue
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`to the rapidly progressing hydrolysis of aqueous bendamustine
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`hydrochloride solutions, only freshly made up solutions .
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`.
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`. must be injected
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`immediately after their preparation.” Id. at 5. Maas determined the stability
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`(tgo) of Ribomustin® in aqueous NaCl solution (0.25 mg/ml, 0.9% NaCl
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`solution) is 120 hours at 4°C and 9 hours at 23°C. Id. at 5. In another
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`example, Gust recognized that “bendamustin[e] hydrolyzes in water similar
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`to other N-lost compounds.” Ex. 1009, 292. Gust also cited the stability
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`data reported in Maas. Id. Thus, we are persuaded that, at the time of the
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`’190 patent invention, one of ordinary skill in the art would have been
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`motivated to improve the stability of Ribomustin®, the bendamustine drug
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`on the market.
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`As Petitioner points out, Teagarden identifies using TBA in pre-
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`lyophilization formulation for unstable drugs. Pet. 5-6 (citing Ex. 1002
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`1111 45-46), id. at 25 (citing Ex. 1007, 117, 118). Teagarden explains:
`
`A major challenge in developing a sterile injectable product
`can be its instability in solution. Most freeze-dried products are
`developed as this dosage form in order to circumvent poor
`stability.
`The manufacture of
`a
`freeze-dried product
`necessitates that the product is usually first manufactured as a
`solution,
`filtered to sterilize, aseptically filled, and finally
`lyophilized to remove the solvents.
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`Ex. 1007, 117. According to Teagarden, the organic solvents used in the
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`pre-lyophilization solution “can have a profound effect on the chemical
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`stability.” Pet. 25 (citing EX. 1007, 117).
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`Specifically, Teagarden describes that freeze-drying unstable drugs
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`from a TBA/water solution “significantly reduced” the degradation rate,
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`sometimes “by a factor of approximately 4-5.” Id. (citing Ex. 1007, 117,
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`118). Teagarden comments that the decreased degradation rate enables
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`manufacturing at ambient conditions without requiring cooling of the
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`solution, allows formulation and filling on a production scale over a 24-hour
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`period, and provides longer shelf-life of the lyophilized product at ambient
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`temperature. Ex. 1009 11 45 (citing Ex. 1007, 117, 118). Teagarden predicts
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`that “[t]his type of effect would be expected to be observed for many other
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`drug products which are degraded in the presence of water.” Id. 11 46 (citing
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`Ex. 1007, 117).
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`Based on the current record, we are persuaded that an ordinary artisan,
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`motivated to improve the stability of Ribomustin®, would have looked to
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`Teagarden’s teaching of the benefits of TBA. In addition, as noted by
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`Petitioner, during prosecution of the ’ 190 patent, the applicants stated that
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`Ribomustin® was “historically lyophilized from a solution of ethanol, water,
`
`mannitol, and bendamustine.” Pet. 26 (citing Ex. 1005, 367). Thus,
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`Petitioner argues, based on the teachings of Teagarden, it would have been
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`obvious to substitute ethanol with TBA. Id. Patent Owner now disputes its
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`own statement that Ribomustin® was lyophilized from an ethanol solution
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`as “lacking support.” Prelim. Resp. 19. We are not persuaded based on the
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`record before us.
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`During prosecution, the applicants argued to the examiner that
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`lyophilizing bendamustine from a TBA solution as claimed would avoid the
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`formation of bendamustine ethyl ester, a degradation product formed when
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`bendamustine was lyophilized from an ethanol solution. Ex. 1005, 367.
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`Based on such representation, the examiner allowed the challenged claims
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`despite concluding that the prior art suggested “using a combination of
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`mannitol and tertiary-butyl alcohol with bendamustine to produce a
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`formulation to be lyophilized.” Id. at 593. The examiner reasoned that the
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`applicants “unexpectedly” found that using TBA led to “no more than 0.5%
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`formation of bendamustine ethyl ester.” Id. Patent Owner may not, after
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`obtaining the challenged patent based on that assertion, take an inconsistent
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`position without presenting persuasive evidence. See New Hampshire v.
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`Maine, 532 U.S. 742, 749 (2001) (explaining that “absent any good
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`explanation, a party should not be allowed to gain an advantage by litigation
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`on one theory, and then seek an inconsistent advantage by pursuing an
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`incompatible theory”).
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`Based on the current record, we find Patent Owner’s other arguments
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`similarly unpersuasive. For example, Patent Owner contends that Teagarden
`
`teaches several co-solvent systems and Petitioner does not show why a
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`skilled artisan would have chosen TBA. Prelim. Resp. 27. In fact, even
`
`though Teagarden lists the properties of other solvents, it discusses TBA in
`
`detail, gives specific examples of formulations using TBA, and identifies
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`TBA as advantageous over other solvents. Ex. 1007, in passim. Patent
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`Owner also argues that “the possible approaches to solving the
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`bendamustine problem were not known or finite.” Prelim. Resp. 27. This
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`attorney argument, unsupported by sufficient evidence, is not entitled to
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`much weight.
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`Patent Owner further asserts that the co-solvent systems “can cause a
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`multitude of problems” and thus, using TBA in the pre-lyophilization
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`formulation is unpredictable. Id. at 27-30. Specifically, according to Patent
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`Owner, Teagarden warns that lyophilizing a TBA-containing formulation
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`may cause dried powder near the neck of a vial, which “is not desired
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`because of both a poor appearance and the possibility of negatively
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`impacting the seal with the rubber closure.” Id. at 29 (citing Ex. 1007, 119).
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`In addition, when using TBA, “both formulation and process control
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`required optimization to maximize drying rates and to minimize residual
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`solvent levels at the end of drying.” Id. (citing Ex. 1007, Abstract, emphasis
`
`added by Patent Owner). These “multitude of problems,” Patent Owner
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`argues, “would discourage any formulator from using TBA because of the
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`unpredictability of the results.” Id. We are not persuaded.
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`First, the appearance and the seal with the rubber closure are not a part
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`of any challenged claims. Nor do we consider them, based on the current
`
`record, to lead to unpredictability in the obviousness analysis. Second,
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`obviousness does not require absolute predictability of success. In re
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`0 ’FarreZZ, 853 F.2d 894, 903 (Fed. Cir. 1988). Instead, for obviousness, all
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`that is required is a reasonable expectation of success. Id. at 904. We are
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`persuaded that the combination of the Rote Liste and Teagarden teaches all
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`the limitations required in claim 1, i.e., bendamustine HCl, mannitol, TBA,
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`and water. Optimization of the formulation flows from the “normal desire of
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`scientists or artisans to improve upon what is already generally known.” In
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`re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003). Patent Owner points to
`
`no persuasive evidence indicating that the optimization was anything other
`
`than the exercise of ordinary skill in the art.
`
`Patent Owner also contends that objective indicia demonstrate the
`
`claimed invention would not have been obvious. Prelim. Resp. 34-37. We
`
`are not persuaded based on the current record.
`
`For objective evidence of secondary considerations to be accorded
`
`substantial weight, Patent Owner must establish a nexus between the
`
`evidence and the merits of the claimed invention. Wyers v. Master Lock C0. ,
`
`616 F.3d 1231, 1246 (Fed. Cir. 2010). Patent Owner emphasizes that the
`
`inventive aspect of the challenged claims lies in using TBA in the pre-
`
`lyophilization formulation. Prelim. Resp. 11-13. TREANDA®, which
`
`Patent Owner alleges as using the formulation of the ’190 patent (Prelim.
`
`Resp. 14), however, does not include TBA. See Ex. 2001, 5 (showing
`
`bendamustine HCl, Propylene Glycol, USP, and N,N-Dimethylacetamide,
`
`EP as ingredients in TREANDA® Injection, and bendamustine HCl and
`
`mannitol as ingredients in TREANDA® for Injection). As a result, Patent
`
`Owner has not established sufficiently a nexus between the addition of TBA,
`
`and the regulatory approval, the alleged acclaim and copying by others, as
`
`well as the asserted commercial success, of TREANDA®.
`
`Patent Owner argues that “adding TBA to the bendamustine/mannitol
`
`composition produced a variety of unexpected and desirable results,” such as
`
`improved bendamustine stability and fewer impurities. Prelim. Resp. 37.
`
`Patent Owner cites the ’ 190 patent as support. Id. (citing Ex. 1001, 30:9-22,
`
`Figs. 2-4). We are not persuaded.
`
`15
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`FRESENIUS KABI 1012-0015
`
`
`
`IPR2015-00503
`
`Patent 8,436,190 B2
`
`In the ’190 patent, the passage Patent Owner relies on discloses that
`
`“the effect of alcohols on bendamustine stability is unique, unexpected and
`
`useful in manufacturing bendamustine with fewer impurities since an
`
`aqueous solution can be used while maintaining the stability of
`
`bendamustine.” Ex. 1001, 30: 10-14 (emphasis added). In other words, the
`
`unexpected results Patent Owner underlines do not appear to be unique to
`
`TBA. See id. at 30: 15-16 (“All alcohols at 30% (v/v) reduced the formation
`
`of impurities HP1 and Dimer at 5° C. for up to 24 hours”) (emphasis
`
`added). The ’ 190 patent does state that “TBA was found to be the best
`
`stabilizer” of the six alcohols tested. Id. at 30: 14-15. Teagarden, however,
`
`specifically identifies improved stability of both pre-lyophilization solutions
`
`and lyophilized products as the advantages of using TBA over other
`
`solvents. Ex. 1007, 117-18, 123. Therefore, based on the current record,
`
`Patent Owner’s objective indicia do not persuade us not to institute a trial.
`
`In sum, based on the current record, we conclude Petitioner has
`
`established a reasonable likelihood it would prevail in showing that claim 1
`
`would have been obvious over the Rote Liste and Teagarden,
`
`Claims 2 and 3
`
`Claim 2 depends from claim 1 and recites concentration ranges of
`
`bendamustine/bendamustine HCl (12 to 17 mg/ml), mannitol (20-30 mg/ml)
`
`and TBA (10-50% (v/v)). Claim 3 depends from claim 2 and recites
`
`specific concentrations of bendamustine/bendamustine HCl (15 mg/ml),
`
`mannitol (25.5 mg/ml), and TBA (30% (v/v)).
`
`16
`
`FRESENIUS KABI 1012-0016
`
`
`
`IPR20l5-00503
`
`Patent 8,436,190 B2
`
`Citing the Declaration of Dr. Suryanarayanan, Petitioner argues that
`
`“[i]t would have been obvious to one of ordinary skill in the art that the
`
`amounts disclosed in the Rote Liste of bendamustine HCl and mannitol can
`
`readily be achieved by pre-lyophilization concentrations that fall within the
`
`ranges recited in claim 2.” Pet. 27 (citing Ex. 1002 1] 75) (emphasis added).
`
`Petitioner also asserts that it would have been “obvious to modify the
`
`amounts of bendamustine hydrochloride and mannitol disclosed in the Rote
`
`Liste to arrive at the concentrations recited in claim 3 as a matter of routine
`
`product optimization.” Id. at 27-28.
`
`We disagree with Petitioner’s reasoning, as it is based on a hindsight
`
`approach. Petitioner does not either identify disclosure in the prior art or
`
`explain the general knowledge of a skilled artisan that would have suggested
`
`the concentrations of the pre-lyophilized ingredients recited in claim 2.
`
`Instead, Dr. Suryanarayanan states:
`
`For example, a bendamustine hydrochloride concentration of
`about 16.7 mg/ml and a mannitol concentration of 20.0 mg/ml,
`which both fall in the range of concentrations recited in claim 2,
`could be used in a pre-lyophilization volume of 1.5 ml.
`Lyophilization of this volume would result in dry amounts of
`about 25 mg of bendamustine hydrochloride and 30 mg of
`mannitol, as recited in the Rote Liste.
`
`Ex. 1002 1] 75 (emphasis added). Dr. Suryanarayanan, however, does not
`
`explain, without the knowledge of the recited concentrations, why a skilled
`
`artisan would have picked a pre-lyophilization volume of 1.5 ml.
`
`Indeed, one of ordinary skill in the art could have used 1 ml (with
`
`25 mg/ml bendamustine HCl and 30 mg/ml mannitol), 2 ml (with
`
`12.5 mg/ml bendamustine HCl and 15 mg/ml mannitol), or 3 ml (with
`
`17
`
`FRESENIUS KABI 1012-0017
`
`
`
`IPR2015-00503
`
`Patent 8,436,190 B2
`
`8.33 mg/ml bendamustine HCl and I 0 mg/ml mannitol) pre-lyophilization
`
`solution. Lyophilization of each solution would result in dry compositions
`
`in the amounts recited in the Rote Liste. But in all of those solutions, either
`
`or both of bendamustine HCl and mannitol concentrations would fall outside
`
`the recited ranges. Petitioner does not explain adequately why an ordinary
`
`artisan would have selected a composition with bendamustine HCl and
`
`mannitol in concentrations within the recited ranges. We, thus, conclude
`
`Petitioner has not established a reasonable likelihood it would prevail in
`
`showing that claims 2 and 3 would have been obvious over the Rote Liste
`
`and Teagarden.
`
`Claim 4
`
`Claim 4 recites “[a] lyophilized pharmaceutical composition made
`
`from the pharmaceutical composition according to claim 1.”
`
`Claim 4, a product-by-process claim, is directed to the freeze-dried
`
`powder comprising bendamustine HCl and mannitol. See Ex. 2001, 5
`
`(showing TREANDA for injection is supplied as lyophilized powder of
`
`bendamustine HCl and mannitol), see also Prelim. Resp. 14 (asserting that
`
`TREANDA uses the formulation of the ’ 190 patent). In determining the
`
`patentability of the product-by-process claim here, we focus on the product
`
`and not the process of making it. See Amgen Inc. v. F. Hoflman—La Roche
`
`Ltd, 580 F.3d 1340, 1369 (Fed. Cir. 2009). “If the product in a product-by-
`
`process claim is the same as or obvious from a product of the prior art, the
`
`claim is unpatentable even though the prior product was made by a different
`
`process.” In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985).
`
`18
`
`FRESENIUS KABI 1012-0018
`
`
`
`IPR2015-00503
`
`Patent 8,436,190 B2
`
`The Rote Liste discloses a dry substance comprising bendamustine
`
`HCl and mannitol, Ex. 1006, 8. Petitioner contends that the composition
`
`disclosed in the Rote Li ste was produced from lyophilizin g a liquid solution.
`
`Id. at 28 (citing Ex. 1005, 367). Petitioner also asserts that Teagarden
`
`teaches using TBA in formulations intended for lyophilization. Id.
`
`According to Petitioner, it would have been obvious to one of ordinary skill
`
`in the art, “having already combined the teachings of the Rote Liste and
`
`Teagarden to arrive at the composition of claim 1 .
`
`.
`
`. to lyophilize the
`
`composition using standard freeze-drying techniques that were known in the
`
`art .
`
`.
`
`. thereby arrive at the lyophilized pharmaceutical composition of claim
`
`4.” Pet. 28-29 (internal citations omitted).
`
`Based on the current record, we find Petitioner’s arguments
`
`persuasive. Thus, we conclude Petitioner has established a reasonable
`
`likelihood it would prevail in showing that claim 4 would have been obvious
`
`over the Rote Liste and Teagarden.
`
`Claims5 6 8 and9
`
`Claim 5 depends from claim 4 and further recites the concentration
`
`ranges of bendamustine HCl, mannitol, and TBA. Claim 6 depends from
`
`claim 5 and recites specific concentrations of bendamustine HCl, mannitol,
`
`and TBA. Claims 8 and 9 depend from claims 5 and 6, respectively, and
`
`further require the lyophilized pharmaceutical composition to “contain[] not
`
`more than about 0.5% bendamustine ethylester.”
`
`Petitioner’s argument regarding the obviousness of claims 5 and 6
`
`over the combination of the Rote Liste and Teagarden, in its entirety, reads:
`
`19
`
`FRESENIUS KABI 1012-0019
`
`
`
`IPR2015-00503
`
`Patent 8,436,190 B2
`
`The ranges and concentrations recited in claims 5 and 6 are
`identical to those recited in claims 2 and 3, and would have
`been obvious to a person of ordinary skill in the art prior to
`January 14, 2005 for the reasons explained above with respect
`to claims 2 and 3.
`
`Pet. 29. As explained above, Petitioner has not established a reasonable
`
`likelihood it would prevail in showing that claims 2 and 3 would have been
`
`obvious over the Rote Liste and Teagarden. Thus, we similarly conclude
`
`Petitioner has not established a reasonable likelihood it would prevail in
`
`showing that claims 5 and 6, as well as their dependent claims, claims 8 and
`
`9, would have been obvious over the Rote Liste and Teagarden.
`
`Claim 7
`
`Claim 7 depends from claim 4 and further requires the lyophilized
`
`pharmaceutical composition to “contain[] not more than about 0.5%
`
`bendamustine ethylester.” Referring to Table 13 of the ’l90 patent,
`
`Petitioner argues that even though Ribomustin® was lyophilized from an
`
`ethanol solution, it “contained less than 0.5% bendamustine ethylester.” Id.
`
`Thus, according to Petitioner, it would have been obvious to a skilled artisan
`
`that substituting ethanol with TBA in the pre-lyophilization solution would
`
`not lead to the formation of additional bendamustine ethylester, because, as
`
`acknowledged by Patent Owner, bendamustine ethylester is formed only by
`
`reaction of bendamustine with ethanol. Id. at 30-31. Based on the current
`
`record, we find Petitioner’s argument persuasive. Thus, we conclude
`
`Petitioner has established a reasonable likelihood it would prevail in
`
`20
`
`FRESENIUS KABI 1012-0020
`
`
`
`IPR2015-00503
`
`Patent 8,436,190 B2
`
`showing that claim 7 would have been obvious over the Rote Liste and
`
`Teagarden,
`
`Obviousness over the Rote Liste, Teagarden, and Nuijen
`
`Petitioner asserts that claims 1-9 would have been obvious over the
`
`Rote Liste, Teagarden, and Nuijen. Pet. 34-48. For purposes of this
`
`Decision, we assume, without deciding, that one of ordinary skill in the art
`
`would have had a reason to combine the teachings of the Rote Liste,
`
`Teagarden, and Nuij en.
`
`As explain
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