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`U.S. Patent No. 8,455,524
`Petition for Inter Partes Review
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`Sandoz Inc.
`Petitioner
`
`v.
`
`EKR Therapeutics, LLC (f/k/a EKR Therapeutics, Inc.)
`Patent Owner
`
`
`Patent No. 8,455,524
`Issue Date: June 4, 2013
`Title: Methods of Treatment With Pre-Mixed, Ready-To-Use Pharmaceutical
`Compositions
`_______________
`Inter Partes Review No. ______
`____________________________________________________________
`
`DECLARATION OF ALPASLAN YAMAN, PH.D.
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`ny-1159996
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`1
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`Sandoz Exhibit 1002 Page 1
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`U.S. Patent No. 8,455,524
`Petition for Inter Partes Review
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`Attorney Docket No.: 129352800700
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`TABLE OF CONTENTS
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`
`Page
`INTRODUCTION .......................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................ 1
`II.
`III. MATERIALS CONSIDERED ....................................................................... 3
`IV. SUMMARY OF OPINIONS .......................................................................... 4
`A. Ground 1: Claims 1-28 Obvious Over Cardene PDR and JP
`’364 ....................................................................................................... 4
`B. Ground 2: Claims 1-28 Would Have Been Obvious Over the
`Cardene PDR and JP ’364 further in view of the ’405 Patent
`and Baaske ............................................................................................ 5
`V. DEFINITIONS AND STANDARDS ............................................................. 6
`VI. PERSON OF ORDINARY SKILL IN THE ART ......................................... 8
`VII. CLAIM CONSTRUCTION ........................................................................... 9
`1.
`“Pre-mixed” ............................................................................... 9
`2.
`“A total impurity formation” ................................................... 12
`VIII. THE ’524 PATENT AND PROSECUTION FILE HISTORY ................... 14
`IX. BACKGROUND AND ANALYSIS OF THE PRIOR ART ....................... 16
`A.
`The State of the Art as of April 2006 ................................................. 16
`B.
`The JP ’364 Publication ..................................................................... 19
`C.
`Cardene PDR ...................................................................................... 25
`D.
`The ’405 Patent .................................................................................. 27
`E.
`Baaske................................................................................................. 35
`CLAIM BY CLAIM ANALYSIS OF INVALIDITY ................................. 40
`A. Ground 1: Claims 1-28 Are Rendered Obvious By the Cardene
`PDR and JP ’364 ................................................................................ 40
`1.
`Claim 1 ..................................................................................... 41
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`X.
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`-i-
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`U.S. Patent No. 8,455,524
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`Claim 2 ..................................................................................... 58
`2.
`Claim 3 ..................................................................................... 59
`3.
`Claims 4-7 ................................................................................ 60
`4.
`Claims 8-12 .............................................................................. 65
`5.
`Claims 13-14 ............................................................................ 66
`6.
`Claims 15-18 ............................................................................ 66
`7.
`Claims 19-22 ............................................................................ 67
`8.
`Claims 23-26 ............................................................................ 68
`9.
`10. Claims 27-28 ............................................................................ 69
`B. Ground 2: Claims 1-28 Would Have Been Obvious Over the
`Cardene PDR in View of JP ’364, Baaske and the ’405 Patent ......... 69
`1.
`Claim 1 ..................................................................................... 71
`2.
`Claim 2 ..................................................................................... 86
`3.
`Claim 3 ..................................................................................... 87
`4.
`Claims 4-7 ................................................................................ 89
`5.
`Claims 8-12 .............................................................................. 94
`6.
`Claims 13-14 ............................................................................ 95
`7.
`Claims 15-18 ............................................................................ 95
`8.
`Claims 19-22 ............................................................................ 96
`9.
`Claims 23-26 ............................................................................ 97
`10. Claims 27-28 ............................................................................ 97
`XI. SECONDARY CONSIDERATIONS .......................................................... 97
`A.
`Pharmacists in Hospitals Safely Admix Parenteral Drugs Daily ....... 99
`B. Dr. Brittain’s Concerns Regarding Admixed Parenteral Drug
`Solutions are Irrelevant .................................................................... 102
`C. A Person of Ordinary Skill in the Art Would Have Had a
`Reasonable Expectation of Success ................................................. 104
`D. Dr. Brittain’s Concerns Regarding Hydrolysis Are Not
`Supported by Reliable Data .............................................................. 106
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`-ii-
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`F.
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`Dr. Brittain’s Concerns Regarding Drug Binding Are Not
`Supported by Reliable Data .............................................................. 111
`There Was No Long-felt, But Unmet Need ..................................... 114
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`-iii-
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`Sandoz Exhibit 1002 Page 4
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`U.S. Patent No. 8,455,524
`Petition for Inter Partes Review
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`Attorney Docket No.: 129352800700
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`I, Alpaslan Yaman, Ph.D., make this declaration in connection with the
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`above identified proceeding.
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`I.
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`INTRODUCTION
`1.
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`I have been retained by counsel for Sandoz Inc. (“Sandoz” or
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`“Petitioner”) as a technical expert in connection with the proceeding identified
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`above. I submit this declaration in support of Sandoz’s Petition for Inter Partes
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`Review of United States Patent No. 8,455,524 (“the ’524 patent”).
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`2.
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`I am being compensated for my time in connecting with this
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`proceeding at my standard consulting rate of $450/hour for non-testimony time and
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`$550/hour for testimony time and time spent preparing for testimony. My
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`compensation is not affected by the outcome of this proceeding. I have no
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`personal or financial stake or interest in this matter.
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`3.
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`I have been asked to provide my opinions regarding whether
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`Claims 1-28 of the ’524 patent would have been obvious to a person of ordinary
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`skill in the art at the time of the alleged invention.
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`4.
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`As set forth in more detail below, it is my opinion that claims 1-
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`28 of the ’524 patent would have been obvious to a person of ordinary skill in the
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`art at the time of their invention in view of the prior art I have reviewed.
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`II. BACKGROUND AND QUALIFICATIONS
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`Attorney Docket No.: 129352800700
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`5.
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`I am an expert in the field of large volume parenteral
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`formulation development, and have been an expert since before 2006. In
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`formulating my opinions, I have relied upon my training, knowledge, and
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`experience in the relevant art. A copy of my curriculum vitae is provided as
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`Appendix A to this declaration and provides a comprehensive description of my
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`relevant experience, including academic and employment history, publications and
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`presentations.
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`6.
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`In 1984, I received a BA in Chemistry and Biology from Drake
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`University, and a BS in Pharmacy in 1987. In 1992, I received a Ph.D. in
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`Pharmaceutical Science (with a Major in Industrial Pharmaceutics and a minor in
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`Physical Chemistry) from the University of Missouri.
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`7.
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`A scientist developing a parenteral formulation would
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`thoroughly understand the science of drug development from the pre-formulation
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`stage through formulation development and how that formulation will be
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`manufactured.
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`8.
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`For my work I have been recognized by the International
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`Society of Pharmaceutical Engineers as a Subject Matter Expert in a number of
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`recognized areas of expertise, such as pharmaceutical product development,
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`including pre-formulations, formulations, process development and scale-up (for
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`sterile and non-sterile liquids and semisolid products including controlled release).
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`ny-1159996
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`Sandoz Exhibit 1002 Page 6
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`U.S. Patent No. 8,455,524
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`Attorney Docket No.: 129352800700
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`9.
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`During my career, I have been involved in the development and
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`commercialization of parenteral dosage forms for solutions, solids, and semisolids,
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`with specific experience in lyophilization, aseptic dry powder processes,
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`microspheres, liposomes, suspensions and other complex drug delivery systems.
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`10. During my 28 years in pharmaceutical drug development I have
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`been involved in the development of more than 35 parenteral products, most of
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`which have been commercialized. Specifically, I have personally been involved in
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`the development of at least 4 pre-mixed parenteral drug products.
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`III. MATERIALS CONSIDERED
`11.
`In preparing this declaration, I have reviewed, among other
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`things, the following materials: (a) U.S. Patent No. 8,455,524 (“the ’524 patent”)
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`(Ex. 1001) and certain prosecution history documents (Exs. 1014, 1016-17); (b)
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`U.S. Patent No. 5,164,405 to McFarlane, et al. (“the ’405 Patent”) (Ex. 1003); (c)
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`Japanese Patent Publication JP 2002-177364 to Kenichi, et al., entitled, “Drug
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`Container” (“JP ’364”) (Ex. 1004); (d) Cardene® I.V., Physicians’ Desk
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`Reference, 2004 WL 2459623 (“Cardene PDR”) (Ex. 1005); (e) Baaske, D. M.,
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`“Stability of nicardipine hydrochloride in intravenous solutions,” Am. J. Health
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`Syst. Pharm., 1996, 53, 1701-05 (“Baaske”) (Ex. 1006); (f) Joint Claim
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`Construction and Prehearing Statement filed in Chiesi USA et al. v. Sandoz Inc.,
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`Case No. 1:13-cv-5723 (Dkt. No. 182) (“Joint Claim Construction Statement”)
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`ny-1159996
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`3
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`Sandoz Exhibit 1002 Page 7
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`U.S. Patent No. 8,455,524
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`(Ex. 1008); (g) Declaration under 37 C.F.R. § 1.132 By Dr. Harry G. Brittain,
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`Attorney Docket No.: 129352800700
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`
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`dated July 2, 2009 (“Brittain Decl.”) (Ex. 1009); (h) Zantac Product Label, 2000
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`(“Zantac Label”) (Ex. 1010); (i) Pepcid Product Label, 2001 (“Pepcid Label”) (Ex.
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`1011); (j) Perdipine Product Label, 2001 (“Perdipine Label”) (Ex. 1012); (k)
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`Trissel, Handbook of Injectable Drugs, 13th Ed. (“Trissel”) (Ex. 1013); (l) Baxter
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`Healthcare Corporation Promotional Brochure, 2003 (“Baxter”) (Ex. 1015) and
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`(m) the Petition for Inter Partes Review of the ’524 patent to which this
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`declaration relates.
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`IV. SUMMARY OF OPINIONS
`A. Ground 1: Claims 1-28 Obvious Over Cardene PDR and JP ’364
`12.
`It is my opinion that it would have been obvious to one of
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`ordinary skill in the art to use the 0.1 mg/mL formulation of the Cardene PDR in
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`view of JP ’364 to develop the claimed methods of treatment using pre-mixed
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`nicardipine hydrochloride solutions. In my opinion, a person of ordinary skill in
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`the art would have been motivated to use the container or a non-polar polymer
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`material consistent with the container material from the JP ’364 publication
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`because the JP ’364 publication teaches one of ordinary skill in the art how to
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`make a pre-mixed nicardipine hydrochloride product having minimal drug loss
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`after long-term storage under accelerated conditions. The Cardene PDR discloses
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`an FDA approved 0.1 mg/mL nicardipine hydrochloride parenteral solution and
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`ny-1159996
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`Sandoz Exhibit 1002 Page 8
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`U.S. Patent No. 8,455,524
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`methods for the “treatment of hypertension when oral therapy is not feasible or
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`desirable.”
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`13.
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`In my opinion, the combination of the Cardene PDR and JP
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`’364 disclose or make obvious each and every structural and method limitation of
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`claims 1-28. A person seeking to make a pre-mixed nicardipine hydrochloride
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`parenteral product for use in the United States would have followed the teachings
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`of the Cardene PDR because the Cardene PDR taught the parenteral formulation
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`and methods of treatment for nicardipine hydrochloride that were approved in the
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`U.S. (Cardene PDR at 1, 4) Together, the Cardene PDR and the JP ’364
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`publication provide the roadmap to a pre-mixed nicardipine hydrochloride product.
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`B. Ground 2: Claims 1-28 Would Have Been Obvious Over the
`Cardene PDR and JP ’364 further in view of the ’405 Patent and
`Baaske
`14.
`
`In my opinion, the combination of the Cardene PDR and JP
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`’364, further in view of the ’405 patent and Baaske disclose or make obvious each
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`and every structural and process limitation of claims 1-28. The ’405 patent and
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`Baaske teach one of ordinary skill in the art that PVC is a container material that
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`should be avoided when seeking a container for prolonged storage of nicardipine
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`hydrochloride. These references provide further guidance as to useful pH ranges
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`and compatible i.v. solutions. The teachings of the ’405 patent and Baaske
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`therefore motivate one of ordinary skill in the art to use a container material that is
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`ny-1159996
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`Sandoz Exhibit 1002 Page 9
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`U.S. Patent No. 8,455,524
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`either glass or a non-PVC material, such as the container material taught by JP
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`’364. The combined teachings of JP ’364, Baaske and the ’405 patent would have
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`also provided further motivation and guidance for one of ordinary skill in the art to
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`prepare the FDA-approved nicardipine hydrochloride solutions taught by the
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`Cardene PDR as a pre-mixed product.
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`V. DEFINITIONS AND STANDARDS
`15.
`In forming the opinions expressed in this Declaration, I relied
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`upon my education and experience in the relevant field of the art, and have
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`considered the viewpoint of a person having ordinary skill in the relevant art, as of
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`the earliest alleged priority date, April 18, 2006.
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`16.
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`I understand that prior art to the ’524 patent includes at least
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`patents and printed publications in the relevant art that predate April 18, 2006, the
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`filing date of the earliest provisional application.
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`17.
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`I have also been informed and understand that the subject
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`matter of a patent claim is obvious if the differences between the subject matter of
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`the claim and the prior art are such that the subject matter as a whole would have
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`been obvious at the time the invention was made to a person having ordinary skill
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`in the art to which the subject matter pertains. I have also been informed that the
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`framework for determining obviousness involves considering the following
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`factors: (i) the scope and content of the prior art; (ii) the differences between the
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`ny-1159996
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`Sandoz Exhibit 1002 Page 10
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`prior art and the claimed subject matter; (iii) the level of ordinary skill in the art;
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`and (iv) any objective evidence of non-obviousness. I understand that the claimed
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`subject matter would have been obvious to one of ordinary skill in the art if, for
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`example, it results from the combination of known elements according to known
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`methods to yield predictable results, the simple substitution of one known element
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`for another to obtain predictable results, use of a known technique to improve
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`similar devices in the same way or applying a known technique to a known device
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`ready for improvement to yield predictable results. I have also been informed that
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`the analysis of obviousness may include recourse to logic, judgment and common
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`sense available to the person of ordinary skill in the art that does not necessarily
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`require explication in any reference.
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`18. When a product is available, design incentives and other market
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`forces can prompt variations of it, either in the same field or a different one. If a
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`person having ordinary skill in the relevant art can implement a predictable
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`variation, obviousness likely bars its patentability. For the same reason, if a
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`technique has been used to improve one device and a person having ordinary skill
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`in the art recognizes that it would improve similar devices in the same way, using
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`the technique is obvious unless its actual application is beyond his or her skill. I
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`understand that a claim may be obvious if common sense directs one of ordinary
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`skill in the art to combine multiple prior art references. While it may be helpful to
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`identify a reason for this combination, common sense should guide and no rigid
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`requirement of finding a teaching, suggestion, or motivation to combine is
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`required.
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`19.
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`I have also been informed and understand that certain factors
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`may support or rebut the obviousness of a claim. I understand that such secondary
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`considerations include, among other things, commercial success of the patented
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`invention, skepticism of those having ordinary skill in the art at the time of
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`invention, unexpected results of the invention, any long-felt but unsolved need in
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`the art that was satisfied by the invention, the failure of others to make the
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`invention, praise of the invention by those having ordinary skill in the art, and
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`copying of the invention by others in the field. I understand that there must be a
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`nexus—a connection—between any such secondary considerations and the
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`claimed invention.
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`VI. PERSON OF ORDINARY SKILL IN THE ART
`20.
`In my opinion, a person having ordinary skill in the art as of
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`April 2006 would have been a person with at least a graduate degree in
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`pharmaceutics or a closely related field, and at least five years of experience in the
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`preparation of aqueous pharmaceutical dosage forms in the pharmaceutical
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`industry. This person would know how to obtain and evaluate drug analytical data,
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`such as impurity profiles and quantities, from an analytical or similar laboratory.
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`ny-1159996
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`Sandoz Exhibit 1002 Page 12
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`A person of ordinary skill could have a lower level of formal education if such
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`Attorney Docket No.: 129352800700
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`person has more years of directly relevant experience. A person of ordinary skill
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`in the art may consult with others in the relevant field, including consulting with a
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`health care professional.
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`VII. CLAIM CONSTRUCTION
`21.
`I have been informed and understand that the patent claims are
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`to be construed from the perspective of one of ordinary skill in the art at the time of
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`the claimed invention, and that during inter partes review, claims are to be given
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`their broadest reasonable construction consistent with the specification.
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`22.
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`I have been asked to provide my opinion on two claim terms:
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`“pre-mixed” and “a total impurity formation” by discussing what one of ordinary
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`skill in the art at the time of the patent filing would regard as their broadest
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`reasonable interpretation, consistent with the specification. In each case my
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`opinion agrees with the position taken in Sandoz’s Petition for Inter Partes
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`Review.
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`1.
`“Pre-mixed”
`23. The term “pre-mixed” appears in independent claims 1-3 and 8
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`of the ’524 patent.
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`24. My opinion is that one of ordinary skill in the art would
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`understand “pre-mixed” to mean “an aqueous solution that is mixed and ready to
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`use prior to its point-of-care administration.”
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`25. The term pre-mixed would be understood by a person of
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`ordinary skill in the art to be from the perspective of the person who administers
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`the parenteral composition, such as a nurse, doctor or other trained healthcare
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`professional, the end-user. Therefore, “pre-mixed” would be understood by the
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`end-user to mean a solution that was mixed for them, prior to their receipt of the
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`solution for administration.
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`26.
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`I have been informed that the patent owner (“Applicant”) has
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`proposed that a pre-mixed composition or solution means, “a ready-to-use
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`pharmaceutical composition that is an aqueous solution already mixed from the
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`point of manufacture and is stable, allows medical personnel to use prepared
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`containers containing an injectable formulation off the shelf without additional
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`preparation, avoids potential contamination problems, and eliminates dosage
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`errors.” (Joint Claim Construction Statement, Ex. A at 1.)
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`27.
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`In my opinion, the term “pre-mixed” would not be limited to a
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`manufactured, pre-mixed composition or solution. The basis for my opinion is
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`two-fold, first my own experience as a pharmacist, and second the disclosure in the
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`patent specification.
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`28. My experience as a night-shift hospital pharmacist in a Cardiac
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`Trauma Center during graduate school informed my understanding of the field of
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`pharmacy and pharmaceutics, which helped me in my career as a drug formulator.
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`As a pharmacist, I pre-mixed parenteral drug formulations routinely for other
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`hospital personnel, such as doctors and nurses. While numerous manufacturers,
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`some with my assistance, have developed pre-mixed, ready-to-use formulations,
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`we view those products to be “pre-mixed” for the pharmacist rather than the end-
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`user. Therefore, by limiting the term “pre-mixed” to manufactured, pre-mixed
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`formulations, the Applicant is eliminating the pre-mixing on the part of the
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`pharmacist. Such a limiting definition would be artificial, and not in line with
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`what a hospital pharmacist does as part of their function and responsibilities, i.e.,
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`pre-mixing parenteral solutions for the end user.
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`29.
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`It is also my opinion that to construe the term pre-mixed to be
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`limited to “already mixed from the point of manufacture,” would narrow the term
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`to exclude formulations specifically disclosed in the specification. The ’524
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`specification discloses, “[i]n some embodiments, the pre-mixed pharmaceutical
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`compositions are dispensed in intravenous bags, such as pre-mix bags and admix
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`bags.” (’524 patent at 9:45-47.) The process where a pharmacist prepares a
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`parenteral drug composition is known as admixing. Therefore, a person of
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`ordinary skill in the art would understand “admix bags” to mean nicardipine
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`U.S. Patent No. 8,455,524
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`hydrochloride compositions prepared by pharmacists, prior to their administration
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`by doctors or nurses.
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`30. The ’524 specification also states, “[t]he term ‘pre-mixed’ may
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`also mean a pharmaceutical composition wherein the liquid solution and the active
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`pharmaceutical ingredient are separated from the point of manufacture and in
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`storage.” (’524 patent at 11:34-37.) To exclude pre-mixed formulations where the
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`liquid solution and active are separated from the point of manufacture would
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`narrow the meaning of the term to less than that understood by the person of
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`ordinary skill in the art, based on their own knowledge and the specification itself.
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`However, while I believe the construction above to be correct, it is my opinion that
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`the patent claims are invalid under the narrower construction of the Applicant,
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`particularly in view of the teachings of JP ’364, as discussed below.
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`2.
`31.
`
`“A total impurity formation”
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`Independent claims 1-3 and 8 of the ’524 patent contain the
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`term “a total impurity formation.”
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`32.
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`It is my opinion that “total impurity formation” means “total
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`nicardipine-related impurity formation.”
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`33. My construction of this term comes from the disclosure in the
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`specification, which in my view modifies the plain and ordinary meaning as it is
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`sometimes used in the art.
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`U.S. Patent No. 8,455,524
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`34. A person of ordinary skill in the art would assume the term total
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`impurity formation to mean any formation of impurity, from either the synthesis of
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`the molecule, or through later processing, and finally storage. However, the claims
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`fail to identify any source for the impurity formation, and a person of ordinary skill
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`would generally need to know the identity of an impurity in order to accurately
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`measure it. Without knowledge of the source or chemical structure of the impurity,
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`one cannot make a standard by which to measure a detector response, and an
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`absolute quantitation of the amount of impurities formed, say for example from an
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`excipient or even from the container itself, would not be possible. Nicardipine
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`related impurities, however, have been identified and studied. (See Baaske at
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`1702-03.)
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`35.
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`I have been informed that if the value of a claim term cannot be
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`measured, then the claims may be invalid as indefinite. For this reason, I looked to
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`the specification for guidance as would one of ordinary skill in the art.
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`36. My opinion is confirmed by the specification, which shows that
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`when measuring “total impurity formation,” the inventors are referring to
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`impurities formed by degradation of nicardipine. Example 2 of the specification is
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`directed to measuring “loss in product potency,” which may be due to “degradation
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`and adsorption.” (’524 patent at 15:13-15.) It notes that “[a]t pH 3.3, the drop in
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`% drug remaining is attributed to an increase in total impurities (FIGS. 2B and
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`U.S. Patent No. 8,455,524
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`3B), rather than drug loss due to adsorption.” (Id. at 15:19-21.) The next
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`Attorney Docket No.: 129352800700
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`sentences make clear that the example, and the figures, is addressing “the
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`formation of nicardipine-related impurities (FIGS. 2B and 3B).” (Id. at 15:21-23.)
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`37. The next example continues this approach, referencing Figures
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`4A and 4B as illustrating “the formation of nicardipine-related impurities.” (Id. at
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`15:47-49.) The captions to Figures 2B, 3B, 4A, and 4B use the inventor’s
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`shorthand term “total impurity formation,” which the specification makes clear
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`means nicardipine degradation products, i.e., that they are nicardipine-related
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`impurities. Therefore, a person of ordinary skill in the art would have understood
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`that the inventors intended the term “total impurity formation” to mean “a total
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`nicardipine-related impurity formation” after dilution of the drug because that is
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`how they themselves measured and used the term in the specification.
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`38. To the extent “total impurity formation” is construed more
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`broadly than I have construed the term, it would be invalid as indefinite.
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`39.
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`In my opinion, the remaining terms of the ’524 patent should be
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`construed to have their ordinary meaning in the art because these terms are known
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`in the art and their plain and ordinary meaning is the broadest reasonable
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`interpretation for these terms.
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`VIII. THE ’524 PATENT AND PROSECUTION FILE HISTORY
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`U.S. Patent No. 8,455,524
`Petition for Inter Partes Review
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`Attorney Docket No.: 129352800700
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`40. The ’524 patent is generally directed to methods for treating
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`high blood pressure or inducing hypotension by administering a pre-mixed
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`nicardipine injectable solution with certain stability and purity properties. Without
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`conceding that the ’524 patent claims are entitled to the priority date of the
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`provisional application on its face, the priority date is not earlier than April 16,
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`2006.
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`41. During prosecution, the examiner rejected the pending claims
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`as anticipated by Baaske, or as obvious over Baaske in view of 3 other references.
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`(November 30, 2102 Office Action at 3-11.)
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`42. After an interview, the Applicant then amended the claims to
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`introduce the “contact with non-polar polymer” and stability limitations, and
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`submitted the declaration of Dr. Harry Brittain that was originally submitted while
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`prosecuting U.S. Patent No. 7,612,102. (February 28, 2013 Response and
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`Amendment at 2-3, 7-9.)
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`43.
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`In the Reasons for Allowance, the examiner stated that the prior
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`art of record did “not render obvious the diluted nicardipine hydrochloride with
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`tonicity agent, claimed pH range stored in contact with non-polar polymers
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`wherein the stability is maintain [sic] for at least three months.” (Notice of
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`Allowance at 4.) The examiner, however, did not have JP ’364—a prior art
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`reference forming a grounds for this petition—which discloses a stable formulation
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`ny-1159996
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`15
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`U.S. Patent No. 8,455,524
`Petition for Inter Partes Review
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`of nicardipine hydrochloride in a pre-mixed form stored in contact with non-polar
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`Attorney Docket No.: 129352800700
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`
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`polymers. Until the Applicant amended the claims to limit the storage of the
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`composition to be in contact with non-polar polymers, the examiner had rejected
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`them under 35 U.S.C. § 102(b) based on Baaske—another prior art reference
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`forming a grounds for this petition. (Id. at 3.) Baaske teaches the stability
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`properties of dilute nicardipine solutions. When JP ’364 and Baaske are accounted
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`for, the subject matter claimed in the ’524 would have been obvious. The ’524
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`patent claims should not have been allowed and should now be cancelled.
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`IX. BACKGROUND AND ANALYSIS OF THE PRIOR ART
`A. The State of the Art as of April 2006
`44. The ’524 patent is directed to methods of treatment using pre-
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`mixed, ready to use pharmaceutical compositions containing nicardipine
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`hydrochloride as the active ingredient.
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`45. Nicardipine hydrochloride is not a new drug. The compound
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`itself was patented in 1976. (’524 patent at 1:19-24, Cover at [56].)
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`46. As discussed below in more detail, an intravenous formulation
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`of nicardipine hydrochloride was approved by the FDA in 1992. The 2004 PDR
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`entry for the Cardene I.V. ampul is attached as Ex. 1012 to the IPR. It contains a
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`description of the product, and instructions for the use of the product. This product
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`U.S. Patent No. 8,455,524
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`was supplied as a solution to be diluted with a standard diluent before intravenous
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`Attorney Docket No.: 129352800700
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`
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`administration to a patient. return
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`47. Diluting intravenous drugs with these types of standard diluents
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`is very common.
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`48. Companies have developed pre-mixed parenteral formulations
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`for many years. For example, a pre-mix formulation of Zantac was approved in
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`2000, and a pre-mixed Pepcid parenteral drug product was developed in 2001.
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`(Zantac Label, Pepcid Label.)
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`49.
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`In general, a formulator prefers to use the simplest approach
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`and to utilize excipients and components that have previously been approved by
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`the FDA. The FDA publishes a list of all inactive ingredients used in approved
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`drug products on its website. The list includes the dosage forms and concentration
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`ranges. A formulator would prefer to use the concentrations of