Paper No. 7
`Filed: February 8, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`FRESENIUS KABI USA, LLC,
`Petitioner,
`
`v.
`
`CEPHALON, INC.,
`Patent Owner.
`______________________
`
`Case IPR2016-00111
`Patent No. 8,895,756 B2
`
`______________________
`
`CEPHALON, INC.’S PRELIMINARY PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION .........................................................................................1
`
`BACKGROUND............................................................................................4
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Inventors Named on the ’756 Patent Identified A Problem
`Not Recognized in the Prior Art............................................................4
`
`The Inventions of the ’756 Patent .........................................................6
`
`The Claims of the ’756 Patent.............................................................10
`
`Treanda for Injection...........................................................................11
`
`III. DEFINITION OF AN ORDINARY ARTISAN AND CLAIM
`CONSTRUCTION.......................................................................................12
`
`IV. THE PETITION FAILS TO MAKE THE SHOWING
`REQUIRED UNDER 35 U.S.C. § 314(a)...................................................12
`
`A.
`
`Ground 1: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-4 of the ’756
`Patent Are Obvious over the Ribomustin Product Monograph in
`view of Alexander or Sauerbier ..........................................................14
`
`1.
`2.
`3.
`4.
`5.
`
`No Prior Art Disclosure of Problems with Ribomustin............14
`The Ribomustin Product Monograph .......................................15
`The Alexander Patent................................................................17
`The Sauerbier Patent .................................................................22
`Claim-by-Claim ........................................................................25
`a.
`Claims 1-3.......................................................................25
`b.
`Claim 4............................................................................27
`
`Ground 2: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-4 of the ’756
`Patent Are Obvious over the Ribomustin Product Monograph,
`Alexander or Sauerbier, and Teagarden..............................................28
`
`Ground 3: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-4 of the ’756
`
`B.
`
`C.
`
`i
`
`

`
`Page
`
`Patent Are Obvious over the Ribomustin Product Monograph,
`Alexander or Sauerbier, Teagarden, and DeLuca...............................32
`
`D.
`
`Ground 4: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-4 of the ’756
`Patent are Obvious over Maas and the Ribomustin Product
`Monograph in View of Alexander or Sauerbier and Teagarden.........36
`
`V.
`
`PETITIONER’S GROUNDS 1-4 ARE REDUNDANT AND
`VIOLATE THE BOARD’S RULES..........................................................37
`
`VI. CONCLUSION ............................................................................................39
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1966)................................................................................................12
`
`Illumina, Inc. v. Trs. of Columbia Univ.,
`IPR2012-00006, 2013 WL 5653110 (PTAB May 10, 2013) .............................37
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ......................................................................12, 13
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)......................................................................................12, 13
`
`Liberty Mutual Ins. Co. v. Progressive Casualty Ins. Co.,
`CBM2012-0003, Paper 7 (PTAB Oct. 25, 2012) ...............................................38
`
`Oracle Corp. v. Clouding IP, LLC,
`IPR2013-00075, Paper 15 (PTAB June 13, 2013) .............................................37
`
`Statutes
`
`35 U.S.C. § 103(a) ...................................................................................................12
`
`35 U.S.C. § 325(d) ...................................................................................................39
`
`Other Authorities
`
`37 C.F.R § 42.1(b) ...................................................................................................37
`
`37 C.F.R. § 42.108(b) ..............................................................................................37
`
`iii
`
`

`
`PATENT OWNER’S LIST OF EXHIBITS
`
`EXHIBIT
`
`DESCRIPTION
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`TREANDA® Prescribing Information
`
`“Treanda New Drug Application for the Treatment of
`Chronic Lymphocytic Leukemia Granted Priority
`Review Status by FDA,” Drugs.com (December 3,
`2007)
`File History of U.S. Patent No. 8,609,863
`
`“FDA Approves Treanda,” Drugs.com (March 20,
`2008)
`“Cephalon Receives FDA Approval for Treanda to
`Treat Patients with Relapsed Indolent Non-Hodgkin’s
`Lymphoma,” Drugs.com (October 31, 2008)
`Brad S. Kahl, et al., “Bendamustine Is Effective
`Therapy in Patients with Rituximab-Refractory,
`Indolent B-cell Non-Hodgkin Lymphoma: Results
`From a Multicenter Study,” Cancer 106 (January 1,
`2010)
`K. Sue Robinson, et al., “Phase II Multicenter Study
`of Bendamustine Plus Rituximab in Patients with
`Relapsed Indolent B-Cell and Mantle Cell Non-
`Hodgkin’s Lymphoma,” 26 J. Clin. Oncol. 4473
`(September 20, 2008)
`Wolfgang U. Knauf, et al., “Phase III Randomized
`Study of Bendamustine Compared with Chlorambucil
`in Previously Untreated Patients with Chronic
`Lymphocytic Leukemia,” 27 J. Clin. Oncol. 4278
`(September 10, 2009)
`Wolfgang U. Knauf, et al., “Bendamustine Compared
`with Chlorambucil in Previously Untreated Patients
`with Chronic Lymphocytic Leukaemia: Updated
`Results of a Randomized Phase III Trial,” 159 Brit. J.
`Hematology 67 (August 4, 2012)
`
`iv
`
`

`
`EXHIBIT
`
`DESCRIPTION
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`Norbert Niederle, et al., “Bendamustine Compared to
`Fludarabine as Second-Line Treatment in Chronic
`Lymphocytic Leukemia,” 92 Ann. Hematology 653
`(January 23, 2013)
`Teva Pharmaceutical Industries Limited, Form 20-F,
`2014
`Teva Pharmaceutical Industries Limited, Form 20-F,
`2011
`Cephalon, Inc., Form 10-K, 2010
`
`Cephalon, Inc., Form 10-K, 2009
`
`Cephalon, Inc., Form 10-K, 2008
`
`Bendamustine, Keating et al., Nature Reviews Drug
`Discovery 7, 473-474 (June 2008)
`Cancer Chemotherapy and Biotherapy: Principles and
`Practice (Dec. 7, 2011)
`
`v
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`I.
`
`INTRODUCTION
`
`Patent Owner Cephalon, Inc.’s U.S. Patent No. 8,895,756 B2 (“the ’756
`
`Patent”) claims the reconstituted form of a novel lyophilized bendamustine
`
`formulation that Patent Owner markets as Treanda® (bendamustine hydrochloride)
`
`for injection (“Treanda for injection”). (Ex. 2001, 1). Treanda is FDA-approved
`
`to treat patients with chronic lymphocytic leukemia and indolent B-cell non-
`
`Hodgkin lymphoma.
`
`Petitioner Fresenius Kabi USA, LLC seeks to invalidate the ’756 Patent,
`
`relying on redundant combinations of prior art references that were all before the
`
`Examiner during prosecution. Petitioner fails to demonstrate a reasonable
`
`likelihood that it would prevail if review were instituted.
`
`In Ground 1, Petitioner asserts that the claims of the ’756 Patent are obvious
`
`over the Ribomustin® Product Monograph (Ex. 1005) in view of U.S. Patent
`
`4,537,883 (“Alexander”) (Ex. 1006) or U.S. Patent 5,204,335 (“Sauerbier”) (Ex.
`
`1007). The Ribomustin Product Monograph describes the composition of
`
`Ribomustin, a bendamustine product which was sold commercially in Germany
`
`long before the priority date of the ’756 Patent. However, Petitioner does not show
`
`that the Ribomustin Product Monograph would have motivated a person of
`
`ordinary skill in the art to alter the 1:1.2 ratio by weight of bendamustine to
`
`mannitol found in Ribomustin, much less to reduce that ratio to 1:1.7 as recited in
`
`1
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`the claims of the ’756 Patent. Moreover, the Alexander and Sauerbier patents on
`
`which Petitioner relies, make no mention of bendamustine and thus shed no light
`
`on the obviousness of the claims of the ’756 Patent. To the extent a person of
`
`ordinary skill in the art looked to Alexander and Sauerbier for guidance in making
`
`a bendamustine formulation, those patents would have taught away from the
`
`claimed inventions. In Alexander and Sauerbier, the ratio of active pharmaceutical
`
`ingredient (API) to mannitol is higher than in the prior art Ribomustin product.
`
`However, the claims of the ’756 Patent require lower ratios of API to mannitol
`
`than in Ribomustin.
`
`Ground 2 of the Petition is predicated on the art underlying Ground 1 with
`
`the addition of D. L. Teagarden, Practical Aspects of Lyophilization using non-
`
`aqueous co-solvent systems, 15 European J. of Pharm. Sciences 115 (2002)
`
`(“Teagarden”) (Ex. 1008). However, Teagarden makes no mention of
`
`bendamustine and says nothing that would lead a person of ordinary skill in the art
`
`to reduce the ratio of bendamustine to mannitol found in Ribomustin or to double
`
`the concentration of bendamustine that exists in reconstituted Ribomustin, as
`
`required by the claims of the ’756 Patent. Simply put, Ground 2 suffers from the
`
`same shortcomings as Ground 1.
`
`2
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`In Ground 3, Petitioner adds P.P. DeLuca, et al. Ch. 5, Formulation of Small
`
`Volume Parenterals in K.E. Avis, et al., eds., Pharmaceutical Dosage Forms:
`
`Parenteral Medications, Vol 1, New York: Marcel Dekker (1992) (“DeLuca”) (Ex.
`
`1011) to further support its obviousness argument. DeLuca discusses
`
`lyophilization and teaches the use of mannitol as a bulking agent. However,
`
`DeLuca does not remedy the deficiencies of Grounds 1 and 2. DeLuca does not
`
`mention bendamustine and does not suggest that a person of ordinary skill in the
`
`art would have had reason to modify the bendamustine to mannitol weight ratio
`
`that is found in Ribomustin, particularly to raise the amount of mannitol relative to
`
`bendamustine as required by the claims of the ’756 Patent.
`
`In Ground 4, Petitioner adds B. Maas, et al., Stability of Bendamustine
`
`Hydrochloride in Infusion Solutions, 49 Pharmazie 775 (1994) (“Maas”) (Ex.
`
`1009), to the art cited in Ground 2. Maas concerns the instability of bendamustine
`
`in water and the increased stability of bendamustine in an NaCl solution when
`
`admixed for infusion.1 Maas contributed nothing to the understanding of a person
`
`1 The title of the Maas reference provided here is a translation of the original
`
`German title, Stabilität von Bendamustinhydrochlorid in Infusionslösungen. While
`
`Petitioner relies on Maas in arguing Ground 1, Petitioner only expressly identifies
`
`Maas as an invalidating prior art reference in Ground 4. That underscores Patent
`
`3
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`of ordinary skill in the art with respect to the ratio of bendamustine to mannitol in
`
`or the concentration of bendamustine in a formulation. Thus, Maas adds nothing to
`
`Petitioner’s obviousness arguments, which are without merit.
`
`Accordingly, Petitioner has failed to establish a reasonable likelihood that at
`
`least one of the challenged claims of the ’756 Patent is unpatentable. Patent
`
`Owner, therefore, respectfully submits that the Board should deny the Petition.
`
`II.
`
`BACKGROUND
`
`A.
`
`The Inventors Named on the ’756 Patent Identified
`A Problem Not Recognized in the Prior Art
`
`Bendamustine was initially synthesized in 1963 in the East German
`
`Democratic Republic. (Ex. 1001, 1:60-63). The compound is “an atypical
`
`structure with a benzimidazole ring, whose structure includes an active nitrogen
`
`mustard[.]” (Ex. 1001, 1:43-47). Beginning in 1971, the drug was available in
`
`East Germany as Cytostasan®; it was later manufactured in re-unified Germany as
`
`Ribomustin. (Id. at 1:60-64). Neither Cytostasan nor Ribomustin was ever
`
`approved by the U.S Food and Drug Administration (“FDA”) and, before the
`
`invention of the ’756 Patent, bendamustine was unavailable to patients in the
`
`United States. (Ex. 2002, 1).
`
`Owner’s argument, detailed below (Section V), that Grounds 1 and 4 are redundant
`
`and violate the Board’s rules.
`
`4
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`Based on the information publicly available at the time of the inventions of
`
`the ’756 Patent claims, Ribomustin, as formulated, appeared to be a viable
`
`candidate for FDA approval. Although bendamustine was known to degrade in the
`
`presence of water, the published product information indicated that the lyophilized
`
`Ribomustin product could be reconstituted in water relatively quickly such that the
`
`product would not degrade to the point that it was unusable. Researchers thus
`
`concluded that reconstituted Ribomustin was suitable for infusion into patients.
`
`(See Ex. 1009, 777 (“Likewise for the recommended administration as a short
`
`infusion over 30 min, no stability problems are expected, since these bendamustine
`
`preparations have a stability of 9 h at room temperature.” (emphasis added))).
`
`In 2003, Salmedix, Inc. (“Salmedix”), a small pharmaceutical company
`
`(later acquired by Patent Owner), evaluated Ribomustin for purposes of seeking
`
`FDA approval to sell it in the United States. (Ex. 1001, 5:18-38). Salmedix
`
`licensed confidential information from Fujisawa Deutschland regarding the process
`
`for manufacturing Ribomustin and visited the German manufacturing facilities.
`
`Salmedix determined that the FDA would not approve Ribomustin as then
`
`formulated and that “an alternative to the Ribomustine® formulation of
`
`Bendamustine HCl” was needed. (Ex. 2003, 52).2 Salmedix was concerned that,
`
`by modern FDA standards, the degradant levels in Ribomustin were too high. (Ex.
`
`2 Salmedix also referred to Ribomustin as “Ribomustine,” as does the ’756 Patent.
`5
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`1001, 20:20-33). In addition, in practice, reconstituting the lyophilized drug took
`
`significantly longer (“may take 30-45 minutes”) than the publicly available product
`
`information indicated. (Id. at 32:40-44). The inventors realized that besides being
`
`burdensome for healthcare professionals tasked with reconstituting the Ribomustin
`
`for infusion, the unexpectedly slow reconstitution process increased the potential
`
`for loss of potency and for impurity formation due to the hydrolysis of
`
`bendamustine in water. (Id. at 2:29-37). The inventors of the ’756 Patent thus
`
`identified “a need for lyophilized formulations of bendamustine that are easier to
`
`reconstitute and which have a better impurity profile than the current lyophilate
`
`(lyophilized powder) formulations of bendamustine.” (Id. at 2:38-41).
`
`The problems with Ribomustin stability, lyophilization, and reconstitution
`
`had not previously been reported in the prior art. The inventors were the first to
`
`recognize the problems with Ribomustin and the first to conduct studies to fully
`
`understand the scope of the deficiencies.
`
`B.
`
`The Inventions of the ’756 Patent
`
`Salmedix undertook an extensive research and development program aimed
`
`at creating a bendamustine formulation that would satisfy FDA standards. (Ex.
`
`2003, 52-72). In an effort to develop a formulation that was easier to reconstitute
`
`and had “a better impurity profile than Ribomustin” (Ex. 1001, 2:38-41), the
`
`inventors conducted a multi-faceted inquiry, balancing interrelated factors such as
`
`6
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`chemical reactivity, solubility, physical properties, and compatibility with various
`
`excipients. (Id. at 12:4-35:11).
`
`The inventors of the ’756 Patent determined the solubility of bendamustine
`
`hydrochloride in alcohol solutions, finding that solubility is dependent on
`
`temperature and the amount of alcohol in the aqueous solution. (Id. at 18:60-19:6).
`
`They also discovered that “smaller alcohols such as methanol and ethanol have less
`
`of an effect on solubility as compared with larger alcohols (tertiary-butanol and n-
`
`butanol)” and that “the shape of the alcohol is also important.” (Id. at 19:13-15).
`
`The patent discloses that the “two alcohols with the greatest effect on solubility
`
`were n-propanol and tertiary-butanol.” (Id. at 19:15-18).
`
`The inventors also evaluated the effect of various alcohols on the
`
`degradation of bendamustine in an effort to develop formulations that would (i)
`
`allow longer fill-finish times; (ii) provide lyophilate powders that could be
`
`reconstituted more quickly than Ribomustin; and/or (iii) provide lyophilized
`
`preparations of bendamustine with a better impurity profile for certain impurities
`
`than Ribomustin. (Id. at 20:17-33). As reported in the ’756 Patent, the inventors
`
`discovered that “[a]lthough alcohols are frequently used in lyophilization to aid in
`
`solubility problems, 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.”
`
`7
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`(Id. at 31:9-14). The inventors disclosed that “TBA was found to be the best
`
`stabilizer of the six alcohols tested[.]” (Id. at 31:14-15).
`
`Further, the inventors studied various pre-lyophilization formulations of
`
`bendamustine in an effort to optimize the lyophilization cycle. (Id. at 24:48-53).
`
`The ’756 Patent specification discloses the testing of multiple such formulations
`
`with varying concentrations of bendamustine, mannitol, and alcohols in water. (Id.
`
`at 24:46-27:6).
`
`In addition, the inventors analyzed the effect of mannitol on bendamustine
`
`solubility and on the appearance of the product (id. at 31:48-50) and found the
`
`following:
`
`Mannitol decreases the solubility of bendamustine (at 15
`mg/mL) in both ethanol and TBA aqueous solutions. For
`example, solutions containing 5% and 10% ethanol and
`TBA without mannitol did not precipitate over 24 hours.
`However, for samples with mannitol (Table 1) precipitate
`was observed within 24 hours. There was no precipitate
`with aqueous solutions containing 30% (v/v) TBA, 15
`mg/mL bendamustine, and 25.5 mg/mL mannitol. In
`order to maintain a well formed cake resistant to
`breakage during handling, a minimum of 134 mg/vial of
`mannitol was required with no difference observed in
`vials up to 200 mg/vial of mannitol.
`(Id. at 31:50-61).
`
`8
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`The ’756 Patent inventors found that “[a]ll alcohols tested increased the
`
`stability of bendamustine,” “[h]owever, a significant mole fraction was required to
`
`affect the stability of the filling solution and the ease of manufacturing.” (Id. at
`
`31:62-64). The patent specification discloses that “[s]maller alcohols have the
`
`undesirable effect of lowering the freezing point of the bulk solution and thus
`
`requiring long lyophilization cycles at lower temperatures” and “[h]igher
`
`concentrations of methanol and ethanol produced unattractive cakes that were
`
`difficult to reconstitute.” (Id. at 31:65-32:2). The patent explains the problem:
`
`The ability to utilize a smaller vial is constrained by the
`concentration or solubility of bendamustine in the
`aqueous/organic solution. At lower concentrations of
`ethanol, methanol, isopropanol and n-propanol, which
`produced acceptable cake appearance, a more dilute
`solution of bendamustine is required due to solubility
`limitations. To maintain a presentation with 100 mg of
`bendamustine per vial, a vial larger than 50 mL would be
`required. . . . [A]t the lower alcohol concentration, the
`chemical stability was not sufficient to allow for
`acceptable filling times.
`(Id. at 32:14-24).
`
`The inventors found unexpectedly that by using their novel formulation for
`
`lyophilized bendamustine hydrochloride, the vial size required to fill 100 mg of
`
`9
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`bendamustine could be reduced in comparison to the vials that were used in
`
`producing the prior art Ribomustin product. As reported in the ’756 Patent
`
`specification:
`
`Since the concentration of bendamustine is higher in a
`30% TBA/water saturated solution as compared with
`other alcohol solutions, it is anticipated that the vial size
`required to fill 100 mg of bendamustine can be decreased
`from the current Ribomustin® presentation.
`(Id. at 31:30-34). The inventors also found that the use of TBA in the pre-
`
`lyophilization solution reduced the reconstitution time to 3-10 minutes as
`
`compared with 30-45 minutes for Ribomustin. (Id. at 32:40-43).
`
`C.
`
`The Claims of the ’756 Patent
`
`Claims 1-4 of the ’756 Patent read as follows:
`
`1. A vial containing a reconstituted solution of
`bendamustine hydrochloride and mannitol in sterile water
`for injection, wherein the ratio by weight of
`bendamustine hydrochloride to mannitol in the vial is
`15:25.5, and wherein the bendamustine hydrochloride is
`present in the vial at a concentration of 100 mg per 20
`mL.
`2. The vial of claim 1, wherein the vial contains 25 mg
`of bendamustine hydrochloride.
`3. The vial of claim 1, wherein the vial contains 100 mg
`of bendamustine hydrochloride.
`10
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`4. A 20 mL vial containing 100 mg of bendamustine
`hydrochloride and 170 mg of mannitol reconstituted in
`sterile water for injection.
`(Ex. 1001, Claims 1-4).
`
`D.
`
`Treanda for Injection
`
`In 2007, the FDA granted “priority review” status to Cephalon’s New Drug
`
`Application for Treanda® for injection, a lyophilized bendamustine product which
`
`embodies the claimed inventions of the ’756 Patent, meaning that the drug would
`
`potentially provide significant improvements in the safety or effectiveness of the
`
`treatment of serious conditions when compared to standard applications. (Ex.
`
`2002, 1). The FDA approved Treanda for injection in 2008. (Ex. 2004, 1; Ex.
`
`2005, 1).
`
`Researchers hailed Treanda for injection as a significant advance over prior
`
`chemotherapy drugs and it quickly became a commercial success. (Ex. 2006 at
`
`106; Ex. 2007 at 4473; Ex. 2008 at 4378; Ex. 2009 at 67; Ex. 2010 at 653).
`
`Overall, since launch in 2008, Treanda for injection has generated over $3 billion
`
`in sales in the United States. (Ex. 2011 at 58; Ex. 2012 at 61; Ex. 2013 at 42; Ex.
`
`2014 at 57; Ex. 2015 at 61).3
`
`3 Patent Owner reserves the right to address secondary indicia of non-obviousness
`
`in detail in the event the Board decides to institute.
`
`11
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`III. DEFINITION OF AN ORDINARY ARTISAN AND CLAIM
`CONSTRUCTION
`
`Even if the Board accepts Petitioner’s definition of a person of ordinary skill
`
`in the art and proposed “broadest reasonable constructions” of claim terms, the
`
`Board should conclude that, as discussed below, Petitioner has failed to establish a
`
`reasonable likelihood that it would prevail in showing the unpatentability of claims
`
`1-4 of the ’756 Patent if a review were instituted.
`
`Patent Owner reserves the right to address Petitioner’s definition of one of
`
`ordinary skill in the art, if necessary, in its Patent Owner’s Response.
`
`IV. THE PETITION FAILS TO MAKE THE SHOWING REQUIRED
`UNDER 35 U.S.C. § 314(a)
`
`A claim is unpatentable under 35 U.S.C. § 103(a) 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. KSR
`
`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). Obviousness is a question of
`
`law based on underlying factual findings, including, among others, the scope and
`
`content of the prior art, and the differences between the claims and the prior art.
`
`Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966). A
`
`determination of obviousness must include “articulated reasoning with some
`
`rational underpinning to support the legal conclusion of obviousness.” In re Kahn,
`
`12
`
`

`
`IPR2016-00111
`Patent Owner’s Preliminary Response
`
`441 F.3d 977, 988 (Fed. Cir. 2006). In undertaking such a determination, it is
`
`“important to identify a reason that would have prompted a person of ordinary skill
`
`in the relevant field to combine the elements [of the prior art] in the way the
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`claimed new invention does.” KSR, 550 U.S. at 418.
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`As shown below, nothing in the art would have motivated a person of
`
`ordinary skill in the art to modify prior formulations of bendamustine
`
`hydrochloride to make the reconstituted solution of bendamustine hydrochloride
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`and mannitol covered by Claims 1-4 of the ’756 Patent. The prior art did not
`
`support a reasonable expectation that the reconstituted solutions of bendamustine
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`hydrochloride and mannitol covered by claims 1-4 of the ’756 Patent would
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`successfully improve upon the formulation of Ribomustin. The prior art cited in
`
`the Petition, if anything, teaches away from the inventions of the ’756 Patent
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`claims.
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`Thus, the Board should deny the Petition without instituting a review.
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`A.
`
`Ground 1: Petitioner Has Not Demonstrated a Reasonable
`Likelihood that It Would Prove that Claims 1-4 of the ’756 Patent
`Are Obvious over the Ribomustin Product Monograph in view of
`Alexander or Sauerbier
`
`In Ground 1, Petitioner argues that Claims 1-4 of the ’756 Patent are invalid
`
`as obvious over the Ribomustin Product Monograph in view of Alexander or
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`Sauerbier. The Examiner considered all three references during prosecution of the
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`’756 Patent. (Ex. 1002, 379-85).
`
`1.
`
`No Prior Art Disclosure of Problems with Ribomustin
`
`Although Ribomustin had been on sale in Germany for decades in advance
`
`of the priority date of the ’756 Patent, Petitioner cites no prior art reporting
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`degradant problems with Ribomustin. The art did not suggest that there was a
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`problem that could be solved by modifying the formulation of Ribomustin to make
`
`the inventions claimed in the ’756 Patent.
`
`The Petition improperly relies on the disclosure of the ’756 Patent itself as
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`the basis for arguments that problems with the stability, lyophilization, and
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`reconstitution of Ribomustin had been identified in the prior art. The ’756 Patent
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`specification is the only disclosure to which Petitioner points to support the
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`proposition that the slow reconstitution of Ribomustin supposedly was a known
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`problem (Pet. 2) as was the “need . . . for lyophilized formulations that are easier
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`to reconstitute.” (Pet. 16 (quoting Ex. 1001, 2:38-39)). Petitioner quotes the
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`IPR2016-00111
`Patent Owner’s Preliminary Response
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`specification as describing the reconstitution of Ribomustin as “difficult,”
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`“burdensome and time-consuming for the healthcare professional,” and
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`“increas[ing] the potential for loss of potency and impurity formation due to the
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`hydrolysis of the product by water.” (Pet. 2 (citing Ex. 1001, 2:29-37)). While
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`Petitioner suggests that in view of Maas there would have been a motivation to
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`reduce the reconstitution time of bendamustine (id. at 16-17), Maas actually
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`teaches the contrary. Maas stated: “For the recommended administration as a short
`
`infusion [of Ribomustin] over 30 min, no stability problems are expected, since
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`these bendamustine preparations have a stability of 9 h at room temperature.” (Ex.
`
`1009, 775).
`
`2.
`
`The Ribomustin Product Monograph
`
`The Examiner considered the Ribomustin Product Monograph (Ex.1005)
`
`during prosecution of the ’756 Patent. (Ex. 1002, 384). The Product Monograph,
`
`dated 2002, discloses that Ribomustin was available outside of the United States in
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`vials containing either 25 mg of bendamustine together with 30 mg of mannitol or
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`100 mg of bendamustine together with 120 mg of mannitol. (Ex. 1005, 8). The
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`weight ratio of bendamustine hydrochloride to mannitol in Ribomustin is thus
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`1:1.2.
`
`The Ribomustin Product Monograph would not have motivated a person of
`
`ordinary skill in the art to modify the formulation of Ribomustin described therein,
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`let alone made obvious compositions having the novel ratio of bendamustine
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`hydrochloride to mannitol claimed in the ’756 Patent. There is nothing in the
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`Product Monograph pointing to concerns about the stability of the pre-
`
`lyophilization bulk solution of Ribomustin. Moreover, the Product Monograph
`
`does not suggest that any lyophilized composition of bendamustine hydrochloride
`
`other than Ribomustin is suitable for pharmaceutical use. Accordingly, in view of
`
`the Ribomustin Product Monograph, a person of ordinary skill in the art would not
`
`have had any reasonable expectation of success in improving the pre-lyophilization
`
`bulk solution of Ribomustin. There certainly would have been no expectation that
`
`the product would have been improved by specifically making a lyophilized
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`composition having a weight ratio of bendamustine hydrochloride to mannitol of
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`The Ribomustin Product Monograph also does not buttress Petitioner’s
`
`argument with respect to the obviousness of the ’756 Patent claim limitations
`
`specifying a bendamustine concentration of 5 mg/mL (recited in the claims as 100
`
`mg per 20 mL). The Product Monograph discloses that the concentration of
`
`bendamustine in reconstituted Ribomustin is 2.5 mg/mL (disclosed as 25 mg in 10
`
`mL or 100 mg in 40 mL). (Ex. 1005, 9). The Product Monograph does not
`
`suggest, however, that one of ordinary skill the art would have had a reasonable
`
`expectation of success in doubling the concentration of bendamustine as required
`
`by the clams of the ’756 Patent.
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`3.
`
`The Alexander Patent
`
`The Alexander patent, entitled “Lyophilized Cyclophosphamide,” was also
`
`considered by the Examiner during prosecution of the ’756 Patent. (Ex. 1002,
`
`379). The disclosure in Alexander is limited to the compound known as
`
`cyclophosphamide and improved solid compositions of cyclophosphamide. There
`
`is no mention of bendamustine hydrochloride.
`
`Alexander reports “the discovery that a lyophilized cyclophosphamide-
`
`mannitol solid composition has improved thermal stability when it contains an
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`amount of water approximately equimolar to the cyclophosphamide content taken
`
`as the anhydride” and “the discovery that the desirable physical properties of the
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`solid composition appear to be achieved only by using mannitol as the major
`
`excipient.” (Ex. 1006, 3:45-58).
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`Alexander discloses that “[c]yclophosphamide was thoroughly tested with
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`those excipients compatible with parenteral administration to determine if a
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`suitable lyophilizate cake could be formed by freeze-drying.” (Id. at 4:36-39).
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`The excipients included lactose, dextrose, tartaric acid, urea, L-arginine,
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`polyvinypyrrolidone, KH2PO4, K2HPO4, NA2CO3, NAHCO3, and mannitol. (Id. at
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`4:44-65). Moreover, Alexander evaluated various concentrations of each excipient
`
`in pre-lyophilization solutions. (Id. at 4:36-65). Alexander states that
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`“[u]nexpectedly, only two excipients from this group” — NaHCO3 and mannitol
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`— “exhibited favorable cake-forming ability in the presence of
`
`cyclophosphamide.” The “two prototype formulations” “retained their original
`
`shape, possessed suitable texture and appearance, and dissolved easily upon
`
`reconstitution with water.” (Id. at 5:30-36). Thus, “only mannitol at
`
`concentrations of 7% W/V or below, and sodium bicarbonate were initially found
`
`to be acceptable excipients in the cyclophosphamide lyophilization process.” (Id.
`
`at 5:39-43).
`
`Although both bendamustine and cyclophosphamide are nitrogen mustard
`
`compounds, significant differences between the chemical structures of
`
`bendamustine and cyclophosphamide are readily apparent.
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`(Ex. 2016, 473-74). Petitioner fails to demonstrate that notwithstanding the
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`pronounced differences between the chemical structures of cyclophosphamide and
`
`bendamustine, a person of ordinary skill in the art would reasonably have expected
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`that Alexander’s teaching about the use of mannitol with cyclophosphamide would
`
`apply to the use of mannitol with bendamustine. Moreover, the ’756 Patent
`
`concerns the use of mannitol in pre-lyophilization solutions containing organic
`
`solvents such as ethanol and tertiary butyl alcohol (“TBA”). Alexander discusses
`
`the