Case No. IPR2015-00503
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AGILA SPECIALTIES INC. and MYLAN LABORATORIES LIMITED,
`
`Petitioners
`
`CEPHALON, INC.
`
`Patent Owner
`
`Case No. IPR2015-00503
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`Patent No. 8,436,190
`
`CEPHALON, INC.’S PRELIMINARY PATENT OWNER RESPONSE
`
`FRESENIUS KABI 1028-OOO1
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AGILA SPECIALTIES INC. and MYLAN LABORATORIES LIMITED,
`
`Petitioners
`
`CEPHALON, INC.
`
`Patent Owner
`
`Case No. IPR2015-00503
`
`Patent No. 8,436,190
`
`CEPHALON, INC.’S PRELIMINARY PATENT OWNER RESPONSE
`
`FRESENIUS KABI 1028-OOO1
`
`
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`TABLE OF CONTENTS
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`has
`
`1"
`
`INTRODUCTION ............................................................................. . .3
`
`THE ‘190 PATENT ........................................................................... ..8
`
`Cephalon’s Invention and Patent....................................................... .. 11
`
`P5
`
`Regulatory Approval and Market Response ..................................... .. 14
`
`III.
`
`AGILA’S PETITION ...................................................................... ..l7
`
`Alleged Grounds of Unpatentability ................................................. .. l7
`
`P5
`
`Claim Construction............................................................................ .. 18
`
`Statement of Material Facts ............................................................... ..l9
`
`IV.
`
`ARGUMENT ................................................................................... ..l9
`
`Grounds l-3: Agila Fails to Show a Reasonable Likelihood of Proving
`
`Obviousness ....................................................................................... ..2l
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`References Describing RIBOMUSTIN® and TBA Were Before the
`
`Examiner, Who Did Not Reject the Claims In View of Them ......... ..2l
`
`The Combination of the Rote Liste and Teagarden Is Only Arrived at
`
`Through Hindsight Reasoning .......................................................... ..24
`
`Nuijen and Gust are Inapposite ......................................................... ..30
`
`Unexpected Results and Objective Indicia Show The ‘ 190 Patent’s
`
`Inventiveness ..................................................................................... . .34
`
`Ground 4: The Rote Liste Does Not Anticipate Claims 4, 5, 7, and 8
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`........................................................................................................... .38
`
`.<
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`AGILA’S PETITION VIOLATES THE BOARD’S RULES ..... ..4l
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`CONCLUSION ................................................................................ . .42
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`FRESENIUS KABI 1028-0002
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`Case No. IPR2015-00503
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`Cepha10n’s Preliminary Response
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`TABLE OF AUTHORITIES
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`Page(s)
`
`Cases
`
`Crocs, Inc. v. Int ’l Trade Comm ’n,
`
`598 F.3d 1294 (Fed. Cir. 2010) ........................................................................ ..34
`
`Diversitech Corp. v. Century Steps, Inc.,
`850 F.2d 675 (Fed. Cir. 1988) .......................................................................... ..37
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) ....................................................................... ..35
`
`In re Fritch,
`972 F.2d 1260 (Fed. Cir. 1992) .......................................................................... ..6
`
`In re McLaughlin,
`443 F.2d 1392 (C.C.P.A. 1971) ........................................................................ .35
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ........................................................................................ ..20, 30
`
`Illumina, Inc. v. Tr. ofColumbia Univ.,
`IPR2012-00006, 2013 WL 5653110 (Patent Tr. & App. Bd. 2013) ................ ..41
`
`Interconnect Planning Corp. v. Feil,
`774 F.2d 1132 (Fed. Cir. 1985) ........................................................................ .30
`
`Knoll Pharm. Co., Inc. v. Teva. Pharm. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) ........................................................................ ..35
`
`Leo Pharm. Proa’s., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................................ .34
`
`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co.,
`CBM2012-00003, 2012 WL 9494791 (Patent Tr. & App. Bd.
`2012) ................................................................................................................. ..41
`
`Merck & Co., Inc. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ........................................................................ .36
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`FRESENIUS KABI 1028-0003
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`Case No. IPR2015-00503
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`Cepha10n’s Preliminary Response
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`Norian Corp. v. Stryker Corp.,
`432 F.3d 1356 (Fed. Cir. 2005) ........................................................................ ..39
`
`Omron Oilfield & Marine, Inc. v. MD/Totco,
`IPR2013-00265, 2013 WL 8595961 (Patent Tr. & App. Bd. 2013) .......... ..34, 35
`
`OrtlzmI\/IcNeil Plzarm, Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................................ .34
`
`San0fi—Syntlzelab0 v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .................................................................. ..36, 38
`
`Syntex (U.S./1.) LLC v. Apotex Inc.,
`2006 WL 1530101 (N.D. Cal. June 2, 2006) .................................................... .36
`
`Takeda Chem. Indus. Ltd. v. Alplzaplzarm Pl)/., Ltd,
`492 F.3d 1350 (Fed. Cir. 2007) ....................................................................... ..33
`
`WL. Gore & Ass0cs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... ..6
`
`WM. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ........................................................................ .38
`
`Statutes and Regulations
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`35 U.S.C. § 103 .......................................................................................... ..17, 18, 20
`
`35 U.S.C. §314(a) ................................................................................................. ..19
`
`35 U.S.C. §325(d) ............................................................................................. ..4, 21
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`37 C.F.R. §42.108(b) ............................................................................................ ..20
`
`ii
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`FRESENIUS KABI 1028-0004
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`I.
`
`INTRODUCTION
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`Patent Owner Cephalon Inc.’s (“Cephalon’s”) U.S. Patent No. 8,436,190
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`(“the ‘190 Patent”) claims a new bendamustine composition used to treat cancers
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`such as non-Hodgkin lymphoma (“NHL”) and chronic lymphocytic leukemia
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`(“CLL”). Doctors and patients have hailed Cephalon’s invention as a leap forward
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`over prior chemotherapy drugs, and Cephalon’s TREANDA® product for injection
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`has been a huge commercial
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`success.
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`Agila Specialties Inc. and Mylan
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`Laboratories Limited (referred to collectively as “Agila”) nonetheless petition to
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`invalidate Cephalon’s patent in view of nothing more than a rehashing of prior art
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`teachings that were before the Examiner during prosecution of the claims at issue.
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`But Agila fails to demonstrate there is a reasonable likelihood it will prevail
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`regarding at least one of the claims it challenges in the petition, for at least the
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`following reasons:
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`First, Agila’s primary reference — the “Rote Liste” — is a German drug index
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`that merely discloses a dry substance containing bendamustine hydrochloride and
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`mannitol, marketed as RIBOMUSTIN®.
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`(EX. 1006.)
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`Independent claim 1 of the
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`‘190 Patent, however, recites a composition of bendamustine or bendamustine
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`hydrochloride, mannitol,
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`tertiary-butyl alcohol
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`(“TBA”) and water.
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`The
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`remaining claims that Agila challenges all depend from claim 1. During
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`prosecution of the ‘ 190 Patent, RIBOMUSTIN® was discussed at length, not only
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`FRESENIUS KABI 1028-0005
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`in the ‘l90 Patent specification but also in several references considered by the
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`Examiner. See, e. g., EX. 1001, 1:50-65 (“[t]he current lyophilized formulation of
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`bendamustine (Ribomustin®) contains bendamustine hydrochloride and mannitol
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`in a sterile lyophilized form as a white powder for intravenous use following
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`reconstitution”); see also 2:44-48.
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`Despite these detailed disclosures,
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`the
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`Examiner did not find that RIBOMUSTIN® defeated the patentability of the
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`claims, alone or in combination with any other references disclosed during
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`prosecution, including the teachings of Teagarden.
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`Id. at 2:60-62 (“Teagarden et
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`al. disclose[s] lyophilized formulations of prostaglandin E-l made by dissolving
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`PGE-l
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`in a solution of lactose and tertiary butyl alcohol
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`(U.S. Patent No.
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`5,770,230).”)1 This is reason enough to reject Agila’s petition. 35 U.S.C. § 325(d)
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`(allowing the Board to reject a petition where the “same or substantially the same
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`prior art... previously w[as] presented to the Office”) But if the Board is inclined
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`to review the art anew, the only possible conclusion is that the Rote Liste (alone or
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`1 In its Petition, Agila relies upon a Teagarden review article titled “Practical
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`Aspects of Lyophilization Using Non-Aqueous Co-Solvent Systems,” Eur. J.
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`Pharmaceut. Sci. (EX. 2007). The Teagarden patent disclosed and described in the
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`‘l90 Patent’s specification contains essentially the same teachings concerning
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`TBA as the article relied upon by Agila.
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`FRESENIUS KABI 1028-0006
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`in combination) neither anticipates nor renders obvious the challenged claims of
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`the ‘ 190 Patent.
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`Agila readily admits that a combination of bendamustine, mannitol, TBA,
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`and water is not disclosed in the Rote Liste.
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`(Petition at 8.) Agila nonetheless
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`erroneously argues that the Rote Liste anticipates dependent claims 4, 5, 7 , and 8
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`(Ground 4) through a tortured claim construction that
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`ignores the fact
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`these
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`dependent claims explicitly recite pharmaceutical compositions made from the
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`composition of claim 1. That claim 1 requires a composition having TBA and
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`water cannot be disregarded. The Rote Liste thus cannot anticipate the claims and
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`Agila’s Ground 4 must be rejected.
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`Agila’s one and only articulated motivation to combine the Rote Liste with
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`Teagarden (Ground 1) plus the Nuijen and Gust references (Grounds 2 and 3) is
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`“to gain the many benefits of using TBA” for “a water unstable drug, such as
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`bendamustine.” (Petition at 24.) But this “problem” was first identified (and then
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`solved) by the inventors of the
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`‘190 Patent.
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`Agila acknowledges that
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`bendamustine compositions like RIBOMUSTIN® were marketed in Germany for
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`more than forty years.
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`(EX. 1001 at 1:50-57.) Yet not one of the many references
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`cited by Agila in its Petition identifies any deficiency in bendamustine products
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`over the decades or even the alleged “motivation” that Agila claims would have
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`prompted the combination. Unable to rely on objective evidence, Agila’s petition
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`FRESENIUS KABI 1028-OOO7
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`resorts to imbuing one of ordinary skill in the art with knowledge of the ‘190
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`Patent, when no prior art reference of record conveys or suggests that knowledge.
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`This is nothing more than “the insidious effect of a hindsight syndrome wherein
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`that which only the inventor taught is used against its teacher.” WL. Gore &
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`Ass0cs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983). The claimed
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`invention of the ‘ 190 Patent cannot be used as an instruction manual or template to
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`piece together the teachings of the prior art so that the claimed invention is
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`rendered obvious. In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992).
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`Second, Agila’s references would not have predictably led one of ordinary
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`skill in the art to a bendamustine/mannitol/TBA/water composition.
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`Insofar as
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`TBA was known, it was merely one of an almost limitless number of co-solvent
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`combinations, and thus not the predictable choice. As for Teagarden, it discusses
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`numerous organic solvents in the context of the lyophilization of five drugs,
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`including prostaglandin E1. Agila’s petition utterly fails to address the significant
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`structural and physico-chemical differences between these drugs and bendamustine
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`or the impact of these differences on drug stability or reconstitution time.
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`It thus
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`fails to demonstrate that the suggested modification of RlBOMUSTIN® would
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`predictably produce the claimed invention.
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`In fact, Teagarden repeatedly emphasizes the unpredictable nature of
`
`formulation development. EX. 1007 at 115-116 (“The development scientist must
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`FRESENIUS KABI 1028-0008
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`be aware that use of these organic/water co-solvent systems can cause a multitude
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`of problems...,’’ (emphasis added)), 131 (“The practicalities of use of these co-
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`solvent systems must be properly assessed before they should be considered for
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`use.
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`This especially applies when using them in the manufacturing” of a
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`phannaceutical injectable product, (emphasis added)).
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`For all of these reasons and those detailed below, Ground 1 must be rejected.
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`Neither Nuijen nor Gust — both inapposite here — remedy the deficiencies of the
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`Rote Liste in View of Teagarden. Accordingly, Grounds 2 and 3 must be rejected
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`as well.
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`Third, the objective indicia demonstrate the ‘l90 Patent’s inventiveness.
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`The patent specification shows the unexpected results of exceptional stability, ease
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`of manufacturing, and ease of reconstitution.
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`Furthermore, doctors, patients,
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`regulators, and cancer advocacy groups have all praised TREANDA® as a
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`significantly improved cancer treatment. TREANDA® has accordingly been a
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`major success, with sales routinely beating market expectations. Additionally,
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`many competitors such as Agila and Mylan are copying the invention. The ‘I90
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`Patent cannot be deemed obvious in these circumstances—if it were, then others
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`surely would have brought an improved bendamustine/mannitol/TBA/water
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`composition drug to market decades sooner than Cephalon.
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`FRESENIUS KABI 1028-0009
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`Fourth, and finally, Agila’s Petition violates the Board’s rules concerning
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`redundant and duplicative arguments.
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`For these reasons and those set forth in detail below, Cephalon respectfully
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`requests that the Board deny Agila’s petition.
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`II.
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`THE ‘190 PATENT
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`The invention of the ‘190 Patent pertains to the field of pharmaceutical
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`compositions for the treatment of various diseases, especially neoplastic diseases
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`and autoimmune diseases.
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`(EX. 1001 at 1:6-11.) The challenged claims recite
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`pharmaceutical
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`formulations comprising nitrogen mustards, particularly the
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`nitrogen mustard bendamustine or bendamustine HCl. Bendamustine (4-{5-
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`[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid, is an atypical
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`structure with a benzimidazole ring, whose structure includes an active nitrogen
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`mustard (see Formula I, which shows bendamustine hydrochloride):
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`Fnmnula I
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`(:1/\‘
`N
`I \® ()H -IT(','l
`-// "““:N\
`
`/N
`
`O
`
`Cl
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`(Id. at 1:33-49.)
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`Bendamustine was initially synthesized in 1963 in Germany and was
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`available from 1971 to 1992 under the name CYTOSTASAN®.
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`(Id. at 1:50-52.)
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`Since that
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`time,
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`it has been marketed in Germany under the trade name
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`FRESENIUS KABI 1028-0010
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`RIBOMUSTIN®.
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`(Id. at 1:53-54.) Prior to the inventions of the ‘ 190 Patent,
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`bendamustine compositions were widely used in Germany to treat CLL, Hodgl<in’s
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`disease, NHL, multiple myeloma, and breast cancer (id. at 1:54-57), but never were
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`approved for sale or use in the United States.
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`Bendamustine
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`is
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`supplied as
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`a
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`lyophilized (freeze-dried)
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`product.
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`RIBOMUSTIN® (which the
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`specification discloses
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`contains bendamustine
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`hydrochloride and mannitol in a sterile lyophilized form as a white powder for
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`intravenous use following reconstitution) is unstable when exposed to light.
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`(Id. at
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`1:60-65.) Therefore, the product is stored in brown or amber-colored glass bottles.
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`(Id) The inventors of the ‘190 Patent discovered that the lyophilized formulation
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`of bendamustine contains degradation products or impurities that may occur during
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`manufacturing of the drug substance and/or during the lyophilization process used
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`to make the finished drug product.
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`(Id. at 1:65-2:2.)
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`The ‘190 Patent specification also teaches that bendamustine is formulated
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`as a lyophilized powder for injection with 100 mg of drug per 50 mL vial or 25 mg
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`of drug per 20 mL vial. The vials are opened and reconstituted as close to the time
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`of patient administration as possible. The product is reconstituted with 40 mL (for
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`the 100 mg presentation) or 10 mL (for the 25 mg presentation) of sterile water for
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`injection. The reconstituted product is further diluted into 500 mL, q.s., 0.9%
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`FRESENIUS KABI 1028-0011
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`Sodium Chloride for Injection. The route of administration is by intravenous
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`infusion over 30 to 60 minutes.
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`(Id. at 2:3-l2.)
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`The inventors observed that reconstitution of bendamustine lyophilized
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`powder is difficult.
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`(Id. at 2:20-21.) Reports from the clinic indicated that
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`reconstitution can require at least fifteen minutes and may require as long as thirty
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`minutes.
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`(Id. at 2:21-23.) Besides being burdensome and time-consuming for the
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`healthcare professional responsible for reconstituting the product, the inventors
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`realized that lengthy exposure of bendamustine to water during the reconstitution
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`process increased the potential for loss of potency and impurity formation due to
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`the hydrolysis of the bendamustine product by water.
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`(Id. at 23-28.)
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`The inventors thus identified “a need for lyophilized formulations of
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`bendamustine that are easier to reconstitute and which have a better impurity
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`profile
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`than the
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`current
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`lyophilate
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`(lyophilized powder)
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`formulations of
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`bendamustine.” In other words, there was a need for an improvement over the
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`RlBOMUSTIN® product described in the Rote Liste that was available at the time
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`of the invention.
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`(Id. at 2:29-32.)
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`The inventors of the ‘ 190 Patent began experimenting to determine if it was
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`possible to prepare formulations that were easier to reconstitute and that had “a
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`better impurity profile than Ribomustin®” with respect to impurities, including
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`hydroxyl-chloro (“HPl”), bendamustine dimer, and bendamustine ethylester, prior
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`10
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`FRESENIUS KABI 1028-0012
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`Case No. lPR2015-00503
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`Cephalon’s Preliminary Response
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`to reconstitution, upon storage of the lyophilate, or following reconstitution and
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`admixture.
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`(Id. at 20:24-42.)
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`The results of their experiments indicated that the stability of bendamustine
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`HCl with respect
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`to HP1
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`and dimer
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`improves with increasing alcohol
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`concentration.
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`(Id. at 24:47-49, Figs. 2-4.) The results further indicated that “the
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`effect of alcohols on bendamustine stability is unique, unexpected and useful in
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`manufacturing bendamustine with fewer impurities since an aqueous solution can
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`be used while maintaining the stability of the bendamustine.”
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`(Id. at 309-22.)
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`TBA was found to be the best stabilizer.
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`(Id. at 30: 14-15, Figs. 2-4.)
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`A.
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`Cephal0n’s Invention and Patent
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`The
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`inventors
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`further discovered that
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`since
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`the
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`concentration of
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`bendamustine is higher in a 30% TBA/water saturated solution as compared with
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`other alcohol solutions, the vial size required to fill 100 mg of bendamustine could
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`be decreased from the RIBOMUSTIN® presentation. (Id.)
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`Mannitol was selected as a bulking agent “in order to maintain a formulation
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`similar to RlBOMUSTIN®.” (Id. 30:47-61.) The inventors conducted studies to
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`evaluate the effect of mannitol on bendamustine solubility and the appearance of
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`the product.
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`They discovered that mannitol decreased the solubility of
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`bendamustine (at 15 mg/mL) in both ethanol and TBA aqueous solutions.
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`(Id.)
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`For example, solutions containing 5% and 10% ethanol and TBA without mannitol
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`ll
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`FRESENIUS KABI 1028-0013
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`Case No. lPR2015-00503
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`Cephalon’s Preliminary Response
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`did not precipitate over 24 hours. However, for samples with mannitol, precipitate
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`was observed within 24 hours. There was no precipitate with aqueous solutions
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`containing 30% (v/v) TBA, 15 mg/mL bendamustine, and 25.5 mg/mL mannitol.
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`(Id.)
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`The inventors learned that all of the alcohols they tested increased the
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`stability and solubility of bendamustine.
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`(Id. at 30:62-31:12.) However, a
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`significant mole fraction was required to affect the stability of the filling solution
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`and the ease of manufacturing. (Id.) Smaller alcohols had the undesirable effect of
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`lowering the freezing point of the bulk solution and thus requiring long
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`lyophilization cycles at lower temperatures. Higher concentrations of methanol
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`and ethanol produced unattractive cakes that were difficult to reconstitute. The
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`inventors prepared and lyophilized 10% ethanol, 20% ethanol, 10% iso-propanol,
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`20% iso-propanol, or 30% TBA aqueous solutions containing bendamustine (15
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`mg/mL), and mannitol (25.5 mg/mL). They learned that lyophilized vials filled
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`from solutions of 10% ethanol, 20% ethanol, 10% iso-propanol, 20% iso-propanol
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`produced either a collapsed cake or a film residue.
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`(Id.) Additionally,
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`reconstitution of 10% ethanol, 20% ethanol, 10% iso-propanol, 20% iso-propanol
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`lyophilized vials were difficult and did not fully dissolve until >45 n1inutes.
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`(Id.)
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`The 30% TBA solvent system produced an acceptable cake.
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`(Id. at 31:8-12.)
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`12
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`FRESENIUS KABI 1028-0014
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`Case No. lPR2015-00503
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`Cephalon’s Preliminary Response
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`The inventors theorized that the problems associated with RlBOMUSTIN®
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`reconstitution may be associated with precipitation caused by melt back (presence
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`and evaporation of a liquid) during lyophilization.
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`(Id. at 31:25-42.) The inventors
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`further identified a solution to this problem based on the use of TBA. (Id) Indeed,
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`the inventors discovered that lyophilates produced with 30% (v/v) TBA according
`
`to
`
`the
`
`invention
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`reconstituted within
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`3-10
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`n1inutes
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`as
`
`compared
`
`to
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`RIBOMUSTIN®, which may take 30-45 minutes. (ld.)
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`With an effective priority date of January 14, 2005, Cephalon filed for a
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`patent on its invention. During prosecution, the Examiner concluded that:
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`[T]he prior art teaches a formulation of bendamustine and mannitol to
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`be lyophilized. The prior art also teach[es that] a combination of
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`mannitol, tertiary-butyl alcohol, water, and an anti-neoplastic agent
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`can be lyophilized. The prior art suggests 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. However, Applicant has unexpectedly
`
`found that
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`the addition of tertiary-butyl alcohol stabilizes the
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`formulation such that bendamustine degradation is negligible (no
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`more than 0. 5% formation of bendamustine ethyl ester).
`
`(EX. 1005 at Notice of Allowability dated February 4, 2013 at 2, emphasis added.)
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`The Examiner thus allowed the ‘ 190 Patent’s claims over the art of record.
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`The PTO accordingly issued the ‘190 Patent on May 7, 2013.
`
`It has 9
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`claims—one independent claim (1), and 8 dependent claims.
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`13
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`FRESENIUS KABI 1028-0015
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`
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`The independent claim is for a “[a] pharmaceutical composition comprising
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`bendamustine or bendamustine hydrochloride, mannitol, tertiary-butyl alcohol and
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`7
`water.’ Claims 2 and 3 specify concentrations of bendamustine, mannitol, and
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`TBA. Claim 4 claims “[a] lyophilized pharmaceutical composition made from the
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`pharmaceutical composition according to claim 1.” Claims 5-6 depend from claim
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`4 and specify concentrations of bendamustine, mannitol, and TBA. Claims 7, 8
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`and 9 depend from claim 4, 5, and 6, respectively, and specify that the composition
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`contains not more than about 0.5% bendamustine ethylester.
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`(See EX. 1001, 34:19-
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`60.)
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`B.
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`Regulatory Approval and Market Response
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`The FDA approved TREANDA® in March 2008, before the PTO issued the
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`‘190 Patent.
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`As
`
`shown in the prescribing information, bendamustine is
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`TREANDA®’s active ingredient, and mannitol is an excipient.
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`(TREANDA®
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`Prescribing Information, EX. 2001.)
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`TREANDA® thus uses Cephalon’s
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`formulation under the ‘ 190 Patent.
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`The drug also won U.S. approval seven months later as a second (or later)
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`line therapy for patients with the indolent or slow-growing form of NHL. (Id) A
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`trial with more than 500 patients showed TREANDA® delayed cancer growth for
`
`55 months, compared with 35 months for those taking the standard regimen. After
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`a median observation time of 32 months, 40% of the TREANDA®-treated patients
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`14
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`FRESENIUS KABI 1028-0016
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`
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`had the disease completely disappear, compared with 31% on the older therapy.
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`TREANDA® also had fewer infections and less hair loss than the standard
`
`therapy,
`
`the research found.
`
`(“Cephalon’s Treanda Poised for 10-Fold Sales
`
`Surge,” Bloomberg, EX. 2002.)
`
`In another clinical
`
`trial
`
`related to CLL,
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`TREANDA® was compared to chlorambucil (another drug approved by the Food
`
`and Drug Administration).
`
`(Ex. 2003.) Both medications were given without any
`
`other chemotherapy agents. There were 153 patients who took TREANDA®, and
`
`148 patients who took chlorambucil. TREANDA® provided a higher overall
`
`response rate vs. chlorambucil.
`
`(Id.)
`
`In fact, 59% of patients responded to
`
`TREANDA® and 26% of patients responded to chlorambucil.
`
`(Id.) TREANDA®
`
`has also been granted orphan drug status by the FDA for the treatment of CLL and
`
`NHL.
`
`The response to TREANDA® has been extraordinary, and doctors have
`
`been impressed. “It’s basically a homerun — not only was it less toxic, but it was
`
`more efficacious,” said Richard Van Etten, director of the Tufts Medical Center
`
`Cancer Center in Boston.
`
`(EX. 2002.) “It is potentially practice-changing.” (Id.)
`
`Indeed, “CHOP2 has been the standard of care for three decades, and this is the
`
`2 “CHOP” is a short-hand for a chemotherapy drug combination consisting of
`
`cyclophosphamide, doxorubicin hydrochloride, oncovin, and prednisone.
`
`15
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`FRESENIUS KABI 1028-0017
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`
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`first
`
`truly diflerent combination,” said Vincent Picozzi, a hematologist and
`
`oncologist at the Virginia Mason Clinic in Seattle, and a scientific committee
`
`member at the American Society of Hematology.
`
`(Ia’., emphasis added.) Using
`
`TREANDA® instead of the CHOP cocktail in slow-moving NHL treatment could
`
`increase the number of U.S. patients taking TREANDA® each year to about
`
`30,000 people, according to investment bank and asset management firm Piper
`
`Jaffray.
`
`(Ia’.) Dr. Kanti Rai, Chief of Hematology Oncology at Long Island Jewish
`
`Medical Center, said: “I am very pleased to learn of the FDA’s approval of
`
`bendamustine for the treatment of relapsed/refractory indolent lymphomas. As is
`
`the case also with CLL, patients suffering from relapsed/refractory indolent
`
`lymphoma do not have many options available to them for a treatment regimen
`
`which has demonstrated efficacy following a prospectively conducted clinical
`
`study. Bendamustine is a welcomed addition to an otherwise depressingly small
`
`number of available lists.”
`
`(“FDA approves bendamustine hydrochloride for
`
`NHL,” HemOnc Today, Nov. 4, 2008, EX. 2004.)
`
`TREANDA®’s sales performance reflects the enthusiasm. TREANDA®
`
`sales in the United States passed $1 billion in 2011 and were reported to be over $3
`
`billion over the last 7 years.
`
`(“Cephalon drug Treanda passes $1B in sales,”
`
`Philadelphia Business Journal, EX. 2005, see generally Cephalon Form l0Ks and
`
`Teva Pharmaceuticals Industries Limited Fonn 20-Fs, Exs. 2006-2010.)
`
`16
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`FRESENIUS KABI 1028-0018
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`
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`III. AGILA’S PETITION
`
`Despite the plaudits and market success, Agila now advances anticipation
`
`and obviousness grounds to try to invalidate the ‘190 Patent because it wishes to
`
`infringe the patent.
`
`A.
`
`Alleged Grounds of Unpatentability
`
`In its Ground 1, Agila argues the Rote Liste in View of Teagarden renders
`
`obvious all of the claims of the ‘190 Patent under 35 U.S.C. § 103 (Claims 1-9).
`
`But Agila concedes that the Rote Liste does not teach TBA and Teagarden does
`
`not consider bendamustine.
`
`(Petition at 9.) Agila also ignores the fact that the
`
`Examiner already determined that Cephalon’s claims
`
`are patentable over
`
`references that describe RIBOMUSTIN® and TBA. Agila further fails to show
`
`that a person of ordinary skill would have been motivated to make such a
`
`combination or would have had a reasonable expectation of successfully doing so.
`
`In its Ground 2, Agila argues that Nuijen (EX. 1008) (in combination with
`
`the Rote Liste and Teagarden) would have inspired a forrnulator to use mannitol
`
`and TBA when formulating anti-cancer drugs, allegedly rendering claims 1-9 of
`
`the ‘190 Patent obvious under 35 U.S.C. § 103. Nuijen, however, concerns a
`
`vastly different drug — aplidine — “a novel representative of an evolving group of
`
`anticancer agents derived from marine sources.”
`
`(EX. 1008 at 193.) Agila
`
`concedes
`
`that “Nuijen does not disclose a pre-lyophilization solution of
`
`17
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`FRESENIUS KABI 1028-0019
`
`
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`Case No. IPR20 15-00503
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`Cephalon’s Preliminary Response
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`bendamustine or bendamustine hydrochloride.”
`
`(Petition at 9.) Agila further
`
`wholly fails to address the significant physico-chemical differences between
`
`bendamustine and aplidine and their impact on lyophilization, especially stability.
`
`Accordingly, Nuijen does not resolve the deficiencies of the Rote Liste and
`
`Teagarden,
`
`In Ground 3, Agila argues that Gust (EX. 1009) (in combination with the
`
`Rote Liste, Teagarden, and Nuijen) would have suggested to a formulator that
`
`bendamustine hydrolyzes in water and creates degradation products, allegedly
`
`rendering claims 7-9 of ‘l90 Patent obvious under 35 U.S.C. § 103. But Agila
`
`concedes that Gust does not disclose a lyophilized composition of bendamustine or
`
`bendamustine hydrochloride containing not more than about 0.5% bendamustine
`
`ethylester as recited in claims 7-9.
`
`(Petition at 11.) As a result, Gust does not
`
`resolve the deficiencies of the Rote Liste, Teagarden, and Nuijen.
`
`In Ground 4, Agila argues that the Rote Liste anticipates claims 4, 5, 7, and
`
`8. Agila’s argument is based on a flawed claim construction that asks the Board to
`
`ignore that claims 4, 5, 7, and 8 depend on claim 1, which recites elements (TBA
`
`and water) that are indisputably not disclosed in the Rote Liste.
`
`B.
`
`Claim Construction
`
`Cephalon reserves its right to address Agila’s claim construction proposals
`
`and definition of one of ordinary skill in the art in its Patent Owner’s Response, if
`
`18
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`FRESENIUS KABI 1028-0020
`
`
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`Case No. IPR2015-00503
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`Cephalon’s Preliminary Response
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`needed.
`
`For purposes of this Preliminary Response, Cephalon only disputes
`
`Agila’s proposed claim construction of “made from.
`
`The remaining claim terms
`
`77
`
`need no construction to determine whether to institute the proceeding.
`
`“Made From.” As part of its misguided attempt to convert claims 4, 5, 7,
`
`and 8 to product-by-process claims — despite the fact that these claims depend from
`
`claim 1, a composition claim — Agila proposes that “made from” means “made
`
`from the process of lyophilizing.” But the plain meaning of claim 4 and the claims
`
`dependent thereon indicates that “made from” refers to the composition of claim 1,
`
`not the “process” of lyophilizing.
`
`(See Ex. 1001, claim 4.) Agila’s attempt to
`
`insert process steps where there are none should be rejected.
`
`C.
`
`Statement of Material Facts
`
`Cephalon does not dispute Agila’s material fact 1. Cephalon disputes
`
`material facts 2, 3, and 4 as lacking support in the citations provided by Agila.
`
`IV. ARGUMENT
`
`Cephalon respectfully requests that the Board deny Agila’s Petition for
`
`failing to show a reasonable likelihood of success in proving that the ‘ 190 Patent is
`
`invalid. 35 U.S.C. § 314(a) (Board “may not authorize an [IPR] to be instituted”
`
`unless it determines that the petition “shows that there is a reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
`
`in the petition”).
`
`19
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`FRESENIUS KABI 1028-0021
`
`
`
`Case No. IPR20 15-00503
`
`Cephalon’s Preliminary Response
`
`A patent is invalid only “if the differences between the subject matter sought
`
`to be patented and the prior art are such that the subject matter as a whole would
`
`have been obvious at the time the invention was made to a person having ordinary
`
`skill
`
`in the art
`
`to which said subject matter pertains.”
`
`35 U.S.C. § lO3(a).
`
`Obviousness is a question of law, based on underlying factual determinations
`
`including: “the scope and content of the prior art;” “differences between the p
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