IPR2016-00217
`Patent Owners’ Preliminary Response
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________________________________
`
`MYLAN PHARMACEUTICALS INC. & MYLAN LABORATORIES
`LIMITED,
`Petitioners,
`
`v.
`
`BAXTER INTERNATIONAL INC. & BAXTER HEALTHCARE S.A.,
`Patent Owners.
`____________________________________________
`
`Case IPR2016-00217
`Patent 6,310,094 B1
`____________________________________________
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`

`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`TABLE OF CONTENTS
`
`
`
`
`
`I. 
`II. 
`
`INTRODUCTION ........................................................................................... 1 
`BACKGROUND OF THE TECHNOLOGY .................................................. 3 
`A. 
`Esmolol Hydrochloride ......................................................................... 3 
`B. 
`Disadvantages of Prior Esmolol Formulations ..................................... 4 
`C. 
`The Baxter ʼ094 Patent Claims ............................................................. 7 
`III.  CLAIM CONSTRUCTION ............................................................................ 9 
`A. 
`“injectable, aqueous pharmaceutical composition” ............................ 10 
`B. 
`“forming an aqueous composition . . . in a sealed container . . .” ....... 18 
`C. 
`“providing the container with a moisture barrier” .............................. 18 
`D. 
`“an aluminum overpouch” .................................................................. 18 
`IV.  THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1-3 ARE ANTICIPATED BY THE PDR
`(GROUND 1) ................................................................................................. 19 
`A. 
`Legal Standard ..................................................................................... 19 
`B. 
`The PDR (Ex. 1005) ............................................................................ 20 
`C. 
`The PDR Does Not Anticipate Claims 1-3 Of The ʼ094 Patent ......... 22 
`THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1-3 ARE OBVIOUS OVER THE PDR
`(GROUND 2) ................................................................................................. 24 
`A. 
`Legal Standard ..................................................................................... 24 
`B. 
`Claims 1-3 Are Not Obvious Over the PDR ....................................... 25 
`VI.  THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 4-7 ARE OBVIOUS OVER THE PDR IN
`VIEW OF TURCO AND LEE (GROUND 3) .............................................. 31 
`A. 
`Turco (Ex. 1006) ................................................................................. 31 
`B. 
`Lee (Ex. 1007) ..................................................................................... 32 
`C. 
`The PDR Does Not Disclose Key Limitations Of Claims 4-7 ............ 33 
`D. 
`Turco Does Not Disclose Key Limitations Of Claims 4-7 ................. 35 
`
`V. 
`
`- i -
`
`

`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`2. 
`
`2. 
`
`
`
`
`E. 
`F. 
`
`C. 
`
`Lee Does Not Disclose Key Limitations Of Claims 4-7 ..................... 36 
`Claims 4-7 Are Not Obvious Over the PDR In View Of Turco And
`Lee ....................................................................................................... 37 
`1. 
`Petitioners Have Failed To Demonstrate That A Person of Skill
`In The Art Would Have Had A Reasonable Expectation Of
`Success Of Autoclaving Aqueous Esmolol Solutions .............. 37 
`Petitioners Have Failed To Demonstrate That A Person of Skill
`In The Art Would Have Had A Reason Or Motivation To
`Combine PDR, Turco, And Lee To Autoclave Aqueous
`Esmolol Solutions ..................................................................... 45 
`VII.  THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 7-9 ARE OBVIOUS OVER THE PDR IN
`VIEW OF TURCO, LEE, AND SOMMERMEYER ʼ894 (GROUND 4) ... 47 
`A. 
`Sommermeyer ʼ894 (Ex. 1008) ........................................................... 47 
`B. 
`Sommermeyer ʼ894 Does Not Disclose Key Limitations Of Claims 7-
`9 ........................................................................................................... 47 
`Claims 7-9 Are Not Obvious Over the PDR In View Of Turco, Lee,
`And Sommermeyer ʼ894 ..................................................................... 48 
`1. 
`Petitioners Have Failed To Demonstrate That A Person Of Skill
`In The Art Would Have Had A Reasonable Expectation Of
`Success In Autoclaving Aqueous Esmolol Solutions In A
`Polymeric, PVC-Free Container ............................................... 49 
`Petitioners Have Failed To Demonstrate Either That A Person
`Of Skill In The Art Would Have Had A Reason Or Motivation
`To Combine PDR, Turco, Lee, And Sommermeyer ʼ894 To
`Autoclave Aqueous Esmolol Solutions In A Polymeric PVC-
`Free Container ........................................................................... 51 
`VIII.  CONCLUSION .............................................................................................. 52 
`
`- ii -
`
`
`
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Acme Scale Co., Inc. v. LTS Scale Co., LLC,
`615 Fed. Appx. 673 (Fed. Cir. 2015) .................................................................. 11
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 26
`
`In re Cuozzo Speed Technologies, LLC,
`793 F.3d 1268 (Fed. Cir. 2015), cert. granted, 2016 U.S. LEXIS
`632 (U.S., Jan. 15, 2016) .................................................................................... 11
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 24
`
`Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) .......................................................................... 24
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 24
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 26
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 25
`
`In re Morris,
`127 F.3d 1048 (Fed. Cir. 1997) .......................................................................... 11
`
`Moses Lake Industries, Inc. v. Enthone, Inc.,
`IPR2014-00243, Order Denying Institution (June 18, 2014) ............................. 25
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 20
`
`- iii -
`
`

`
`
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2014-01233, Order Denying Institution (Feb. 10, 2015) ............................. 25
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 11
`
`PPC Broadband, Inc. v. Corning Optical Communications RF, LLC,
`No. 2015-1364, slip op. (Fed. Cir. Feb. 22, 2016) ....................................... 12, 13
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ............................................................................ 9
`
`Tessera, Inc. v. International Trade Commission,
`646 F.3d 1357 (Fed. Cir. 2011) .......................................................................... 19
`
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1325 (Fed. Cir. 2010) .......................................................................... 20
`
`Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 20
`
`35 U.S.C. § 314 .......................................................................................................... 3
`
`Regulations
`
`37 C.F.R. § 42.100(b) ................................................................................................ 9
`
`37 C.F.R. § 42.108 ..................................................................................................... 3
`
`Other Authorities
`
`MPEP § 2111 ........................................................................................................... 11
`
`
`
`- iv -
`
`

`
`
`
`
`I.
`
`INTRODUCTION
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited (collectively
`
`“Petitioners”) petition the Board to institute inter partes review of claims 1-9 of
`
`U.S. Patent No. 6,310,094 (“the ʼ094 patent”) based on grounds that are deficient.
`
`The Petition and accompanying Declaration of Dr. Robert Linhardt (Ex. 1002)
`
`(“Linhardt Declaration” or “Linhardt Decl.”) fail to address—much less satisfy—
`
`the factual and legal requirements for establishing anticipation and/or obviousness
`
`of the challenged claims covering pharmaceutical compositions and methods for
`
`making them.
`
`First, the “Brevibloc® Injection” section of the 1999 Physicians’ Desk
`
`Reference (53rd Edition), pp. 624-626 (“the PDR”) (Ex. 1005) fails to anticipate or
`
`render obvious claims 1-3 of the ʼ094 patent because the PDR discloses two
`
`formulations, one formulation a 10 mg/mL vial that does not contain the “osmotic
`
`adjusting agent” of the claims, and the other a concentrated 250 mg/mL ampul that
`
`is neither “ready-to-use” nor “aqueous” as required by the claims. Moreover, the
`
`PDR does not teach or suggest a ready-to-use esmolol hydrochloride formulation
`
`(“esmolol”) that is stable and has been terminally sterilized by autoclaving, as
`
`would be necessary for anticipation or obviousness under a proper construction of
`
`the claim limitation “an injectable, aqueous pharmaceutical composition.” Further,
`
`1
`
`
`

`
`
`
`it would not have been obvious for a person of ordinary skill in the art to make a
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`stable, ready-to-use aqueous esmolol solution that includes an osmotic-adjusting
`
`agent and has been autoclaved, because of the known inherent instability of
`
`esmolol in aqueous solutions and the propensity for esmolol to undergo increased
`
`hydrolytic degradation at higher temperatures.
`
`Second, the prior art fails to render obvious claims 4-9 of the ʼ094 patent
`
`because none of the prior art teaches or suggests that an esmolol hydrochloride
`
`solution is terminally sterilizable by autoclaving, and it would not have been
`
`obvious for a person of skill in the art to autoclave an esmolol hydrochloride
`
`solution with a reasonable expectation of success, because of the known instability
`
`of esmolol hydrochloride in aqueous solutions and heightened propensity for
`
`esmolol hydrochloride to undergo degradation by hydrolysis under increased
`
`temperature. The ability of other ester-containing compounds to be autoclaved is
`
`not applicable to esmolol hydrochloride due to significant differences in chemical
`
`structure that influence susceptibility to degradation. Furthermore, the prior art
`
`fails to render obvious claim 7 because none of the prior art discloses a polymeric
`
`container that is free of polyvinyl chloride and is able to store a solution of esmolol
`
`hydrochloride, and a person of skill in the art would not have had a reasonable
`
`expectation of success in view of the problems presented by plastic containers that
`
`were known in the art, including leaching, adsorption, and water loss.
`
`2
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`In view of Petitioners’ failure—and inability—to satisfy the requirements for
`
`proving anticipation and obviousness, Petitioners cannot demonstrate that they
`
`have a reasonable likelihood of establishing the unpatentability of any challenged
`
`claim, and the Board should decline to institute inter partes review. See 35 U.S.C.
`
`§ 314; 37 C.F.R. § 42.108.
`
`II.
`
`BACKGROUND OF THE TECHNOLOGY
`
`A. Esmolol Hydrochloride
`
`Esmolol hydrochloride is one type of a class of drugs known as “beta
`
`blockers.” Beta blockers block beta adrenergic receptors of the heart, arteries, and
`
`certain other human tissues, and thereby lessen the effects of stress hormones on
`
`those tissues. Accordingly, esmolol hydrochloride (also referred to herein as
`
`“esmolol”) is frequently used to treat or prevent various cardiac disorders. See,
`
`e.g., ʼ094 patent at 1:13-15 (Ex. 1001).
`
`Most beta blockers have long durations of action and are therefore
`
`administered to cardiac patients over relatively long periods of time. See id. at
`
`1:15-23. Esmolol differs from conventional beta blockers, however, in that it is
`
`fast-acting and has a short duration in the body. See id. at 1:13-15, 24-28.
`
`Because of its fast onset and short duration, esmolol is particularly desirable in
`
`critical care settings where it is necessary to reduce a patient’s heart rate quickly or
`
`improve heart rhythm, such as when the patient is suffering a heart attack, or
`
`3
`
`
`

`
`
`
`during or after surgery. See id. at 1:17-30. Esmolol compositions are generally
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`administered by healthcare providers (e.g., doctors or nurses) via injection into the
`
`patient’s bloodstream. See id. at 1:52-2:14.
`
`B. Disadvantages of Prior Esmolol Formulations
`
`Esmolol’s short duration in the body—and the above-described
`
`advantageous properties of esmolol—are attributable to the presence of a methyl
`
`ester group in esmolol’s molecular structure. See, e.g., id. at 1:24-31; see also U.S.
`
`Patent No. 4,857,552 (“Rosenberg ʼ552”) at 1:20-26 (Ex. 1012). The methyl ester
`
`group in esmolol had been found to be unstable in an aqueous environment
`
`because of a marked susceptibility to hydrolytic degradation—i.e., esmolol
`
`degrades in the presence of water. See, e.g., ʼ094 patent at 1:31-33 (Ex. 1001); Lee
`
`et al., “High-Performance Liquid Chromatographic Method for the Determination
`
`of Esmolol Hydrochloride,” J. Pharm. Sci., 73(11): 1660-61 (Nov. 1984) (“Lee”)
`
`(Ex. 1007); Rosenberg ʼ552 at 1:20-29 (Ex. 1012); Expert Declaration of Steve J.
`
`Bannister, Ph.D. Regarding Claim Construction (dated November 16, 2015),
`
`Baxter Healthcare Corp. et al. v. Mylan Labs. Ltd et al., C.A. No. 1:14-cv-07094-
`
`JBS-JS (D.N.J.) (“Bannister Decl.”) ¶ 24 (Ex. 2001). As a result, at the time of the
`
`claimed invention, esmolol formulations were known to be unstable in aqueous
`
`environments. See id.
`
`4
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`Moreover, the stability of esmolol hydrochloride in water was known to be
`
`mediated by the rate of hydrolysis of the methyl ester group, and it was further
`
`known that the rate of hydrolysis is dependent on several factors, including the
`
`temperature of the solution, the pH of the solution, and the concentration of
`
`esmolol and excipients in the solution. See Bannister Decl. ¶ 24 (Ex. 2001). For
`
`example, it was known that the rate of hydrolysis of esmolol in an aqueous solution
`
`was reduced by the use of acetate as a buffer, maintaining the pH as close to 5.0 as
`
`possible, minimizing the concentration of esmolol in the solution, and minimizing
`
`the concentration of buffer used. See ʼ094 patent at 1:34-40 (Ex. 1001); Rosenberg
`
`ʼ552 at 2:39-51 (Ex. 1012). However, those prior art buffered esmolol
`
`formulations still suffered from a number of problems.
`
`For example, prior art esmolol formulations, which were packaged in small
`
`volume glass vials or ampules, were susceptible to hydrolytic degradation at
`
`elevated temperatures and were believed to risk degradation upon autoclaving (a
`
`form of sterilization that subjects the product to high-temperature, pressurized
`
`steam for a period of time sufficient to kill any viable microorganisms). See ʼ094
`
`patent at 1:40-59 (Ex. 1001); Bannister Decl. ¶¶ 26-27 (Ex. 2001). As a result,
`
`those compositions were prepared aseptically, rather than terminally sterilized. See
`
`ʼ094 patent at 1:43-44 (Ex. 1001); see also Rosenberg ʼ552 at 8:54-9:2 (Ex. 1012).
`
`“Terminal” sterilization involves sterilizing the final product after the composition
`
`5
`
`
`

`
`
`
`has been made and put into its packaging (such as by autoclaving), in contrast to a
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`process known as aseptic filling, which involves making and packaging the
`
`product in a sterile environment. See Bannister Decl. ¶ 27 (Ex. 2001). Terminal
`
`sterilization, as by autoclaving, is typically preferred over aseptic filling because it
`
`reduces the risk of microbiological contamination and ensures the safety of the
`
`finished product. See, e.g., ʼ094 patent at 1:44-47, 2:5-14 (Ex. 1001); FDA
`
`Proposed Rules, 56 Fed. Reg. 51354 (1991) (Ex. 1023); Bannister Decl. ¶ 27 (Ex.
`
`2001).
`
`In addition, some of the prior art compositions were small-volume injectable
`
`concentrates that, for purposes of intravenous infusion, required further dilution in
`
`pharmaceutically acceptable diluents prior to use. See ʼ094 patent at 1:48-53 (Ex.
`
`1001); Bannister Decl. ¶ 28 (Ex. 2001). This created a potential opportunity for
`
`calculation or dilution error in a hospital setting. See ʼ094 patent at 1:53-55 (Ex.
`
`1001). The dilution step would typically be performed by drawing the concentrate
`
`from the ampule into a syringe, and then injecting the concentrate into a large
`
`volume IV bag, typically between 250 cc and 500 cc, that contained saline solution
`
`or other intravenous fluids. See Bannister Decl. ¶ 49 (Ex. 2001). Furthermore,
`
`even if this dilution step is done using aseptic handling techniques, it nevertheless
`
`introduces the possibility of contamination, which was of primary concern. See
`
`ʼ094 patent at 1:54-55; Bannister Decl. ¶ 49 (Ex. 2001).
`
`6
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`Thus, at the time of the claimed invention, there remained a need for ready-
`
`to-use, large volume esmolol compositions that were suitable for injection and
`
`stable to autoclaving, such that they were microbiologically safe and stable in vitro
`
`during storage. See ʼ094 patent at 1:56-2:5 (Ex. 1001).
`
`C. The Baxter ʼ094 Patent Claims
`
`The inventors of the ʼ094 patent found, unexpectedly, that a stable,
`
`autoclavable, aqueous preparation of esmolol hydrochloride can be obtained by
`
`formulating esmolol with particular concentrations of a buffering agent and an
`
`osmotic-adjusting agent. In contrast to prior art formulations that “cannot survive
`
`autoclaving,” the patented compositions and methods of making these
`
`compositions are “stable against hydrolytic degradation and other adverse chemical
`
`reactions, and possess[] a pharmaceutically-acceptable shelf-life.” ʼ094 patent at
`
`2:1-5 (Ex. 1001). Accordingly, the claimed compositions and methods “enhance[]
`
`patient safety and physician/nurse compliance with [the] use of esmolol injection
`
`[products].” Id. at 2:13-14.
`
`As its title (“Ready-to-Use Esmolol Solution”) suggests, the ʼ094 patent is
`
`limited to ready-to-use esmolol compositions. The Abstract refers, for instance, to
`
`“[a] ready-to-use injectable, aqueous pharmaceutical composition for the treatment
`
`of cardiac conditions.” Id. at Abstract. Likewise, the “Summary of the Invention”
`
`states that “[t]he present invention relates to a ready-to-use injectable, aqueous
`
`7
`
`
`

`
`
`
`pharmaceutical composition . . . .” Id. at 1:4-10. The “Detailed Description of the
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`Invention” states that “[t]he present invention provides a stable, ready-to-use
`
`parenteral solution” and that “[t]he product is a ready-to-use infusion which can be
`
`used directly without requiring any additional procedures for dilution.” Id. at 1:62-
`
`63; 2:5-7. Avoiding the need for a dilution step “eliminates the risk of
`
`microbiological contamination during aseptic handling and any potential
`
`calculation or dilution error.” Id. at 2:5-12.
`
`The Petition challenges claims 1-9 of the ʼ094 patent. Independent claim 1
`
`defines a pharmaceutical composition, and is reproduced below for the
`
`convenience of the panel:
`
`1. An injectable, aqueous pharmaceutical composition for the
`treatment of cardiac conditions, having a pH between 3.5 and 6.5 and
`comprising
`a. 0.1-100 mg/ml methyl-3-[4-(2-hydroxy-3-isopropylamino)
`propoxy] pheylproprionate hydrochloride (esmolol hydrochloride),
`b. 0.1-5.0 mg/ml buffering agent, and
`c. 1-100 mg/ml osmotic-adjusting agent.
`
`Dependent claims 2 and 3, both of which depend from claim 1, claim specific
`
`buffering agents and specific osmotic-adjusting agents, respectively.
`
`Independent claim 4 defines a method for preparing a pharmaceutical
`
`composition, and is reproduced below for the convenience of the panel:
`
`8
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`4. A method for preparing a sterile, injectable aqueous
`pharmaceutical composition for the treatment of cardiac conditions,
`comprising forming an aqueous composition having a pH between 3.5
`and 6.5
`comprising methyl-3-[4-(2-hydroxy-3-isopropylamino)
`propoxy] phenylpropionate hydrochloride (esmolol hydrochloride), a
`buffering agent, and an osmotic-adjusting agent in a sealed container,
`and autoclaving for a period of time sufficient to render the
`composition sterile.
`
`Dependent claim 5 claims specific concentration ranges for esmolol hydrochloride,
`
`the buffering agent, and the osmotic-adjusting agent, while dependent claim 6
`
`claims a temperature range and time range for the autoclaving step. Dependent
`
`claim 7 recites that the container is made of a flexible polymeric container free
`
`from polyvinyl chloride. Dependent claims 8 and 9 recite that the container has a
`
`moisture barrier (claim 8) that is an aluminum overpouch (claim 9).
`
`III.
`
`CLAIM CONSTRUCTION
`
`In an inter partes review, patent claims are to be given their broadest
`
`reasonable interpretation in light of the specification as commonly understood by
`
`those of ordinary skill in the art. See 37 C.F.R. § 42.100(b). Applying the claim
`
`construction standard of Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005),
`
`however, would not change the proposed constructions or conclusions reached in
`
`this petition. The final construction of terms in the challenged claims is not
`
`9
`
`
`

`
`
`
`dependent on application of the “broadest reasonable interpretation” standard, but
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`would apply equally under the Phillips standard. The prior art fails to anticipate or
`
`render obvious the challenged claims under any reasonable interpretation of the
`
`claim terms in view of the specification.
`
`In their Petition, Petitioners proposed constructions for four claim terms,
`
`which are discussed below.
`
`A.
`
`“injectable, aqueous pharmaceutical composition”
`
`The term “injectable, aqueous pharmaceutical composition” appears in claim
`
`1 of the ʼ094 patent. Petitioners have proposed the term to mean “a pharmaceutical
`
`composition containing water, and suitable for injection into a patient.” Petition,
`
`Paper 3 at 13. Petitioners fail to cite to any intrinsic or extrinsic support for their
`
`proposed construction. Patent Owners disagree with Petitioners’ proposed
`
`construction. The broadest reasonable interpretation of this term in light of the
`
`specification of the ʼ094 patent is “a stable, ready-to-use parenteral solution in
`
`which water is the solvent and that has been subjected to terminal sterilization by
`
`autoclaving.”
`
`The Federal Circuit has held that under the broadest reasonable
`
`interpretation standard of claim construction, “the PTO applies to the verbiage of
`
`the proposed claims the broadest reasonable meaning of the words in their ordinary
`
`usage as they would be understood by one of ordinary skill in the art, taking into
`
`10
`
`
`

`
`
`
`account whatever enlightenment by way of definitions or otherwise that may be
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`afforded by the written description contained in the applicant’s specification.” In
`
`re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997) (emphasis added). See also
`
`MPEP § 2111. The Federal Circuit has on numerous occasions affirmed the Patent
`
`Office’s reliance on the written description of the specification to construe a claim
`
`term under the broadest reasonable interpretation standard. See, e.g., In re Cuozzo
`
`Speed Techs., LLC, 793 F.3d 1268, 1280 (Fed. Cir. 2015), cert. granted, 2016 U.S.
`
`LEXIS 632 (U.S., Jan. 15, 2016) (holding that the Board correctly construed the
`
`term “integrally attached” to mean “discrete parts physically joined together as a
`
`unit without each part losing its own separate identity” because the specification
`
`“repeatedly refers to a speed limit indicator independent of any speedometer and
`
`states that ‘the present invention essentially comprises a speed limit indicator
`
`comprising a speed limit display and an attached speedometer.’”); Acme Scale Co.,
`
`Inc. v. LTS Scale Co., LLC, 615 Fed. Appx. 673, 679 (Fed. Cir. 2015) (narrowing
`
`the Board’s construction of the term “material handling vehicle” under the broadest
`
`reasonable interpretation standard to mean “a device that is capable of moving and
`
`whose function is to transport the material to be measured” because the
`
`specification stated that the term “broadly include[s] transportation vehicles”); In
`
`re NTP, Inc., 654 F.3d 1279, 1289 (Fed. Cir. 2011) (narrowing the Board’s
`
`construction of the term “electronic mail message” under the broadest reasonable
`
`11
`
`
`

`
`
`
`interpretation standard in a reexamination proceeding to include, in addition to a
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`destination address and capability for entry of message content, an identification of
`
`an originating processor and a subject, because the “broad construction would
`
`encompass prior art technologies, such as pager messages,” and the specification
`
`describes this term more narrowly); PPC Broadband, Inc. v. Corning Optical
`
`Commc’ns RF, LLC, No. 2015-1364, slip op. at 12 (Fed. Cir. Feb. 22, 2016)
`
`(rejecting the position that “the broadest reasonable construction is always the one
`
`which covers the most embodiments” and holding that “the broadest reasonable
`
`interpretation must be reasonable in light of the claims and specification”).
`
`The first characteristics in Patent Owners’ proposed construction—that the
`
`solution be “stable” and “ready-to-use”—are recited in the specification of the ʼ094
`
`patent: “The present invention provides a stable, ready-to-use parenteral solution
`
`containing . . . .” ‘094 patent at 1:62-63 (Ex. 1001) (emphases added). The
`
`characterization of the “present invention” as being directed to ready-to-use
`
`solutions is repeated throughout the specification of the patent. See e.g., id. at Title
`
`(“Ready-To-Use Esmolol Solution”); Abstract (“a ready-to-use injectable, aqueous
`
`pharmaceutical composition for the treatment of cardiac conditions”); 1:5-7 (“[t]he
`
`present invention relates to a ready-to-use injectable, aqueous pharmaceutical
`
`composition”); see also id.at 2:2-8, 64-66. These characteristics also reflect the
`
`language of the ʼ094 claims themselves. The word “injectable” as used in the
`
`12
`
`
`

`
`
`
`context of the ʼ094 patent reflects that the composition must itself be ready for
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`injection into the patient’s bloodstream without dilution—i.e., it must be ready-to-
`
`use. Bannister Decl. ¶¶ 39-41, 48 (Ex. 2001).
`
`Regarding the second characteristic in the proposed construction—that the
`
`solution must have been subjected to terminal sterilization by autoclaving—the
`
`specification of the ʼ094 patent is clear that the terminal sterilization by
`
`autoclaving of the claimed aqueous esmolol hydrochloride solution was a critical
`
`part of the invention of the ʼ094 patent, and therefore Patent Owners’ proposed
`
`construction properly includes an “autoclaving” limitation. The specification
`
`identifies the problem in the prior art of not being able to autoclave esmolol
`
`hydrochloride solutions due to degradation (see ʼ094 patent at 1:40-43 (Ex. 1001)),
`
`identifies the regulatory authorities’ preference of terminal sterilization, as by
`
`autoclaving, to ensure safety of the finished product (see id. at 1:45-48), and
`
`ultimately describes a novel esmolol hydrochloride solution that is autoclavable
`
`and has been autoclaved (see id. at 1:62-2:14; 2:64-4:40). Accordingly, when the
`
`“enlightenment … [that is] afforded by the written description contained in the
`
`applicant’s specification” is taken into account, the broadest reasonable
`
`construction of the claim term “an injectable, aqueous pharmaceutical
`
`composition” must require terminal sterilization by autoclaving. The Board should
`
`adopt Patent Owners’ proposed construction.
`
`13
`
`
`

`
`
`
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`There is abundant support for Patent Owners’ proposed construction
`
`throughout the specification. For example, the Detailed Description of the
`
`Invention describes the invention as being stable upon terminal sterilization by
`
`autoclaving: “The present invention provides a stable, ready-to-use parenteral
`
`solution containing esmolol hydrochloride and a pharmaceutically acceptable
`
`buffering agent and an osmotic adjusting agent to adjust the tonicity of the
`
`solution. The solution can be packaged in a sealed container and subjected to
`
`terminal sterilization via autoclaving to reduce the microbiological burden of the
`
`formulation.” ʼ094 patent at 1:62-2:1 (Ex. 1001) (emphasis added).
`
`The specification makes clear that a critical problem overcome by the
`
`claimed invention is the inability of previous esmolol solutions to be autoclaved:
`
`“Esmolol hydrochloride formulations of the prior art cannot survive autoclaving.
`
`The present invention is stable against hydrolytic degradation and other adverse
`
`chemical reactions, and possesses a pharmaceutically-acceptable shelf-life.” Id. at
`
`2:1-5 (emphasis added). The specification further describes the problem exhibited
`
`by prior art esmolol solutions: “Prior art formulations maintain a reasonably long
`
`shelf-life, however, they are packaged in glass vials or ampules, and suffer from
`
`severe degradation upon autoclaving. As a result, prior art formulations are
`
`prepared aseptically.” Id. at 1:40-44 (emphasis added). The specification also
`
`explains how terminal sterilization is the regulator-preferred method of
`
`14
`
`
`

`
`
`
`sterilization: “However, terminal sterilization is typically preferred by regulatory
`
`IPR2016-00217
`Patent Owners’ Preliminary Response
`
`authorities as a way of reducing microbiological burden and to ensure the safety of
`
`the finished product.” Id. at 1:45-48 (emphasis added). Indeed, autoclaving is the
`
`only method of terminal sterilization described in the specification of the ʼ094
`
`patent.
`
`By defining what the present invention is and does, the specification of the
`
`ʼ094 patent makes clear that the claimed formulation has necessarily been
`
`autoclaved. This is confirmed by the advantages that the patentees attribute to
`
`their invention: “The present invention is stable against hydrolytic degradation and
`
`other adverse chemical reactions . . . . The product [of the present invention] is a
`
`ready-to-use infusion which can be used directly without requiring any additional
`
`procedures for dilution. This . . . eliminates the risk of microbiological
`
`contamination during aseptic handling and any potential calculation or dilution
`
`error.” ʼ094 patent at 2:2-12 (Ex. 1001) (emphasis added).
`
`Furthermore, all three examples presented in the specification provide for
`
`the terminal sterilization by autoclaving of an esmolol solution after being filled in
`
`bags: “The solution is then filled into 250 ml non-PVC flexible bags . . . . These
`
`bags are sealed in aluminum foil overpouches. The products are then loaded into
`
`an autoclaving sterilizer and sterilized at 121º C. for 36 minutes.” Id. at 3:65-4:7
`
`(emphasis added); see also id. 4:43-5:7. Accordingly, the broadest reasonable
`
`15
`
`
`

`
`
`
`reading of an “injectable, aqueo