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.
`
`_____________________________
`
`IPR2016-00218
`
`Patent No. 6,528,540
`_____________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,528,540
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I. 
`
`INTRODUCTION ................................................................................................. 1 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Brief Overview of the ’540 Patent ........................................................ 1 
`
`Brief Overview of the Prosecution History ........................................... 4 
`
`Brief Overview of the Scope and Content of the Prior Art ................... 5 
`
`Brief Overview of the Level of Skill in the Art .................................... 7 
`
`II. 
`
`GROUNDS FOR STANDING ................................................................................. 9 
`
`III.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ............................................ 10 
`
`IV.  STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED .................................................................................................. 11 
`
`V. 
`
`STATEMENT OF NON-REDUNDANCY ............................................................... 12 
`
`VI.  CLAIM CONSTRUCTION ................................................................................... 13 
`
`1. 
`
`2. 
`
` “an aqueous, sterile pharmaceutical composition” ............................ 13 
`
`“forming an aqueous composition [. . .] in a sealed container [. . .]” . 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 1-6 are Anticipated Under 35 U.S.C.
`§ 102(b) By the PDR ........................................................................... 21 
`
`i. 
`
`ii. 
`
`Claim 1 ...................................................................................... 22 
`
`Claim 2 ...................................................................................... 24 
`
`iii.  Claim 3 ...................................................................................... 25 
`
`-i-
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`

`
`
`Claims 4 and 5 ........................................................................... 25 
`
`Claim 6 ...................................................................................... 26 
`
`iv. 
`
`v. 
`
`B. 
`
`[Ground 2] Claims 1-6 and 12 are Obvious Under 35 U.S.C.
`§ 103 Over the PDR ............................................................................ 30 
`
`i. 
`
`ii. 
`
`Claims 1-6 ................................................................................. 30 
`
`Claim 12 .................................................................................... 33 
`
`C. 
`
`[Ground 3] Claims 1-6, 8-10, and 12-16 are Obvious Under 35
`U.S.C. § 103 Over the PDR, Turco, and Lee ...................................... 38 
`
`i. 
`
`ii. 
`
`Claims 1-6 and 12 ..................................................................... 40 
`
`Claims 8-10 ............................................................................... 44 
`
`iii.  Claim 13 .................................................................................... 46 
`
`iv. 
`
`v. 
`
`Claim 14 .................................................................................... 48 
`
`Claims 15 and 16....................................................................... 49 
`
`X. 
`
`CONCLUSION ................................................................................................... 57 
`
`XI.  PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ....................... 58 
`
`XII.  APPENDIX – LIST OF EXHIBITS ........................................................................ 59 
`
`
`
`-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. 6,528,540 to Liu et al.
`
`(hereinafter “the ’540 patent,” Ex. 1001) that issued on March 4, 2003, and is
`
`currently assigned to Baxter International Inc. (“Patent Owner”). This Petition
`
`demonstrates there is a reasonable likelihood that claims 1-6, 8-10, and 12-16 of
`
`the ’540 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 1-6, 8-10, and 12-16 of the ’540 patent should
`
`be found unpatentable and canceled.
`A. Brief Overview of the ’540 Patent
`Esmolol hydrochloride, a beta-blocker for 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. 10-12.
`
`The ’540 patent is entitled “Esmolol Formulation.” The ’540 patent, with an
`
`earliest claimed priority date of January 12, 2001, is directed to pharmaceutical
`
`compositions of the drug esmolol hydrochloride, and methods of making the drug
`
`composition sterile by autoclaving. Claim 1 recites an aqueous, sterile
`
`1
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`

`
`
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`pharmaceutical composition comprising esmolol hydrochloride, buffering agent,
`
`and osmotic-adjusting agent within specified concentrations, and having a pH
`
`value within a specified range. Ex. 1001, col. 5, l. 61 – col. 6, l. 28. Dependent
`
`claims refer to a narrower range of pH values for the composition (claim 2), to
`
`buffering agents (claim 3), to osmotic-adjusting agents (claims 4 and 5), to ranges
`
`of concentrations (claim 6), to a heat sterilized container (claim 8), which container
`
`is a vial, ampul, bag, bottle, or syringe (claim 9), and which container is from 1 to
`
`500 mL in volume (claim 10).
`
`Claim 12 is an independent claim, and is similar to claim 1, differing in the
`
`recited pH value and the recited concentrations of esmolol hydrochloride, buffering
`
`agent, and osmotic-adjusting agent. Id. at col. 6, l. 65 – col. 7, l. 6.
`
`Claim 13 is an independent claim, and recites a method for preparing an
`
`aqueous, sterile pharmaceutical composition comprising esmolol hydrochloride,
`
`buffering agent, osmotic-adjusting agent, having a pH within a specified range, and
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`further recites forming the composition in a sealed container, which is autoclaved
`
`for a period of time sufficient to render the composition sterile. Id. at col. 7, l. 7 -
`
`col. 8, l. 3. Dependent claims refer to a narrower range of pH values for the
`
`composition (claim 14), and to the autoclaving being at 115 °C to 130 °C for 5 to
`
`40 minutes (claims 15 and 16).
`
`The Background of the Invention of the ’540 patent acknowledges that
`
`esmolol hydrochloride is a well known pharmaceutical treatment for cardiac
`
`disorders. Id. at col. 1, ll. 10-12. The ʼ540 further states, without citation to a
`
`scientific reference or other source, that esmolol hydrochloride is unstable in
`
`-2-
`
`

`
`
`
`aqueous solutions due to the susceptibility of its ester moiety to hydrolytic
`
`degradation. Id. at col. 1, ll. 21-30. According to the ʼ540, “[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 the
`
`concentration of esmolol in the solution, and minimizing the concentration of
`
`buffer used.” Id. at col. 1, ll. 34-38.
`
`Two prior art references are mentioned in the Background of the Invention
`
`of the ’540 patent: U.S. Patent No. 4,857,552 to Rosenberg et al. (filed Jun. 8,
`
`1988) (hereinafter “Rosenberg ’552,” Ex. 1012), and U.S. Patent No. 5,107,609 to
`
`Sartor et al. (filed Jan. 14, 1991) (hereinafter “Sartor ’609,” Ex. 1025). As Sartor
`
`’609 is directed to a “ski boot with improved fit” (see Ex. 1025), it is presumed in
`
`this Petition that the reference to Sartor ’609 made in the ’540 patent was a
`
`mistaken transposition of numbers, and was intended to refer to U.S. Patent No.
`
`5,017,609 to Escobar et al. (filed Nov. 16, 1989) (hereinafter “Escobar ’609,” Ex.
`
`1026), being directed to pharmaceutical compositions for the treatment of cardiac
`
`disorders (see Ex. 1026) .
`
`Regarding the Escobar ʼ609, the ʼ540 states: “U.S. Pat. No. 5,107,609
`
`[5,017,609] discloses a concentrated formulation suitable for ampul packaging
`
`containing esmolol in an aqueous buffer solution, with propylene glycol and
`
`ethanol added to increase solubility of esmolol.” Ex. 1001, col. 1, ll. 44-48.
`
`Contrary to this assertion, there is no teaching in either Escobar ’609 or Sartor ’609
`
`that either propylene glycol or ethanol is used for the purpose of improving the
`
`solubility of esmolol. And, according to Escobar ’609, “[e]thanol has been found
`
`-3-
`
`

`
`
`
`to be important in the stabilization of the β-blocking compound according to the
`
`present invention.” Ex. 1026, col. 4, ll. 57-60 (emphasis added). And according to
`
`Rosenberg ’552, “[c]urrent esmolol formulations use alcohol and propylene glycol
`
`to minimize the concentration of water in the formulation and, therefore slow . .
`
`. [the esmolol] degradation pathway.” Ex. 1012, col. 2, ll. 36-39 (emphasis
`
`added). As noted above, Sartor ’609 is directed to a “ski boot with improved fit”
`
`and provides no teachings related to esmolol. See Ex. 1025. Thus, the ʼ540
`
`statements that propylene glycol and ethanol were used to increase the solubility of
`
`esmolol in solution finds no support in the references cited.
`
`The ʼ540 also asserts: “Esmolol hydrochloride formulations of the prior art
`
`cannot survive autoclaving.” Ex. 1001, col. 2, ll. 9-10. Contrary to these
`
`statements, however, neither Rosenberg ’552 nor Escobar ’609 provide any
`
`teaching that aqueous compositions of esmolol hydrochloride suffer from
`
`degradation upon autoclaving. Ex. 1002, ¶ 22.
`B.
`U.S. Patent Application No. 10/016,260 was filed on October 30, 2001 (Ex.
`
`Brief Overview of the Prosecution History
`
`1004 at 0001), and issued on March 4, 2003 as the ʼ540 patent. Ex. 1001 at [45].
`
`The application was filed as a continuation-in-part of U.S. Patent Application No.
`
`09/759,547, filed on January 12, 2001, now U.S. Patent No. 6,310,094 (hereinafter
`
`“the ’094 patent”), over which the ’540 patent is terminally disclaimed. Ex. 1004 at
`
`0001, 0049-52. An IPR petition for the ʼ094 patent is being filed concurrently with
`
`this petition as IPR2016-00217.
`
`During prosecution of the ’540 patent, the only rejection of claims 1-16 was
`
`-4-
`
`

`
`
`
`for double patenting over the ’094 patent. Ex. 1004 at 0035. A terminal disclaimer
`
`was filed on October 15, 2001 to overcome this rejection. Id. at 0049. An
`
`information disclosure statement was filed by the applicants, but included only one
`
`reference, the Rosenberg ’552 patent (Ex. 1012), which is mentioned in the
`
`Background of the ’540 patent. Ex. 1001, col. 1, l. 42. No additional Office
`
`actions were issued by the examiner, and the claims were allowed as originally
`
`filed. Ex. 1004 at 0053.
`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, ¶ 68. The PDR describes a
`
`concentrated aqueous solution containing esmolol hydrochloride (2500 mg per 10
`
`mL ampul) for dilution prior to injection, and a “ready-to-use” aqueous, injectable
`
`solution of the drug (100 mg per 10 mL vial). Ex. 1005 at 624; see also, Ex. 1002,
`
`¶ 68. 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, ¶¶
`
`69, 71. The ready-to-use solution has a pH of 4.5 to 5.5. Ex. 1005 at 624; see also,
`
`Ex. 1002, ¶ 69. 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, ¶¶ 71-
`
`74. The PDR emphasizes, however, that “massive accidental overdoses of
`
`-5-
`
`

`
`
`
`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
`
`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, ¶ 78. 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, ¶ 79. Turco also teaches the importance of using osmotic-adjusting
`
`agents in large-volume parenteral solutions. Ex. 1006 at 0023; see also, Ex. 1002, ¶
`
`82. Turco additionally teaches the benefits of using plastic containers to house
`
`large-volume parenteral drugs, and provides several examples of suitable polymers
`
`-6-
`
`

`
`
`
`other than PVC. Ex. 1006 at 0044, 0080; see also, Ex. 1002, ¶ 83. Turco is prior
`
`art to the claims of the ʼ540 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
`
`when subjected to boiling (100 °C) for one hour. Ex. 1007 at 1660-61; see also,
`
`Ex. 1002, ¶¶ 85-86. Lee is prior art to the claims of the ʼ540 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, ¶ 36.
`
`Typically this person would have an advanced degree (e.g., a Ph.D.) in organic
`
`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 ¶¶ 34-35.
`
`-7-
`
`

`
`
`
`Petitioner’s 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, 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; see also, Ex.
`
`1003.
`
`Dr. Linhardt has authored or co-authored more than 700 scientific
`
`publications and 6 book chapters, has presented over 130 invited seminars at
`
`-8-
`
`

`
`
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`scientific symposia and educational institutions, and has been listed as an inventor
`
`on 65 issued patents. Ex. 1002, ¶ 5; see also, Ex. 1003. 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; see also, Ex. 1003.
`
`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; see also, Ex. 1003. He has also received
`
`several highly selective and prestigious honors and awards. Ex. 1002, ¶ 6; see
`
`also, Ex. 1003.
`
`Dr. Linhardt is well qualified as an expert, possessing the necessary
`
`scientific, technical, and other specialized knowledge 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 ’540 patent is
`
`available for Inter Partes Review, and Petitioner is not barred or estopped from
`
`requesting Inter Partes Review of the ’540 patent on the grounds identified.
`
`-9-
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`

`
`
`
`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)):
`
`As indicated above, an IPR petition for the related patent, U.S. 6,310,094, is
`
`being filed concurrently with this petition as IPR2016-00217.
`
`Petitioner and a number of other entities are involved in litigation over the
`
`’540 patent and related patent 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. 1027). A complaint
`
`asserting the ’540 patent against Petitioner was served no earlier than November
`
`19, 2014.
`
`Petitioner also identifies the following pending actions involving the ’540
`
`patent: Baxter Healthcare Corporation, Baxter Healthcare S.A., and Baxter
`
`-10-
`
`

`
`
`
`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
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED
`Petitioner requests review of claims 1-6, 8-10, and 12-16 of the ’540 patent
`
`-11-
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`

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`
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`under 35 U.S.C. § 311 and AIA § 6. Petitioner challenges claims 1-6, 8-10, and
`
`12-16 of the ’540 patent on the grounds that each of these claims should be
`
`canceled as unpatentable as follows:
`
`Ground
`
`Claims
`
`Description
`
`1
`
`2
`
`3
`
`1-6
`
`Anticipated under §102(b) by the PDR
`
`1-6, 12
`
`Obvious under §103 over the PDR
`
`1-6, 8-10,
`12-16
`
`Obvious under §103 over the PDR, Turco, and Lee
`
`V.
`
`STATEMENT OF NON-REDUNDANCY
`
`Each of the three Grounds raised in this Petition is meaningfully distinct:
`
`1.
`Ground 1 presents anticipation of claims 1-6 based on the PDR’s
`listing for Brevibloc® Injection, an aqueous pharmaceutical composition
`comprising esmolol hydrochloride and a buffering agent, for dilution into an
`
`osmotic-adjusting agent prior to injection. Claims 1-6 are drawn to an aqueous,
`
`sterile pharmaceutical composition that fails to distinguish over the description of
`Brevibloc® Injection as disclosed in the PDR.
`2.
`Ground 2 differs from Ground 1 in asserting obviousness of claims 1-
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`6 and 12 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 aqueous composition of esmolol hydrochloride suitable for injection, and also
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`teaches diluting a concentrated aqueous solution of esmolol hydrochloride into an
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`osmotic-adjusting agent to make a large volume aqueous composition of esmolol
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`hydrochloride suitable for injection. These teachings render claims 1-6 and 12 of
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`the ’540 patent obvious.
`3.
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`Ground 3 presents obviousness of claims 1-6, 8-10, and 12-16, to
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`aqueous, sterile pharmaceutical compositions and methods of preparation, based on
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`a combination of the PDR, Turco, and Lee. Turco teaches autoclaving of
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`parenteral drug formulations at 121 °C for ten minutes in sealed containers. Lee
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`teaches that esmolol hydrochloride is stable and does not degrade in an aqueous
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`solution heated for at least one hour at a temperature of 100 °C.
`VI. CLAIM CONSTRUCTION
`A claim subject to Inter Partes Review receives the broadest reasonable
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`construction or interpretation in light of the specification of the patent in which it
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`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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`F.3d 1271, 1279-82 (Fed. Cir. 2015). A few terms that warrant discussion are
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`identified and discussed below.
`
`1.
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` “an aqueous, sterile pharmaceutical composition”
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`The term “an aqueous, sterile pharmaceutical composition” appears, e.g., in
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`claim 1 of the ’540 patent. According to the specification of the ’540 patent, a
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`“sterile” composition means “a composition that has been brought to a state of
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`sterility and has not been subsequently exposed to microbiological contamination .
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`. .” Ex. 1001, col. 2, ll. 20-21. The ’540 patent describes terminal sterilization as
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`“a way of reducing microbiological burden . . . to ensure the safety of the finished
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`product.” Id. at col. 1, ll. 56-58. The broadest reasonable interpretation of “an
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`aqueous, sterile pharmaceutical composition” in light of the specification of the
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`’540 patent is “a pharmaceutical composition that contains water, and has reduced
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`microbial burden, regardless of sterilization method.” Ex. 1002, ¶ 38.
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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 13 of the ’540 patent. According to the specification, “[r]eady-to-
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`use formulations are typically packaged in vials, syringes, bags and bottles, while
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`concentrated formulations are typically packaged in ampules.” Ex. 1001, col. 2, ll.
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`53-56. The ’540 patent describes preparing a ready-to-use solution: “[R]eady-to-
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`use solutions are typically filled into ampules . . .” See id. at col. 3, l. 32. In light of
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`the specification of the ’540 patent, the broadest reasonable interpretation of
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`“forming an aqueous composition [. . .] in a sealed container” is to mean “forming
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`an aqueous composition . . . and then placing the aqueous composition in a
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`container and sealing the container.” Ex. 1002, ¶ 39.
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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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`
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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).
`
`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, ¶ 42. 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,
`Ex. 1010 at 81; see also, Ex. 1002, ¶ 42. Brevibloc® Injection was available in two
`formulations: as an injectable ready-to-use formulation, and as a concentrated
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`solution requiring dilution before administering to a patient. Ex. 1009, Ex. 1010,
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`discussed in Ex. 1002, ¶ 43. 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)
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`(hereinafter, “Pearce,” Ex. 1011) at 419; Ex. 1002, ¶ 44.
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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, “[T]he 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; Ex. 1002, ¶ 45. Rosenberg ’552 teaches that maximum stability of
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`esmolol is achieved by maintaining esmolol in solution “as near to pH = 5.0 as
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`possible.” Ex. 1012, col. 2, l. 45, col. 2, l. 68 - col. 3, l. 1; see also, Ex. 1002, ¶ 45.
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`Additionally, Rosenberg ’552 teaches that the free acid product of the degradation
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`of esmolol in water acts as a buffer in solution, providing a self-buffering
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`capability which improves the drug’s stability in aqueous solutions. Ex. 1012, col.
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`1, l. 64 – col. 2, l. 3; see also, Ex. 1002, ¶¶ 46-47. Rosenberg ’552 also teaches
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`that known aqueous formulations of esmolol hydrochloride had the added benefit
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`of having no additional degradation pathways other than the formation of the free
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`acid product. Ex. 1012, col. 3, ll. 61-66; see also, Ex. 1002, ¶¶ 48-49. Rosenberg
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`’552 provides results of a stability study showing esmolol hydrochloride
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`degradation over a period of months at temperatures of up to 75 °C. Ex. 1012, col.
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`9, ll. 37-61. Contrary to a statement in the ʼ540 patent that Rosenberg ʼ552 teaches
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`that esmolol hydrochloride suffers from severe degradation upon autoclaving (Ex.
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`1001, col. 1, ll. 38-44), Rosenberg ʼ552 does not describe stability of esmolol
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`hydrochloride at temperatures above 75 ºC, nor for a time period of less than one
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`month. Ex. 1002, ¶ 50. Similarly, Escobar ’609 describes a study of the long-term
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`stability of esmolol hydrochloride, but does not describe or predict the stability of
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`esmolol hydrochloride at temperatures above 55 °C or for a time period of less
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`than half of one month. See Ex. 1026; see also, Ex. 1002, ¶ 50.
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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
`
`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, ¶¶ 51-
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`52. 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, ¶ 53.
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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.