IPR2016-00218
`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 IPR2016-00218
`Patent 6,528,540 B1
`____________________________________________
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`

`
`
`
`
`IPR2016-00218
`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 ʼ540 Patent Claims ............................................................. 7 
`III.  CLAIM CONSTRUCTION .......................................................................... 10 
`A. 
`“aqueous, sterile pharmaceutical composition” .................................. 10 
`1. 
`“aqueous” composition ............................................................. 13 
`2. 
`“sterile” ..................................................................................... 15 
`“forming an aqueous composition . . . in a sealed container . . .” ....... 18 
`B. 
`IV.  THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1-6 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 1-6 Of The ʼ540 Patent ......... 21 
`THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1-6 AND 12 ARE OBVIOUS OVER THE
`PDR (GROUND 2) ........................................................................................ 24 
`A. 
`Legal Standard ..................................................................................... 24 
`B. 
`Claims 1-6 And 12 Are Not Obvious Over the PDR .......................... 25 
`VI.  THE PETITION FAILS TO ESTABLISH A REASONABLE
`LIKELIHOOD THAT CLAIMS 1-6, 8-10, AND 12-16 ARE OBVIOUS
`OVER THE PDR IN VIEW OF TURCO AND LEE (GROUND 3) ........... 29 
`A. 
`Turco (Ex. 1006) ................................................................................. 29 
`B. 
`Lee (Ex. 1007) ..................................................................................... 30 
`C. 
`The PDR Does Not Disclose Key Limitations Of Claims 1-6, 8-10,
`And 12-16 ............................................................................................ 31 
`
`V. 
`
`- i -
`
`

`
`
`
`
`D. 
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`Turco Does Not Disclose Key Limitations Of Claims 1-6, 8-10, and
`12-16 .................................................................................................... 33 
`Lee Does Not Disclose Key Limitations Of Claims 1-6, 8-10, and 12-
`16 ......................................................................................................... 33 
`Claims 1-6, 8-10, And 13-16 Are Not Obvious Over The PDR In
`View Of Turco And Lee ...................................................................... 34 
`1. 
`Petitioners Have Failed To Demonstrate That A Person Of Skill
`In The Art Would Have Had A Reasonable Expectation Of
`Success Of Sterilizing Aqueous Esmolol Solutions ................. 35 
`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 Sterilize Aqueous Esmolol
`Solutions .................................................................................... 42 
`VII.  CONCLUSION .............................................................................................. 44 
`
`E. 
`
`F. 
`
`2. 
`
`- ii -
`
`
`
`
`
`

`
`
`
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Acme Scale Co., Inc. v. LTS Scale Co., LLC,
`615 Fed. Appx. 673 (Fed. Cir. 2015) .................................................................. 12
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 27
`
`Braintree Laboratories, Inc. v. Novel Laboratories, Inc.,
`749 F.3d 1349 (Fed. Cir. 2014) .......................................................................... 15
`
`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) .......................................................................... 25
`
`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) ................................................................................................ 25
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 27
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 25
`
`In re Morris,
`127 F.3d 1048 (Fed. Cir. 1997) .................................................................... 11, 15
`
`Moses Lake Industries, Inc. v. Enthone, Inc.,
`IPR2014-00243, Order Denying Institution (June 18, 2014) ............................. 25
`
`- iii -
`
`

`
`
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 20
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2014-01233, Order Denying Institution (Feb. 10, 2015) ............................. 25
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 12
`
`PPC Broadband, Inc. v. Corning Optical Communications RF, LLC,
`No. 2015-1364, slip op. (Fed. Cir. Feb. 22, 2016) ............................................. 12
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .................................................................... 10, 15
`
`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) .......................................................................... 19
`
`Federal Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 20
`
`35 U.S.C. § 314 .......................................................................................................... 3
`
`Regulations
`
`37 C.F.R. § 42.100(b) .............................................................................................. 10
`
`37 C.F.R. § 42.108 ..................................................................................................... 3
`
`Other Authorities
`
`MPEP § 2111 ........................................................................................................... 11
`
`
`
`- iv -
`
`

`
`
`
`I.
`
`INTRODUCTION
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited (collectively
`
`“Petitioners”) petition the Board to institute inter partes review of claims 1-6, 8-
`
`10, and 12-16 of U.S. Patent No. 6,528,540 (“the ʼ540 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 (53d ed., 1999), pp. 624-626 (“the PDR”) (Ex. 1005) fails to anticipate
`
`claims 1-6 of the ʼ540 patent because the PDR discloses two esmolol
`
`hydrochloride (“esmolol”) formulations that do not meet all the limitations of these
`
`claims, i.e., 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 not “aqueous” as required by the claims. The PDR’s teaching of diluting the
`
`concentrated ampul also does not meet all the limitations of the claims because the
`
`diluted esmolol solution is not “sterile,” as claims 1-6 require.
`
`Second, the prior art fails to render obvious claims 1-6, 8-10, and 12-16 of
`
`the ʼ540 patent. A person of ordinary skill in the art would not have had a reason
`
`1
`
`
`

`
`
`
`or motivation to make a sterile, aqueous esmolol formulation that includes an
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`osmotic-adjusting agent, because of the known instability of esmolol in aqueous
`
`solutions. And because of esmolol’s known instability, the skilled artisan would
`
`have had no reasonable expectation that such an aqueous formulation would be
`
`stable. Furthermore, the prior art taught away from adding an osmotic-adjusting
`
`agent to an aqueous esmolol solution.
`
`Third, the prior art fails to render obvious claims 13-16 of the ʼ540 patent
`
`because a person of ordinary skill in the art would not have had a reason or
`
`motivation to autoclave an aqueous esmolol solution with a reasonable expectation
`
`of success, because of the known instability of esmolol hydrochloride in aqueous
`
`solutions and heightened propensity for esmolol to undergo degradation by
`
`hydrolysis under increased temperature. The ability of other ester-containing
`
`compounds to be autoclaved is not applicable to esmolol due to significant
`
`differences in chemical structure that influence susceptibility to degradation.
`
`Moreover, the prior art taught away from subjecting an aqueous esmolol solution
`
`to high temperatures, such as by autoclaving.
`
`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
`
`2
`
`
`

`
`
`
`claim, and the Board should decline to institute inter partes review. See 35 U.S.C.
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`§ 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., ʼ540 patent at 1:10-12 (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
`
`1:12-15. Esmolol differs from conventional beta blockers, however, in that it is
`
`fast-acting and has a short duration in the body. See id. at 1:10-12, 21-29.
`
`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
`
`during or after surgery. See id. at 1:14-29. Esmolol compositions are generally
`
`administered by healthcare providers (e.g., doctors or nurses) via injection into the
`
`patient’s bloodstream. See id. at 2:41-49.
`
`3
`
`
`

`
`
`
`
`B. Disadvantages of Prior Esmolol Formulations
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`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 1:21-28; 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., ʼ540 patent at 1:28-30 (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.
`
`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
`
`4
`
`
`

`
`
`
`esmolol and excipients in the solution. See Bannister Decl. ¶ 24 (Ex. 2001). For
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`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 ʼ540 patent at 1:32-38 (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 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 ʼ540 patent at 1:38-40 (Ex. 1001); Bannister Decl. ¶¶ 26-27
`
`(Ex. 2001). As a result, those compositions were prepared aseptically, rather than
`
`terminally sterilized. See ʼ540 patent at 1:40-41 (Ex. 1001); see also Rosenberg
`
`ʼ552 at 8:54-9:2 (Ex. 1012). “Terminal” sterilization involves sterilizing the final
`
`product after the composition has been made and put into its packaging (such as by
`
`autoclaving), in contrast to a 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
`
`5
`
`
`

`
`
`
`ensures the safety of the finished product. See, e.g., ʼ540 patent at 1:55-58, 2:30-
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`36 (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 ʼ540 patent at 1:45-52 (Ex.
`
`1001); Bannister Decl. ¶ 28 (Ex. 2001). This created a potential opportunity for
`
`calculation or dilution error in a hospital setting. See ʼ540 patent at 2:30-36 (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
`
`ʼ540 patent at 1:53-55 (Ex. 1001); Bannister Decl. ¶ 49 (Ex. 2001).
`
`Thus, at the time of the claimed invention, there remained a need for
`
`aqueous esmolol compositions that were suitable for injection and stable to
`
`autoclaving, such that they were microbiologically safe and stable in vitro during
`
`storage. See ʼ540 patent at 1:32-2:13 (Ex. 1001).
`
`6
`
`
`

`
`
`
`
`C. The Baxter ʼ540 Patent Claims
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`The inventors of the ʼ540 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.” ʼ540 patent at
`
`2:9-14 (Ex. 1001). Accordingly, the claimed compositions and methods “avoid[]
`
`the inconvenience of diluting a concentrated esmolol small volume parenteral
`
`formulation into infusion diluents prior to infusion, as well as eliminates the risk of
`
`microbiological contamination during aseptic handling and any potential
`
`calculation or dilution error.” Id. at 2:31-36.
`
`The ʼ540 patent describes ready-to-use esmolol compositions. The
`
`“Detailed Description of the Invention” states, for instance, that “[t]he product can
`
`take the form of a sterile, ready-to-use formulation for infusion” that “avoids the
`
`inconvenience of diluting a concentrated esmolol small volume parenteral
`
`formulation into infusion diluents prior to infusion.” Id. at 2:30-33. Avoiding the
`
`need for a dilution step “eliminates the risk of microbiological contamination
`
`7
`
`
`

`
`
`
`during aseptic handling and any potential calculation or dilution error.” Id. at 2:33-
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`35.
`
`The Petition challenges claims 1-6, 8-10, and 12-16 of the ʼ540 patent.
`
`Independent claim 1 claims a pharmaceutical composition, and is reproduced
`
`below for the convenience of the panel:
`
`1. An aqueous, sterile pharmaceutical composition suitable for
`parenteral administration for the treatment of cardiac conditions,
`having a pH between 3.5 and 6.5 comprising
`a. 0.1-500 mg/ml methyl-3-[4-(2-hydroxy-3-isopropylamino)
`propoxy] pheylproprionate hydrochloride (esmolol hydrochloride),
`b. 0.01-2 M buffering agent, and
`c. 1-500 mg/ml osmotic-adjusting agent.
`
`Dependent claim 2, which depends from claim 1, claims a narrower pH
`
`range of 4.5 to 5.5. Dependent claims 3 and 4, both of which depend from claim 1,
`
`claim specific buffering agents and specific osmotic-adjusting agents, respectively,
`
`and dependent claim 5, which depends from claim 3, claims specific osmotic-
`
`adjusting agents. Dependent claim 6, which depends from claim 1, claims
`
`narrower ranges of esmolol hydrochloride, buffering agent, and osmotic-adjusting
`
`agent. Claim 8, which depends from claim 1, claims a heat sterilized container that
`
`contains the esmolol composition, and claims 9 and 10 further claims the specific
`
`type of container and the volume of the container.
`
`8
`
`
`

`
`
`
`
`Independent claim 12 claims a pharmaceutical composition and is
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`reproduced below for the convenience of the panel:
`
`12. An aqueous, sterile pharmaceutical composition suitable
`for parenteral administration for the treatment of cardiac conditions,
`having a pH of about 5.0 and comprising about 1-20 mg/ml esmolol
`hydrochloride, 0.02-0.1 M buffering agent and 1-100 mg/ml osmotic-
`adjusting agent, wherein the osmotic-adjusting agent comprises at
`least one of sodium chloride, dextrose, sodium bicarbonate, calcium
`chloride, potassium chloride, sodium lactate, Ringer’s solution and
`lactated Ringer’s solution.
`
`Independent claim 13 claims a method for preparing a pharmaceutical
`
`composition, and is reproduced below for the convenience of the panel:
`
`13. A method for preparing an aqueous, sterile pharmaceutical
`composition suitable for parenteral administration for the treatment of
`cardiac conditions, comprising forming an aqueous composition
`having a pH between 3.5 and 6.5 comprising 0.1-500 mg/ml methyl-
`3-[4-(2-hydroxy-3-isopropylamino)
`propoxy]
`phenylpropionate
`hydrochloride (esmolol hydrochloride), 0.01-2 M buffering agent, and
`1-500 mg/ml osmotic-adjusting agent in a sealed container and
`autoclaving for a period of time sufficient to render the composition
`sterile.
`
`Dependent claim 14 claims a narrower pH range of 4.5 to 5.5, and dependent
`
`claims 15 and 16 claim an autoclaving temperature range of 115º C to 130º C and
`
`an autoclaving time period ranging from 5 to 40 minutes.
`
`9
`
`
`

`
`
`
`III.
`
`CLAIM CONSTRUCTION
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`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
`
`dependent on application of the “broadest reasonable interpretation” standard, but
`
`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 two claim terms,
`
`which are discussed below.
`
`A.
`
`“aqueous, sterile pharmaceutical composition”
`
`The term “aqueous, sterile pharmaceutical composition” appears in claims 1,
`
`12, and 13 of the ʼ540 patent. Petitioners have proposed the term to mean “a
`
`pharmaceutical composition that contains water, and has reduced microbial burden,
`
`regardless of sterilization method.” Petition, Paper 3 at 14. Patent Owners
`
`disagree with Petitioners’ proposed construction. The broadest reasonable
`
`interpretation of this term in light of the specification of the ʼ540 patent is “a
`
`10
`
`
`

`
`
`
`solution in which water is the solvent that has been brought to a state of sterility
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`(i.e., freedom from live bacteria or other microorganisms) and has not been
`
`subsequently exposed to microbiological contamination (i.e., the container holding
`
`the sterile composition has not been compromised).”
`
`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
`
`account whatever enlightenment by way of definitions or otherwise that may be
`
`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
`
`11
`
`
`

`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`
`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
`
`interpretation standard in a reexamination proceeding to include, in addition to a
`
`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 o the claims and specification”).
`
`The proposed constructions of the terms “aqueous” and “sterile” will be
`
`discussed separately below.
`
`12
`
`
`

`
`
`
`
`1.
`
`“aqueous” composition
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`As used in the challenged claims, the term “aqueous” modifies
`
`“pharmaceutical composition.” By far, the most common form of pharmaceutical
`
`composition used for products intended for injection into a patient’s body is a
`
`solution. Bannister Decl. ¶ 63 (Ex. 2001). Consistent therewith, the
`
`pharmaceutical compositions taught in the ʼ540 patent are solutions of esmolol
`
`hydrochloride. See, e.g., ʼ540 patent at 2:3-6 (“The present invention provides a
`
`stable, parenteral composition containing esmolol hydrochloride and a
`
`pharmaceutically acceptable buffering agent and an osmotic adjusting agent to
`
`adjust the tonicity of the solution.”) (emphasis added) (Ex. 1001); 4:15-5:53
`
`(describing Examples 1 to 3: “. . . containing 10 mg/ml esmolol HCl solution”)
`
`(emphasis added).
`
`A person of ordinary skill in the art would further understand that, in the
`
`context of such pharmaceutical compositions, an “aqueous” solution is one in
`
`which water is the solvent. Bannister Decl. ¶ 64 (Ex. 2001). This construction is
`
`consistent with the three exemplary compositions taught in the ʼ540 patent, all of
`
`which are solutions in which water is the solvent. See ʼ540 patent at 4:15-5:53
`
`(Ex. 1001).
`
`Dictionaries confirm that this is the ordinary meaning of the term. For
`
`example, the McGraw-Hill Dictionary of Scientific and Technical Terms (5th ed.,
`
`13
`
`
`

`
`
`
`1994) at 120 (Ex. 2003) defines an “aqueous solution” as “[a] solution with the
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`solvent as water.” The McGraw-Hill Dictionary of Chemistry (3d ed., 1997) at 28
`
`(Ex. 2004) defines “aqueous solution” as “[a] solution with the solvent as water.”
`
`The Academic Press Dictionary of Science and Technology (1992) at 142 (Ex.
`
`2005) also defines “aqueous solution” as “a solution with water as the solvent.”
`
`Bannister Decl. ¶ 65 (Ex. 2001).
`
`Petitioners, by contrast, propose an overbroad definition of “aqueous” that
`
`would encompass any composition “that contains water,” no matter how small or
`
`insignificant an amount of water and no matter what form the composition takes
`
`(e.g., even if it is a solid dosage form). Nothing in the specification dictates that
`
`construction. Indeed, as noted in Dr. Bannister’s declaration, there are numerous
`
`items that contain some amount of water (e.g., salt, sugar, pie crusts, and alcohols,
`
`to name a few), and hence would be encompassed by Petitioners’ proposed
`
`construction, but which no one would consider to be “aqueous.” Bannister Decl.
`
`¶¶ 69-72 (Ex. 2001).
`
`Thus, Patent Owners’ proposal that the “aqueous” esmolol solutions taught
`
`and claimed in the ʼ540 patent are “solutions in which water is the solvent” fully
`
`comports with the broadest reasonable construction of the term as a person of
`
`ordinary skill in the art would interpret it when read in the context of the
`
`specification.
`
`14
`
`
`

`
`
`
`
`2.
`
`“sterile”
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`Patent Owners’ proposed construction is the definition presented in the
`
`specification of the ʼ540 patent:
`
`A “sterile” composition, as used in the context of this
`application, means a composition that has been brought to a state of
`sterility and has not been subsequently exposed to microbiological
`contamination, i.e., the container holding the sterile composition has
`not been compromised.
`
`ʼ540 patent at 2:21-25 (Ex. 1001). As described above, the broadest reasonable
`
`interpretation of a claim term encompasses “taking into account whatever
`
`enlightenment by way of definitions or otherwise that may be afforded by the
`
`written description contained in the applicant’s specification.” In re Morris, 127
`
`F.3d 1048, 1054 (Fed. Cir. 1997) (emphasis added). That is exactly what the
`
`inventors did here, and the Board should adopt the definition they explicitly
`
`provided.1
`
`
`1 Even if the Phillips claim construction standard were to apply, claim terms that
`
`are explicitly defined in the specification should be construed according to these
`
`explicit definitions. See, e.g., Phillips, 415 F.3d at 1316 (Fed. Cir. 2005) (“In such
`
`cases, the inventor’s lexicography governs.”); Braintree Labs., Inc. v. Novel Labs.,
`
`Inc., 749 F.3d 1349, 1355-56 (Fed. Cir. 2014) (reversing the district court’s
`
`15
`
`
`

`
`
`
`
`In this instance, the definition provided in the specification uses the phrase
`
`IPR2016-00218
`Patent Owners’ Preliminary Response
`
`
`“state of sterility”—i.e., “. . . a composition that has been brought to a state of
`
`sterility . . .” (emphasis added), and therefore, for purposes of clarity, Patent
`
`Owners propose that the Board’s construction include an explanation of what is
`
`meant by “sterility.”
`
`As is reflected in pharmaceutical handbooks, standard dictionary definitions,
`
`and expert testimony, it is well established that to be in a “state of sterility,” a
`
`pharmaceutical composition must be free of any live bacteria or other
`
`microorganisms. For instance, Remington: The Science and Practice of Pharmacy
`
`(19th ed., 1995) at 1463 (Ex. 2002) (“Remington 1995”), a leading pharmaceutical
`
`handbook, defines “sterility” as “the absence of viable microorganisms” and
`
`“sterilization” as “a process by which all viable microorganisms are removed or
`
`destroyed, based on a probability function.” Similarly, Webster’s Third New
`
`International Dictionary (2002) at 2238 (Ex. 2006), defines “sterile” as “free from
`
`living organisms and esp. microorganisms.” The American Heritage College
`
`Dictionary (3d ed., 1997) at 1332 (Ex. 2007), defines “sterilize” as “[t]o remove
`
`
`construction that modified the patentee’s express definiti