Paper No. ____
`Filed: November 19, 2015
`
`Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`WILSON SONSINI GOODRICH & ROSATI
`701 Fifth Avenue
`Suite 5100
`Seattle, WA 98104-7036
`Tel.: 206-883-2542
`Fax: 206-883-2699
`Email: sparmelee@wsgr.com
`Email: mrosato@wsgr.com
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC. & MYLAN LABORATORIES LIMITED,
`Petitioners,
`
`v.
`
`BAXTER INTERNATIONAL INC.,
`Patent Owner.
`
`_____________________________
`
`IPR2016-00217
`
`Patent No. 6,310,094
`
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,310,094
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I. 
`
`INTRODUCTION ................................................................................................. 1 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Brief Overview of the ’094 Patent ........................................................ 1 
`
`Brief Overview of the Prosecution History ........................................... 3 
`
`Brief Overview of the Scope and Content of the Prior Art ................... 4 
`
`Brief Overview of the Level of Skill in the Art .................................... 6 
`
`II. 
`
`GROUNDS FOR STANDING ................................................................................. 8 
`
`III.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 .............................................. 9 
`
`IV.  STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED .................................................................................................. 11 
`
`V. 
`
`STATEMENT OF NON-REDUNDANCY ............................................................... 11 
`
`VI.  CLAIM CONSTRUCTION ................................................................................... 12 
`
`1.  
`
`2.  
`
`“an injectable, aqueous pharmaceutical composition” ....................... 13 
`
`“forming an aqueous composition [. . .] in a sealed container [. . .]” . 13 
`
`3.  
`
`“a moisture barrier” ............................................................................. 13 
`
`4. 
`
` “an aluminum overpouch” ................................................................. 14 
`
`VII.  BACKGROUND KNOWLEDGE IN THE ART PRIOR TO JANUARY 12, 2001 .......... 14 
`
`VIII.  OVERVIEW OF DIFFERENCES BETWEEN THE ASSERTED PRIOR ART AND
`THE CLAIMS .................................................................................................... 20 
`
`IX.  DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................... 21 
`
`A. 
`
`[Ground 1] Claims 1-3 are Anticipated Under 35 U.S.C.
`§ 102(b) By the PDR ........................................................................... 21 
`
`i. 
`
`Claim 1 ...................................................................................... 22 
`
`-i-
`
`

`
`B. 
`
`C. 
`
`
`Claims 2 and 3 ........................................................................... 24 
`
`ii. 
`
`[Ground 2] Claims 1-3 are Obvious Under 35 U.S.C. § 103
`Over the PDR ...................................................................................... 27 
`
`[Ground 3] Claims 4-7 are Obvious Under 35 U.S.C. § 103
`Over the PDR, Turco, and Lee ............................................................ 33 
`
`i. 
`
`ii. 
`
`Claim 4 ...................................................................................... 33 
`
`Claim 5 ...................................................................................... 38 
`
`iii.  Claim 6 ...................................................................................... 40 
`
`iv. 
`
`Claim 7 ...................................................................................... 40 
`
`D. 
`
`[Ground 4] Claims 7-9 are Obvious Under 35 U.S.C. § 103
`Over the PDR, Turco, Lee, and Sommermeyer ’894 .......................... 44 
`
`i. 
`
`ii. 
`
`Claim 7 ...................................................................................... 44 
`
`Claims 8 and 9 ........................................................................... 46 
`
`X. 
`
`CONCLUSION ................................................................................................... 49 
`
`XI.  PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ....................... 50 
`
`XII.  APPENDIX – LIST OF EXHIBITS ........................................................................ 51 
`
`
`
`-ii-
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`

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`
`
`I.
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Mylan Pharmaceuticals
`
`Inc. and Mylan Laboratories Limited (collectively referred to herein as
`
`“Petitioner”), request review of United States Patent No. 6,310,094 to Liu et al.
`
`(hereinafter “the ’094 patent,” Ex. 1001) that issued on October 30, 2001, and is
`
`assigned to Baxter International Inc. (“Patent Owner”). This Petition demonstrates
`
`there is a reasonable likelihood that claims 1-9 of the ’094 patent are unpatentable
`
`based on a preponderance of the evidence for failing to distinguish over prior art.
`
`Thus, trial should be instituted by the Patent Trial and Appeal Board and claims 1-
`
`9 of the ’094 patent should be found unpatentable and canceled.
`A. Brief Overview of the ’094 Patent
`Esmolol hydrochloride, a beta-blocker for treating cardiac disorders, was
`
`originally approved by the United States Food and Drug Administration (FDA) in
`
`1988. This prior formulation of esmolol hydrochloride is well-described in the art.
`
`See, e.g., L. Blanski et al., Esmolol, the first ultra-short-acting intravenous beta
`
`blocker for use in critically ill patients, 17 HEART LUNG 80 (1988) (hereinafter
`
`“Blanski,” Ex. 1010); see also, Ex. 1001, col. 1, ll. 13-15.
`
`The ’094 patent is entitled “Ready-To-Use Esmolol Solution,” and has an
`
`earliest claimed priority date of January 12, 2001. Claims of the ʼ094 are directed
`
`to pharmaceutical compositions of esmolol hydrochloride (claims 1-3), and to
`
`methods of making the pharmaceutical composition sterile by autoclaving (claims
`
`4-9). Claim 1 simply recites an aqueous pharmaceutical composition comprising
`
`1
`
`

`
`
`
`esmolol hydrochloride, buffering agent, and osmotic-adjusting agent within
`
`specified concentrations, and having a pH value within a specified range. Ex. 1001,
`
`col. 5, ll. 9-16. Claims 2 and 3 depend from claim 1 and list particular, well-
`
`known buffering agents and osmotic-adjusting agents, respectively. Id. at col. 5, ll.
`
`17-25.
`
`Claim 4 recites a method for preparing a pharmaceutical composition
`
`comprising esmolol hydrochloride, buffering agent, and osmotic-adjusting agent,
`
`but further recites that the composition is in a sealed container, which is autoclaved
`
`for a period of time sufficient to render the composition sterile. Id. at col. 6, ll. 1-9.
`
`Dependent claims refer to specific ranges of concentrations of esmolol
`
`hydrochloride, buffering agent, and osmotic-adjusting agent in the composition
`
`(claim 5), to the autoclaving being at 115 to 130 °C for 5 to 40 minutes (claim 6),
`
`to the container being a flexible, polymeric container free from polyvinyl chloride,
`
`(claim 7), and to the container having a moisture barrier (claim 8), in which the
`
`barrier is an aluminum overpouch (claim 9). Id. at col. 6, ll. 10-23.
`
`The Background of the Invention of the ’094 patent acknowledges that
`
`esmolol hydrochloride is a well-known pharmaceutical treatment for cardiac
`
`disorders. Id. at col. 1, ll. 14-16. The ʼ094 Background further states, without
`
`citation to a scientific reference or other source, that esmolol hydrochloride is
`
`unstable in aqueous solutions due to the susceptibility of its ester moiety to
`
`hydrolytic degradation. Id. at col. 1, ll. 24-33. According to the ʼ094, “[i]n the
`
`past, the rate of degradation of esmolol hydrochloride has been reduced by the use
`
`of acetate as a buffer, maintaining the pH as close to 5.0 as possible, minimizing
`
`-2-
`
`

`
`
`
`the concentration of esmolol in the solution, and minimizing the concentration of
`
`buffer used.” Id. at col. 1, ll. 36-40.
`
`Referring to U.S. Patent No. 4,857,552 to Rosenberg et al. (filed Jun. 8,
`
`1988) (hereinafter “Rosenberg ’552,” Ex. 1012), the ʼ094 asserts: “Prior art
`
`formulations [of esmolol hydrochloride] . . . suffer from severe degradation upon
`
`autoclaving. As a result, prior art formulations are prepared aseptically . . .
`
`However, terminal sterilization is typically preferred by regulatory authorities . . .
`
`to ensure the safety of the finished product.” Id. at col. 1, ll. 40-48. Contrary to the
`
`statement regarding Rosenberg ’552, this reference does not teach that aqueous
`
`compositions of esmolol hydrochloride “suffer from severe degradation upon
`
`autoclaving.” Ex. 1002, ¶ 47.
`B.
`Application No. 09/759,547 was filed on January 12, 2001, and issued on
`
`Brief Overview of the Prosecution History
`
`October 30, 2001 as U.S. Patent No. 6,310,094. During prosecution of the ’094
`
`patent, no Office actions were issued, and no information disclosure statements
`
`were filed. See Ex. 1004. The only prior art reference mentioned by the examiner
`
`was Rosenberg ’552, which appeared in the Background of the ’094 patent, as
`
`discussed above. Ex. 1001, col. 1, ll. 34-50. The claims as originally filed were
`
`subsequently allowed. Ex. 1004 at 0028. According to the examiner’s statement
`
`accompanying the Notice of Allowance, the claims were allowed because “the
`
`prior art fails to teach or suggest the inclusion of an osmotic agent.” Id. However,
`
`as discussed in detail below, printed publications which are prior art to the ’094
`
`patent describe compositions of esmolol hydrochloride containing osmotic-
`
`-3-
`
`

`
`
`
`adjusting agents.
`C. Brief Overview of the Scope and Content of the Prior Art
`The listing for Brevibloc® Injection provided in the 1999 Physicians’ Desk
`Reference (53rd ed., 624-626) Montvale, NJ: PDR Network (hereinafter “the
`PDR,” Ex. 1005), provides product information for Brevibloc® Injection, a “beta1-
`selective (cardioselective) adrenergic receptor blocking agent” comprising esmolol
`
`hydrochloride. Ex. 1005 at 624; see also, Ex. 1002, ¶ 64. The PDR describes a
`
`concentrated, aqueous solution containing esmolol hydrochloride for dilution prior
`
`to injection, and a “ready-to-use” aqueous, injectable solution of the drug. Ex.
`
`1005 at 624; see also, Ex. 1002, ¶ 64. Both the ready-to-use solution and the
`
`concentrated solution described in the PDR contain an acetate buffering system.
`
`Ex. 1005 at 624; see also, Ex. 1002, ¶¶ 65, 67. The ready-to-use solution has a pH
`
`of 4.5 to 5.5. Ex. 1005 at 624; see also, Ex. 1002, ¶ 65. The PDR instructs one to
`
`dilute the concentrated solution in an osmotic-adjusting agent, e.g., sodium
`
`chloride or dextrose, to make an injectable, aqueous pharmaceutical composition.
`
`Ex. 1005 at 626; see also, Ex. 1002, ¶¶ 67-70. The PDR emphasizes, however,
`that “massive accidental overdoses of Brevibloc® have occurred due to dilution
`errors,” including instances resulting in fatalities and permanent disability. Ex.
`
`1005 at 626.
`
`The PDR discloses that the compositions are sterile (id. at 624), though does
`
`not specifically describe the process by which the compositions are made sterile
`
`(e.g., autoclaving, etc). Separate from the drug formulation and administration
`
`aspects, the reference also addresses storage conditions after formulation and
`
`-4-
`
`

`
`
`
`packaging. The reference mentions, among other things, avoiding exposure to
`
`elevated temperatures (id. at 626) in the context of storing the final product (“store
`
`at controlled room temperature”), but provides no insight into the process of
`
`sterilization. Ex. 1002, ¶ 74. The PDR is prior art to the claims of the ʼ094 patent
`
`under 35 U.S.C. § 102(b).
`
`S. Turco and R. E. King, Chapters 4 and 8, STERILE DOSAGE FORMS: THEIR
`
`PREPARATION AND CLINICAL APPLICATION (3rd ed., 1987) (hereinafter “Turco,”
`
`Ex. 1006) teaches the preparation and clinical application of sterile dosage forms,
`
`including the use of an autoclave to sterilize a parenteral drug formulation in a
`
`sealed container: “When the aqueous parenteral product is heat stable, the sealed
`
`final container can be sterilized by autoclaving . . . Autoclaving is the most widely
`
`used and most reliable sterilization method available.” Ex. 1006 at 0015; see also,
`
`Ex. 1002, ¶ 75. Turco also teaches the importance of using osmotic-adjusting
`
`agents in large-volume parenteral solutions. Ex. 1006 at 0023; see also, Ex. 1002, ¶
`
`78. Turco additionally teaches the benefits of using plastic containers to house
`
`large-volume parenteral drugs, and provides several examples of suitable polymers
`
`other than PVC. Ex. 1006 at 0044, 0080; see also, Ex. 1002, ¶ 79. Turco is prior
`
`art to the claims of the ʼ094 patent under 35 U.S.C. § 102(b).
`
`Ying-Chi Lee, David Michael Baaske, and Abu S. Alam, High-Performance
`
`Liquid Chromatographic Method for the Determination of Esmolol Hydrochloride,
`
`73 J. PHARM. SCI. 1660 (1984) (hereinafter “Lee,” Ex. 1007) describes using high-
`
`performance liquid chromatography (HPLC) to determine that esmolol
`
`hydrochloride is stable and does not degrade in an aqueous solution of pH 5.5
`
`-5-
`
`

`
`
`
`when subjected to boiling (100 °C) for one hour. Ex. 1007 at 1660-61; see also,
`
`Ex. 1002, ¶¶ 81-82. Lee is prior art to the claims of the ʼ094 patent under 35
`
`U.S.C. § 102(b).
`
`U.S. Patent No. 5,129,894 to Sommermeyer et al. (filed Aug. 5, 1988)
`
`(hereinafter “Sommermeyer ’894,” Ex. 1008) teaches autoclaving of plastic
`
`containers for parenteral solutions. Ex. 1008, col. 1, ll. 12-20, col. 5, ll. 67-68,
`
`abstract; see also, Ex. 1002, ¶ 87. Sommermeyer ’894 also teaches that there are
`
`toxicity concerns with using PVC bags for parenteral solutions, and teaches
`
`flexible bags for parenteral solutions composed of polymers other than PVC. Ex.
`
`1008, col. 1, ll. 39-54, col. 2, ll. 15-16, abstract; see also, Ex. 1002, ¶¶ 88-89.
`
`Sommermeyer ’894 additionally teaches the use of an aluminum overpouch as a
`
`moisture barrier for a plastic container holding a parenteral solution. Ex. 1008, col.
`
`6, ll. 24-46; see also, Ex. 1002, ¶¶ 90-91. Sommermeyer ’894 is prior art to the
`
`claims of the ʼ094 patent under 35 U.S.C. § 102(b).
`
`D. Brief Overview of the Level of Skill in the Art
`
`A person of ordinary skill in the art in the relevant field as of January 12,
`
`2001, would likely have some combination of the following skills and experience:
`
`(a) knowledge of sterilization methods for pharmaceutical products; (b) experience
`
`with autoclaving; (c) experience designing and preparing liquid drug formulations
`
`intended for parenteral administration; (d) experience designing and preparing
`
`formulations of drugs that are unstable in water; and (e) the ability to understand
`
`results and findings presented or published by others in the field. Ex. 1002, ¶ 31.
`
`Typically this person would have an advanced degree (e.g., a Ph.D.) in organic
`
`-6-
`
`

`
`
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`chemistry, pharmaceutical chemistry, medicinal chemistry, pharmaceutics,
`
`physical pharmacy, or a related field, or would have less education but
`
`considerable professional experience in one or more of these fields. Id. at ¶¶ 29-30.
`
`Petitionerʼs expert, Dr. Robert J. Linhardt, is a Professor and the Ann and
`
`John H. Broadbent Senior Constellation Chair in Biocatalysis and Metabolic
`
`Engineering in the Departments of Chemistry and Chemical Biology, Biology,
`
`Chemical and Biological Engineering at Rensselaer Polytechnic Institute (RPI) in
`
`Troy, New York. Ex. 1002, ¶ 1; see also, Dr. Linhardt’s Curriculum Vitae, Ex.
`
`1003. Dr. Linhardt is also an Adjunct Professor in the Orthopaedics Department at
`
`Mount Sinai School of Medicine as well as an Adjunct Professor of
`
`Pharmaceutical Sciences at Albany College of Pharmacy. Ex. 1002, ¶ 1; see also,
`
`Ex. 1003. Prior to joining the faculty at RPI, Dr. Linhardt was a member of the
`
`faculty in the College of Pharmacy at the University of Iowa for 21 years, starting
`
`in 1982. Ex. 1002, ¶ 1; see also, Ex. 1003.
`
`Dr. Linhardt received an M.A. and a Ph.D. in Organic Chemistry from The
`
`Johns Hopkins University in 1977 and 1979, respectively, followed by post-
`
`doctoral training in Biochemical Engineering at Massachusetts Institute of
`
`Technology. Ex. 1002, ¶ 2; see also, Ex. 1003. His current research program at
`
`RPI focuses on the study of bioactive carbohydrates, particularly the
`
`polysaccharide heparin, an anticoagulant which is administered parenterally, often
`
`continuously, due to its short half-life. Ex. 1002, ¶ 3; see also, Ex. 1003. Dr.
`
`Linhardt has extensive experience with pharmaceutical formulations, including the
`
`sterilization of parenteral formulations via autoclave. Ex. 1002, ¶ 3.
`
`-7-
`
`

`
`
`
`Dr. Linhardt has authored or co-authored more than 700 scientific
`
`publications and 6 book chapters, has presented over 130 invited seminars at
`
`scientific symposia and educational institutions, and has been listed as an inventor
`
`on 65 issued patents. Ex. 1002, ¶ 5. He also serves, or has served, on the editorial
`
`board of 20 peer-reviewed journals such as the Journal of Biological Chemistry,
`
`Applied Biochemistry and Biotechnology, and the Journal of Carbohydrate
`
`Chemistry. Ex. 1002, ¶ 4.
`
`Dr. Linhardt’s research has been funded by such organizations as the
`
`National Institute of Health and the National Science Foundation, as well as other
`
`government agencies and foundations, and he has also served as an Industrial
`
`Consultant in the areas of biocatalysis, biopolymers, carbohydrate chemistry, and
`
`drug delivery since 1981. Ex. 1002, ¶ 4. He has also received several highly
`
`selective and prestigious honors and awards. Ex. 1002, ¶ 6.
`
`Dr. Linhardt is well qualified as an expert, possessing the necessary
`
`scientific, technical, and other specialized knowledge and training as of January
`
`2001 in order to assist in an understanding of the evidence presented herein, as
`
`well as possessing the ability to address pertinent background art and common
`
`knowledge in the art at the relevant time. See Ex. 1003.
`II. GROUNDS FOR STANDING
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’094 patent is
`
`available for Inter Partes Review, and Petitioner is not barred or estopped from
`
`requesting Inter Partes Review of the ’094 patent on the grounds identified.
`
`-8-
`
`

`
`
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited are the
`
`Petitioner in this matter. Mylan Pharmaceuticals Inc. and Mylan Laboratories
`
`Limited are wholly owned subsidiaries of Mylan Inc., as is Mylan Institutional Inc.
`
`Mylan Institutional LLC is an indirectly wholly owned subsidiary of Mylan Inc.
`
`Mylan Inc. is an indirectly wholly owned subsidiary of Mylan N.V. Petitioner
`
`identifies Mylan Inc., Mylan Institutional Inc., Mylan Institutional LLC, and
`
`Mylan N.V. as real parties-in-interest out of an abundance of caution, but this in no
`
`way constitutes an admission that they are or were a real party-in-interest in any
`
`other IPR proceeding.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`An IPR petition for the related patent, U.S. 6,528,540, is being filed
`
`concurrently with this petition as IPR2016-00218.
`
`Petitioner and a number of other entities are involved in litigation over the
`
`’094 patent and related patents in the action styled Baxter Healthcare Corporation,
`
`Baxter Healthcare S.A., and Baxter International, Inc. v. Mylan Laboratories Ltd.
`
`and Mylan Pharmaceuticals Inc., No. 1:14-cv-07094 (JBS-JS), filed by Baxter
`
`Healthcare Corporation in the District of New Jersey (Ex. 1025). A complaint
`
`asserting the ’094 patent against Petitioner was served no earlier than November
`
`19, 2014.
`
`Petitioner also identifies the following pending actions involving the ’094
`
`patent: Baxter Healthcare Corporation, Baxter Healthcare S.A., and Baxter
`
`-9-
`
`

`
`
`
`International, Inc. v. Sagent Pharmaceuticals, Inc., No. 1:15-cv-01684 (JBS-JS),
`
`in the District of New Jersey; Baxter Healthcare Corporation, Baxter Healthcare
`
`S.A., and Baxter International, Inc. v. HQ Specialty Pharma Corp., Welgrace
`
`Research Group, Estate of George Owoo, and Janet Fenning-Owoo (in her
`
`capacity as independent administrator of the estate of George Owoo and as Vice
`
`President of Welgrace Research Group), No. 1:13-cv-06228-JBS-KMW, in the
`
`District of New Jersey.
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Service Information – 37 C.F.R. § 42.8(b)(4).
`
`Petitioner hereby consents to electronic service.
`
`Lead Counsel
`Steven W. Parmelee
`
`Back-up Counsel
`Michael T. Rosato
`
`sparmelee@wsgr.com
`
`mrosato@wsgr.com
`
`WILSON SONSINI GOODRICH & ROSATI,
`
`WILSON SONSINI GOODRICH & ROSATI,
`
`701 Fifth Avenue, Suite 5100
`
`701 Fifth Avenue, Suite 5100
`
`Seattle, WA 98104-7036
`
`Seattle, WA 98104-7036
`
`Tel.: 206-883-2542
`
`
`
`
`
`Tel.: 206-883-2529
`
`
`
`
`
`Fax: 206-883-2699
`
`Fax: 206-883-2699
`
`-10-
`
`

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`
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED
`Petitioner request review of claims 1-9 of the ’094 patent under 35 U.S.C. §
`
`311 and AIA § 6. Petitioner challenges claims 1-9 of the ’094 patent on the
`
`grounds that each of the claims should be canceled as unpatentable as follows:
`
`Ground
`
`Claims
`
`Description
`
`1
`
`2
`
`3
`
`4
`
`1-3
`
`1-3
`
`4-7
`
`7-9
`
`Anticipated under §102(b) by the PDR
`
`Obvious under §103 over the PDR
`
`Obvious under §103 over the PDR, Turco, and Lee
`
`Obvious under §103 over the PDR, Turco, Lee, and
`Sommermeyer ’894
`
`V.
`
`STATEMENT OF NON-REDUNDANCY
`
`Each of the four Grounds raised in this Petition is meaningfully distinct:
`
`1.
`Ground 1 presents anticipation of claims 1-3 based on the PDR’s
`description of Brevibloc® Injection, an aqueous pharmaceutical composition
`comprising esmolol hydrochloride and a buffering agent, for dilution into an
`
`osmotic-adjusting agent prior to injection. Claims 1-3 are drawn to an aqueous
`injectable pharmaceutical composition that fails to distinguish over Brevibloc®
`Injection as disclosed in the PDR.
`
`2.
`
`Ground 2 differs from Ground 1 in asserting obviousness of claims 1-
`
`3 based on the PDR. Obviousness and anticipation are distinct legal criteria for
`unpatentability. The PDR’s listing for Brevibloc® Injection teaches a ready-to-use
`
`-11-
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`

`
`
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`aqueous composition of esmolol hydrochloride suitable for injection, and also
`
`teaches diluting a concentrated aqueous solution of esmolol hydrochloride into an
`
`osmotic-adjusting agent to make a large-volume, aqueous composition of esmolol
`
`hydrochloride suitable for injection. These teachings render claims 1-3 of the ’094
`
`patent obvious.
`3.
`
`Ground 3 presents obviousness of claims 4-7, to methods for
`
`preparing a pharmaceutical composition, based on a combination of the PDR,
`
`Turco, and Lee. Turco teaches autoclaving of parenteral drug formulations at 121
`
`°C for ten minutes in sealed, flexible, polymeric containers that lack polyvinyl
`
`chloride (PVC). Lee teaches that esmolol hydrochloride is stable and does not
`
`degrade in an aqueous solution heated for at least one hour at a temperature of 100
`
`°C.
`
`4.
`
`Ground 4 presents obviousness of claims 7-9, based on a combination
`
`of the PDR, Turco, Lee, and Sommermeyer ’894. Sommermeyer ’894 adds to the
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`combination presented in Ground 3 by explicitly teaching an aluminum overpouch,
`
`which serves as a moisture barrier for a sealed parenteral container, and by
`
`explicitly teaching problems associated with the use of PVC in containers for
`
`parenteral drug compositions.
`VI. CLAIM CONSTRUCTION
`A claim subject to Inter Partes Review receives the broadest reasonable
`
`construction or interpretation in light of the specification of the patent in which it
`
`appears because, among other reasons, the patent owner has an opportunity to
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`amend the claims. 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 778
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`
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`F.3d 1271, 1279-82 (Fed. Cir. 2015). A few terms that warrant discussion are
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`identified and discussed below.
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`1.
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`“an injectable, aqueous pharmaceutical composition”
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`The term “an injectable, aqueous pharmaceutical composition” appears, e.g.,
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`in claim 1 of the ’094 patent. The broadest reasonable interpretation of “an
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`injectable, aqueous pharmaceutical composition” in light of the specification of the
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`’094 patent is “a pharmaceutical composition containing water, and suitable for
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`injection into a patient.” Ex. 1002, ¶ 33.
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`2.
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`“forming an aqueous composition [. . .] in a sealed container [. . .]”
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`The term “forming an aqueous composition [. . .] in a sealed container [. . .]”
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`appears in claim 4 of the ’094 patent. According to the specification,
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`“[c]ompositions according to the present invention are packaged in suitable sealed
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`containers, which may be either glass or polymer-based.” Ex. 1001, col. 2, ll. 38-
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`40. The ’094 patent describes preparing an aqueous composition “. . . in a
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`calibrated compounding tank . . .” which is “then filled into . . . flexible bags . . .
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`These bags are sealed in aluminum foil overpouches.” See id. at col. 3, l. 47 - col.
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`4, l. 5. In light of the specification of the ’094 patent, the broadest reasonable
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`interpretation of “forming an aqueous composition [. . .] in a sealed container” is to
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`mean “forming an aqueous composition . . . and then placing the aqueous
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`composition in a container and sealing the container.” Ex. 1002, ¶ 34.
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`3.
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`“a moisture barrier”
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`The term “a moisture barrier” appears in claim 8 of the ’094 patent.
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`According to the specification, “[t]he polymeric containers can further be provided
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`with a moisture barrier as a secondary packaging system to prevent the loss of
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`water during storage. . .” Ex. 1001, col. 2, ll. 44-46. In light of the ’094 patent
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`specification, the broadest reasonable construction of “a moisture barrier” is “an
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`outer container suited to prevent the loss of water during storage.” Ex. 1002, ¶ 35.
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`4.
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` “an aluminum overpouch”
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`The term “an aluminum overpouch” appears in claim 9 of the ’094 patent.
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`According to the specification, “[a] preferred moisture barrier is an aluminum
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`overpouch.” Ex. 1001, col. 2, ll. 47-48. The specification further discloses bags
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`containing esmolol hydrochloride in solution that are “. . . sealed in aluminum foil
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`overpouches.” Id. at col. 4, ll. 4-5. In light of the ’094 patent specification, the
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`broadest reasonable construction of “an aluminum overpouch” is “an additional
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`and outermost container composed of aluminum, including aluminum foils.” Ex.
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`1002, ¶ 36.
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`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO JANUARY 12, 2001
`The following background publications are discussed in the context of the
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`knowledge and perspective of one of ordinary skill in the relevant art. This
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`provides a factual basis for the discussion about what one of ordinary skill in the
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`relevant art would have known at the time of the invention, i.e., January 12, 2001,
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`and documents the knowledge that skilled artisans would bring to bear in reading
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`the prior art. Ariosa Diagnostics v. Verinata Health, Inc., No. 15-1215, slip op. 1,
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`11-12 (Fed. Cir. Nov. 16, 2015). This knowledge assists in understanding why one
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`of ordinary skill would have been motivated to combine or modify the references
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`asserted in the grounds of this petition to arrive at the claimed invention. As KSR
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`established, the knowledge of such an artisan is part of the store of public
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`knowledge that must be consulted when considering whether a claimed invention
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`would have been obvious. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir.
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`2013).
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`Esmolol hydrochloride, an intravenous drug for the treatment of cardiac
`events, was approved by FDA in 1988 under the trade name Brevibloc® Injection.
`Center for Drug Evaluation and Research, Brevibloc Injection Label, 1988
`(hereinafter, “the Brevibloc® Label,” Ex. 1009); see also, Ex. 1002, ¶ 39. Esmolol
`acts as a cardioselective beta-blocker having a short elimination half-life in the
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`body due to susceptibility of the compound’s ester moiety to hydrolyze. Blanski et
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`al., 17 HEART LUNG 80 (1988) (hereinafter, “Blanski,” Ex. 1010) at 81; see also,
`Ex. 1002, ¶ 39. Brevibloc® Injection was available in two formulations: as an
`injectable ready-to-use formulation, and as a concentrated solution requiring
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`dilution before administering to a patient. Ex. 1009, Ex. 1010, discussed in Ex.
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`1002, ¶ 40. Drug administration errors involving direct injection into patients of
`the undiluted concentrated Brevibloc® solution were a reported source of adverse
`events in the clinic. D. J. Pearce, 43 CAN. J. ANESTH. 419 (1996) (hereinafter,
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`“Pearce,” Ex. 1011) at 419; see also, Ex. 1002, ¶ 41.
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`Ready-to-use formulations of esmolol hydrochloride, in addition to
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`eliminating aseptic dilution processes as well as the danger of inadvertent
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`administration of concentrate, were known to be more stable than concentrated
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`solutions. Rosenberg ’552 notes that, “the rate of degradation of esmolol can be
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`reduced by . . . minimizing the concentration of esmolol in solution . . .” Ex. 1012,
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`col. 2, ll. 42-47; see also, Ex. 1002, ¶ 42. Rosenberg ’552 teaches that maximum
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`stability of esmolol is achieved by maintaining esmolol in solution “as near to pH
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`= 5.0 as possible.” Ex. 1012, col. 2, l. 45, col. 2, l. 68 - col. 3, l. 1; see also, Ex.
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`1002, ¶ 42. Additionally, Rosenberg ’552 teaches that the free acid product of the
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`degradation of esmolol in water acts as a buffer in solution, providing a self-
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`buffering capability which improves the drug’s stability in aqueous solutions. Ex.
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`1012, col. 1, l. 64 – col. 2, l. 3; see also, Ex. 1002, ¶¶ 43-44. Rosenberg ’552 also
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`teaches that known aqueous formulations of esmolol hydrochloride had the added
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`benefit of having no additional degradation pathways other than the formation of
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`the free acid product. Ex. 1012, col. 3, ll. 61-66; see also, Ex. 1002, ¶¶ 45-46.
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`Rosenberg ’552 provides results of a stability study showing esmolol
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`hydrochloride degradation over a period of months at temperatures of up to 75 °C.
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`Ex. 1012, col. 9, ll. 37-61. Contrary to a statement in the ʼ094 patent that
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`Rosenberg ʼ552 teaches that esmolol hydrochloride suffers from severe
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`degradation upon autoclaving (Ex. 1001, col. 1, ll. 40-44), Rosenberg ʼ552 does
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`not describe stability of esmolol hydrochloride at temperatures above 75 ºC, nor
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`for a time period of less than one month. Ex. 1002, ¶ 47.
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`The importance of including osmotic-adjusting agents in a parenteral drug
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`formulation so as to match the tonicity of blood in parenteral drug formulations
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`had been long known: “Osmoticity is of great importance in parenteral injections . .
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`. solutions otherwise hypotonic usually have their tonicity adjusted by the addition
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`of dextrose or sodium chloride . . . Solutions that differ from the serum in tonicity
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`generally are stated to cause tissue irritation, pain on injection and electrolyte
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`shifts.” REMINGTON’S 19TH EDITION: THE SCIENCE AND PRACTICE OF PHARMACY
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`(1995), (hereinafter, “Remington’s,” Ex. 1013) at 0007; see also, Ex. 1002, ¶¶ 48-
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`49. Intravenous fluids containing osmotic-adjusting agents, e.g., sodium chloride,
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`dextrose, lactated Ringer’s injection, and potassium chloride, had been used with
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`compositions of esmolol hydrochloride and were known to be compatible with the
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`drug. Baaske et al., 51 AM. J. HOSP. PHARM. 2693 (1994) (hereinafter, “Baaske,”
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`Ex. 1014) at 2693; see also, Ex. 1002, ¶ 50.
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`The use of autoclaving has long been considered to be sufficient to achieve
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`sterility for pharmaceutical products. See, e.g., Remington’s (1995), Ex. 1013 at
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`0017; see also, Ex. 1002, ¶ 51. According to Remington’s, the process of terminal
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`sterilization is one that destroys viable microorganisms within a final, sealed
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`package. Ex. 1013 at 0014. The use of sterilization for pharmaceutical products by
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`autoclaving was well known in the art: “Sterilization with saturated steam is the
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`method that provides the best combination of flexibility in operation, safe results
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`and low plant and running costs . . . typical operating temperature