Case IPR2016-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FRESENIUS KABI USA, LLC,
`Petitioner
`
`V.
`
`CEPHALON, INC.,
`Patent Owner
`
`Case IPR2016-O01 ll
`
`Patent No. 8,895,756
`
`
`
`DECLARATION OF MICHAEL J. AKERS Ph.D. UNDER 37 C.F.R. 1.68
`
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`
`PATENT NO. 8,895,756
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`FRESENIUS KABI 1012-OOO1
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION .......................................................................................... .. 1
`
`II.
`
`BACKGROUND AND QUALIFICATIONS ............................................... ..l
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ...................... ..6
`
`IV. OVERVIEW OF THE ’756 PATENT ........................................................... ..7
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .................... ..8
`
`VI. BROADEST REASONABLE CONSTRUCTION ....................................... ..8
`
`VII. UNDERSTANDING OF THE LAW ............................................................. ..8
`
`VIII. SCOPE AND CONTENT OF THE PRIOR ART ....................................... ..lO
`
`A. The Ribomustin® Product Monograph ............................................... .. ll
`
`B. Alexander ............................................................................................. .. 12
`
`C.
`
`Sauerbier .............................................................................................. ..l3
`
`D. Teagarden ............................................................................................. ..l5
`
`E. Maas ..................................................................................................... ..l7
`
`F.
`
`Sullivan ................................................................................................ ..l7
`
`G. DeLuca ................................................................................................. ..l7
`
`IX. DETAILED ANALYSIS ............................................................................. ..l8
`
`A.
`
`Summary of Opinion ............................................................................ ..l9
`
`B. One of Ordinary Skill in the Art Would Have Been Motivated to
`Combine the Ribomustin® Product Monograph with Alexander or
`Sauerbier With a Reasonable Expectation of Success to Obtain a
`Lyophilized Formulation of Bendamustine Hydrochloride and Mannitol
`
`FRESENIUS KABI 1012-OOO2
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`

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`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`With More Desirable Cake Characteristics, Including a Faster
`Reconstitution Time, Than Ribomustin® ............................................ ..2O
`
`C. One of Ordinary Skill in the Art Would Have Been Motivated to
`Combine the Ribomustin® Product Monograph with Alexander or
`Sauerbier and Teagarden With a Reasonable Expectation of Success to
`Obtain a Lyophilized Formulation of Bendamustine Hydrochloride and
`Mannitol With More Desirable Cake Characteristics, Including a Faster
`Reconstitution Time, Than Ribomustin® ............................................ ..27
`
`D. One of Ordinary Skill in the Art Would Have Been Motivated to
`Combine the Ribomustin® Product Monograph with Alexander or
`Sauerbier, Teagarden and DeLuca With a Reasonable Expectation of
`Success to Obtain a Lyophilized Fonnulation of Bendamustine
`Hydrochloride and Mannitol With More Desirable Cake
`Characteristics, Including a Faster Reconstitution Time, Than
`Ribomustin®. ....................................................................................... .30
`
`E. One of Ordinary Skill in the Art Would Have Been Motivated to
`Combine Maas and the Ribomustin® Product Monograph with
`Alexander or Sauerbier and Teagarden With a Reasonable Expectation
`of Success to Obtain a Lyophilized Formulation of Bendamustine
`Hydrochloride and Mannitol With More Desirable Cake Characteristics
`and a Better Impurity Profile Than Ribomustin®. .............................. .36
`
`X.
`
`SUPPLEMENTATION ................................................................................ ..4l
`
`XI. CONCLUSION ............................................................................................ ..42
`
`iii
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`FRESENIUS KABI 1012-OOO3
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`

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`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`1, Michael J. Akers, Ph.D. hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained as an expert witness on behalf of Fresenius Kabi
`
`USA, LLC (“Fresenius”) for the above-captioned Petition for Inter Partes Review
`
`(“IPR”) of U.S. Patent No. 8,895,756 (“the ’756 patent”). I have been asked to
`
`provide my opinions regarding the motivation to combine certain prior art
`
`references from the perspective of one of ordinary skill in the art at the time of the
`
`alleged invention.
`
`2.
`
`I am being compensated at a rate of $300 per hour for my study and
`
`testimony in this matter. I am also being reimbursed for reasonable and customary
`
`expenses associated with my work and testimony in this investigation. My
`
`compensation is not contingent on the outcome of this matter or the specifics of my
`
`testimony.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS
`
`3.
`
`I received a Bachelor of Arts degree in Biology from Wabash College
`
`in l968. I received my Ph.D. in Pharmaceutics from the University of Iowa in
`
`1972. I have over 40 years of experience in pharmaceutical formulation and
`
`development, with a special focus on formulation of lyophilized and parenteral
`
`products.
`
`FRESENIUS KABI 1012-OOO4
`
`

`
`Case ]PR20l6-00l ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`4.
`
`From 1974-1977, I was the Senior Scientist and Head of the
`
`Preformulation Research Section of Alcon Laboratories. At Alcon, I personally
`
`participated in the fonnulation development of numerous sterile products,
`
`including Balanced Salt Solution (BSS) 500 ml, BSS PLUS Intraocular Irrigating
`
`Solution, Natcyn (Natamycin) Ophthalmic Suspension, ZOLYSE (alpha-
`
`chymotrypsin) Solution; DENDRID (idoxuridine) Ointment; EPINAL (epinephyrl
`
`borate) Ophthalmic Solution; and TOBREX (tobramycin) Ophthalmic Solution. I
`
`also contributed to numerous IND and NDA submissions.
`
`5.
`
`For nearly 20 years, I held various positions at Eli Lilly and Company
`
`(“Lilly”), including Head of the Parenteral and Liquid Product Department. At
`
`Lilly, I personally participated in the formulation and development of at least 3
`
`lyophilized products, and was the lead scientist on numerous Lilly parenteral
`
`compounds including both proteins and small molecules. I was also responsible for
`
`QC activities for all (>200) Lilly-marketed parenteral products, including insulin
`
`vials and freeze-dried and powder filled items. I personally participated in the
`
`preparation of NDAS for Glucagon Emergency Kit, Tazidime®, Keftab®, Keflet®,
`
`Humulin® Cartridges, Vancocin® Frozen Minibag, and Gemzar®.
`
`6.
`
`From 2002 through my retirement in 2012, I became Senior Director
`
`of Pharmaceutical Research and Development at Baxter Biopharma Solutions
`
`2
`
`FRESENIUS KABI 1012-0005
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`(“Baxter”). At Baxter, I was the leader of the Baxter Lyophilization Center of
`
`Excellence, and personally participated in the formulation of approximately 10
`
`lyophilized compounds. I also provided technical training and offered over 20
`
`lectures on various sterile products.
`
`7.
`
`I have taught extensively in the fields of pharmaceutical formulation
`
`and development with a special focus on development of parenterals. From 1977-
`
`1981, I was Assistant Professor and then Associate Professor at the University of
`
`Tennessee College of Pharmacy. I taught courses on physical chemistry,
`
`parenterals, ophthalmics, and phannaceutical technology. I have also served as an
`
`Adjunct Professor at Purdue University, the University of Illinois College of
`
`Pharmacy, the University of Cincinnati College of Pharmacy, and the Butler
`
`University College of Pharmacy, and have taught an estimated 3000+ professionals
`
`on the basics of sterile product development, manufacturing, and quality control.
`
`8.
`
`I have published 47 peer-reviewed articles in various journals, with a
`
`number of those papers specifically focusing on parenteral and/or lyophilized
`
`formulations. See, e. g., Kim, AI, Akers, MJ, and Nail, SL, The Physical State of
`
`Mannitol After Freeze-Drying: Effects of Mannitol Concentration, Freezing Rate,
`
`and a Non Crystallizing Cosolute, J. Pharm. Sell, 87, 931-931, 1998, Akers, MJ,
`
`Nail, SL, and Groves, MJ, Top Ten Technical Issues in Parenteral Science—
`
`3
`
`FRESENIUS KABI 1012-0006
`
`

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`Case ]PR20l6-00l ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`Revisited, 1997, Pharm Tech, 21, 126-136, 1997; Schwegman, JJ, Hardwick, LM,
`
`and Akers, MJ, Formulation and Process Development of Freeze-Dried
`
`Biopharmaceuticals, Pharm. Dev. Tech., 10, 151-173, 2005 ; and Hardwick, LM,
`
`Paunicka, C, and Akers, MJ, Critical Factors in the Design and Optimization of
`
`Lyophilization Process, Innov. Pharm. Tech., 1, 72-75, 2008.
`
`9.
`
`I also serve or have served on the editorial board of the following
`
`journals: Journal ofParenteral Science and Technology, (1980-2010),
`
`Pharmaceutical Manufacturing, (1982-86); Pharmaceutical Technology, (1983-
`
`present); Interpharm Press, (1991-2000); Pharmaceutical Development and
`
`Technology, (1996-2015);/1APS PharmSci, (1999-present); AAPS PharmaSciTech,
`
`(2001-present), and Journal ofPharmaceutical Sciences, (2005-present).
`
`10.
`
`I am also the author of more than 30 books and/or book chapters, with
`
`a number of those book chapters specifically focusing on parenteral and/or
`
`lyophilized formulations. See, e.g., “Routes of Parenteral Administration”, Duma,
`
`RJ., Akers, MJ, and Turco, S, in Parenteral Medications, 2nd edition, Avis, KE,
`
`Lachman, L, Lieberman, HA, eds., Marcel Dekker, New York, 1992, pp. 17-58,
`
`“Parenteral Preparations”, Akers, MJ, in Remington ’s Pharmaceutical Sciences,
`
`21st ed., Lipponcott Williams & Wilkins, Philadelphia, 2005, pp. 802-836; and
`
`Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity
`
`4
`
`FRESENIUS KABI 1012-0007
`
`

`
`Case ]PR20l6-001 ll
`
`Declaration of Michael J . Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`Testing, 3rd edition, revised and expanded, Akers, MJ, Larrimore, D, and Guazzo,
`
`DM, Marcel Dekker, Inc., New York, 2002, 430 pages.
`
`ll.
`
`I have been invited to lecture internationally on pharmaceutical
`
`technologies, including lyophilization and parenteral formulation. These invited
`
`talks include, e. g., “Top Ten Technical Issues in Parenteral Science” Beiersdorf
`
`Laboratories, Hamburg, Germany, Feb. 23, 1994, “Revisiting the scientific
`
`principles of lyophilization: practical considerations in developing an optimal
`
`freeze drying process” Institute for Int’l Research on Optimizing Freeze-Drying
`
`Cycle Development, Philadelphia, July 30, 2003, and “Scale-Up Issues in Process
`
`Design of Lyophilization Cycles,” Freeze Drying of Pharmaceuticals and
`
`Biologicals, Breckenridge, Colorado, July 29, 2004 (co-authored with Lisa
`
`Hardwick, Wei Kuu, and Jamey Jarman).
`
`12.
`
`I have consulted with 67 pharmaceutical companies throughout my
`
`career. Many of these consultancy arrangements concern phannaceutical
`
`formulation, and, specifically, preparation of parenteral and lyophilized products. I
`
`have also taught sterile products courses at the following pharmaceutical
`
`companies: Roche, Pfizer, Bristol-Myers Squibb, Gensia Sicor, Amgen,
`
`Genentech, Eisai, Alza, Eli Lilly, Merck, and Abbott.
`
`FRESENIUS KABI 1012-0008
`
`

`
`Case ]PR20l6-001 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`13.
`
`I have been a member of numerous professional societies including
`
`the American Association of Pharmaceutical Sciences (“AAPS”), Parenteral Drug
`
`Association, and the United States Phannacoepia. With respect to AAPS, I was the
`
`Co-Chainnan and Founder of the Sterile Products Group. With respect to the
`
`Parenteral Drug Association, I served for several years as co-chair of the
`
`Lyophilization Validation Task Force with Ed Trappler. With respect to the United
`
`States Pharrnacoepia, I served on the expert committee on parenterals from 2005-
`
`2009.
`
`14. A more detailed description of my background, qualifications and a
`
`list of cases in which I have provided testimony either at trial or deposition can be
`
`found in my curriculum vitae (attached hereto as Exhibit A).
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION
`
`15. My opinions are based on my years of education, research and
`
`experience, as well as my investigation and study of relevant materials. In forming
`
`my opinions, I have considered the materials I identify in this report and those
`
`listed in Exhibit B.
`
`16.
`
`I may rely upon these materials and/or additional materials to respond
`
`to arguments raised by Cephalon. I may also consider additional documents and
`
`FRESENIUS KABI 1012-0009
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`information in fonning any necessary opinions — including documents that may
`
`not yet have been provided to me.
`
`17. My analysis of the materials produced in this investigation is ongoing,
`
`and I will continue to review any new material as it is provided. This report
`
`represents only those opinions I have formed to date. I reserve the right to revise,
`
`supplement, and/or amend my opinions stated herein based on new information
`
`and on my continuing analysis of the materials already provided.
`
`IV. OVERVIEW OF THE ’756 PATENT
`
`20.
`
`The ’756 patent was filed on December 19, 2012, and issued on
`
`November 25, 2014. As issued, the ’756 patent contains 4 claims:
`
`1. A vial containing a reconstituted solution of
`bendamustine hydrochloride and mannitol in sterile water
`for injection, wherein the ratio by weight of
`bendamustine hydrochloride to mannitol in the vial is
`15:25.5, and wherein the bendamustine hydrochloride is
`present in the vial at a concentration of 100 mg per 20
`mL.
`
`2. The vial of claim 1, wherein the vial contains 25 mg of
`bendamustine hydrochloride.
`
`3. The vial of claim 1, wherein the vial contains 100 mg
`of bendamustine hydrochloride.
`
`4. A 20 mL vial containing 100 mg of bendamustine
`hydrochloride and 170 mg of mannitol reconstituted in
`sterile water for inj ection.
`
`FRESENIUS KABI 1012-0010
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`21.
`
`I understand that Cephalon argued that the distinction between its
`
`invention and the prior lyophilized formulations of bendamustine hydrochloride
`
`(such as Ribomustin® and Cytostastan® described in the ’75 6 patent) is a
`
`lyophilized formulation that is “easier to reconstitute” and has “a better impurity
`
`profile.” Exh, l00l, col. 2, ll. 38-41.
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART
`
`22.
`
`It is my opinion that one of ordinary skill in the relevant art at the time
`
`of invention (z'.e., in 2005) is a person with a Ph.D. in pharmaceutics,
`
`pharmaceutical sciences, analytical chemistry, or a related field, with at least 3
`
`years of practical experience in formulating and/or analyzing pharmaceutical
`
`formulations.
`
`VI. BROADEST REASONABLE CONSTRUCTION
`
`23.
`
`I understand that a claim subject to inter partes review receives the
`
`broadest reasonable construction in light of the specification of the patent in which
`
`it appears. I also understand that where the patent has not provided a specialized
`
`meaning to a particular claim term, that term should be interpreted according to its
`
`plain and ordinary meaning to one skilled in the art.
`
`VII. UNDERSTANDING OF THE LAW
`
`FRESENIUS KABI 1012-0011
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`

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`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`24.
`
`I understand that patents and printed publications in the relevant art
`
`that predate the January 14, 2005 priority date are prior art to the ’756 patent.
`
`25.
`
`I understand that a claim is invalid if it is obvious. Obviousness
`
`requires that the claim be obvious from the perspective of one of ordinary skill in
`
`the relevant art at the time the alleged invention was made, without the use of post-
`
`filing knowledge. I further understand that an obviousness analysis requires an
`
`understanding of the scope and content of the prior art, any differences between the
`
`alleged invention and the prior art, and the level of ordinary skill in evaluating the
`
`pertinent art.
`
`26.
`
`I understand that a claim may be obvious in light of one or more prior
`
`art references, and that this may be shown by demonstrating that it would have
`
`been obvious to one of ordinary skill in the art to combine the teachings of more
`
`than one prior art reference. I further understand that examples of where it would
`
`have been obvious to one of ordinary skill in the art to combine a piece of prior art
`
`with another piece of prior art, or with other information within the knowledge of
`
`one of ordinary skill in the art, include:
`
`0 Using a known technique, or a technique described in another prior art
`
`reference, to improve similar methods or products in the same way,
`
`0 Using a predictable variation of a known technique, or a technique
`
`9
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`FRESENIUS KABI 1012-0012
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`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`described in another prior art reference, to the same or a different field
`
`based on design incentives or other market forces;
`
`0 Combining prior art elements according to known methods, or
`
`substituting one known element for another, to yield predictable
`
`results,
`
`0 Applying a known technique to a known method or product to yield
`
`predictable results, or applying a technique or approach that would
`
`have been “obvious to try” (choosing from a finite number of
`
`identified, predictable solutions, with a reasonable expectation of
`
`success), or
`
`0
`
`Inferring that some teaching, suggestion, or motivation in the prior art
`
`would have led one of ordinary skill to modify the prior art reference
`
`or combine it with another prior art reference.
`
`27.
`
`I understand that for a motivation to modify the prior art to exist, one
`
`of ordinary skill in the art must have only a “reasonable expectation of success,”
`
`and not “absolute predictability.”
`
`VIII. SCOPE AND CONTENT OF THE PRIOR ART
`
`l0
`
`FRESENIUS KABI 1012-0013
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`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`28.
`
`I understand that a U.S. patent is a formally published document, and
`
`that I may rely on the dates in the patent as to when the patent was filed and when
`
`it was granted.
`
`29.
`
`I understand that the ’756 patent issued from an application filed in
`
`December 2012, but that it claims priority to a provisional application filed in
`
`January 2005. I have been advised that the Ribomustin® Product Monograph (Exh.
`
`1005); Alexander (Exh. 1006), Sauerbier (Exh. 1007), Teagarden (Exh. 1008);
`
`Maas (Exh. 1009); Sullivan (Exh. l0l0) and DeLuca (Exh. l0l l) (discussed
`
`below) are prior art to the ’75 6 patent.
`
`A.
`
`The Ribomustin® Product Monograph
`
`30.
`
`The Ribomustin® Product Monograph was published in 2002 (and
`
`was publicly available in both print and electronic forms), and is attached as
`
`Exhibit 1005 to the IPR.
`
`31.
`
`The Ribomustin® Product Monograph teaches that Ribomustin® was
`
`indicated as single-agent therapy or in combination with other antineoplastic drugs
`
`for the treatment of the following malignancies: Hodgl<in’s disease (stages II-IV);
`
`non-Hodgl<in’s lymphoma, plasmocytoma; chronic lymphocytic leukemia; and
`
`breast cancer.
`
`ll
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`FRESENIUS KABI 1012-0014
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`32.
`
`The Ribomustin® Product Monograph teaches that Ribomustin® was
`
`fonnulated as a lyophilized powder for injection with 100 mg of bendamustine
`
`hydrochloride per vial or 25 mg of bendamustine hydrochloride per vial, and that
`
`Ribomustin® was reconstituted with 40 mL (for the 100 mg vial) or 10 mL (for the
`
`25 mg vial) of sterile water for injection. See Exh. 1005 at 0007-0008, §§ 2.3-2.6.
`
`33.
`
`The Ribomustin® Product Monograph teaches that Ribomustin® was
`
`formulated with bendamustine hydrochloride as the active ingredient and mannitol
`
`as the only other ingredient. See Exh. 1005 at 0055, §§ 1 & 3.3. One of ordinary
`
`skill in the art, therefore, would have understood that Ribomustin® was provided
`
`in a vial having 100 mg bendamustine hydrochloride and 120 mg mannitol (a
`
`weight ratio of 1:1.2) as well as a vial having 25 mg bendamustine hydrochloride
`
`and 30 mg mannitol (a weight ratio of 1:1.2). See Exh. 1005 at 0007, § 2.3.
`
`B.
`
`Alexander
`
`34. Alexander was filed in 1984, and is attached as Exhibit 1006 to the
`
`IPR.
`
`35. Alexander taught one of ordinary skill in the art that the development
`
`of a lyophilized preparation of a pharmaceutical product with “desirable physical
`
`properties [could] be achieved only by using mannitol as the major exczpient.” See
`
`Exh. 1006, col. 3, ll. 53-55 (emphasis in the original).
`
`12
`
`FRESENIUS KABI 1012-0015
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`36. Alexander taught one of ordinary skill in the art that desirable
`
`lyophilized cake characteristics included aspects such as “original shape, no
`
`shrinkage or meltback, good coloration, homogeneity, firmness, and crystallinity”
`
`(Exh. 1006, col. 4, 11. 41-43) and that the lyophilized formulation “dissolved easily
`
`upon reconstitution with water” (Exh. 1006, col. 5, 11. 35-36).
`
`37. Alexander taught one of ordinary skill in the art how to freeze-dry a
`
`prelyophilization solution of cyclophosphamide, mannitol and water to obtain a
`
`lyophilized formulation with desirable cake characteristics. See Exh. 1006, col. 9, 1.
`
`65 — col. 11, l. 52.
`
`38. Alexander taught one of ordinary skill in the art the preparation of
`
`preferred lyophilized formulations of cyclophosphamide and mannitol in a weight
`
`ratio of 1:0.5 to 1:2.0. See Exh. 1006, col. 7, 11. 18-22 (“Preferred solid
`
`compositions of the instant invention are comprised of about 20 parts by weight of
`
`cyclophosphamide, taken as the anhydrous fonn, about 1%-2 parts by weight of
`
`water and from about 10-40 parts by weight of excipient which is primarily
`
`mannitol”).
`
`C.
`
`Sauerbier
`
`39.
`
`Sauerbier was filed in 1991, and is attached as Exhibit 1007 to the
`
`IPR.
`
`13
`
`FRESENIUS KABI 1012-0016
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`40.
`
`Sauerbier taught one of ordinary skill in the art that mannitol
`
`facilitated lyophilized fonnulations having desirable cake characteristics, which
`
`included aspects such as enhanced dissolution properties, thermal stability,
`
`consistency, solubility, microbiological safety, and ease of filling. See Exh. 1007,
`
`col. 2, 1. l2 — col. 3,1. 6.
`
`4l.
`
`Sauerbier taught one of ordinary skill in the art the distinct advantage
`
`that the ifosfamide and mannitol lyophilized fonnulation “dissolves immediately
`
`on addition of solvent.” See Exh. l007, col. 2, ll. 39-40.
`
`42.
`
`Sauerbier taught one of ordinary skill in the art how to freeze-dry a
`
`prelyophilization solution of ifosfamide, mannitol and water to obtain a lyophilized
`
`formulation with desirable cake characteristics. See Exh. l007, col. 6, l. 24 — col. 7,
`
`l. 52.
`
`43.
`
`Sauerbier taught one of ordinary skill in the art the preparation of
`
`preferred lyophilized formulations of ifosfamide and mannitol in a weight ratio of
`
`l:0.l to l:2.5. See Exh. l007, col. 3, 1. 28-34 (“The amount of the hexitol may also
`
`be expressed in relation to the weight of ifosfamide, in which case the amount of
`
`the hexitol is 0.1 to 17, preferably 0.1 to 2.5, in particular 0.6 to 0.8 parts by weight
`
`of the hexitol for each part by weight of ifosfamide. Hexitols which may be used
`
`include: mannitol .
`
`.
`
`. 7’).
`
`l4
`
`FRESENIUS KABI 1012-0017
`
`

`
`Case ]PR20l6-00l ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`D.
`
`Teagarden
`
`44.
`
`Teagarden was published in 2002, and is attached as Exhibit 1008 to
`
`the IPR.
`
`45.
`
`Teagarden reviewed various, non-aqueous co-solvent systems that had
`
`been evaluated for their potential use in the freeze-drying of pharmaceutical
`
`products. See Exh. 1008 at 0001.
`
`46.
`
`Teagarden taught one of ordinary skill in the art that desirable
`
`lyophilized cake characteristics included aspects such as “increased drug wetting
`
`or solubility, increased sublimation rates, increased pre-dried bulk solution or dried
`
`product stability, decreased reconstitution time, and enhancement of sterility
`
`assurance of the pre-dried bulk solution.” See Exh. 1008 at 0001.
`
`47.
`
`Teagarden taught one of ordinary skill in the art that the “co-solvent
`
`system that has been most extensively evaluated was the tert-butanol / water
`
`combination.” See Exh_ 1008 at 0001.
`
`48.
`
`Teagarden taught one of ordinary skill in the art that tert-butanol was
`
`advantageous because it possessed “a high vapor pressure, freezes completely in
`
`most commercial freeze-dryers, readily sublimes during primary drying, can
`
`increase sublimation rates, and has low toxicity.” See Exh. 1008 at 0001.
`
`15
`
`FRESENIUS KABI 1012-0018
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`49.
`
`Teagarden taught one of ordinary skill in the art that the tert-butanol /
`
`water combination had been successfully used in the manufacture of a marketed
`
`inj ectable pharmaceutical product. See Exh. 1008 at 0001.
`
`50.
`
`Teagarden taught one of ordinary skill in the art that the use of a tert-
`
`butanol / water co-solvent system with the proper drying cycle would produce
`
`amorphous cakes with large surface areas, and that these cakes “tended to
`
`reconstitute extremely rapidly upon addition of reconstitution vehicle.” See Exh.
`
`1008 at 0009, § 6, Exh. 1008 at 0007 (“The resulting surface area of the dried cake
`
`increased by approximately 13-fold when the 5% tert-butanol was used”).
`
`5 l.
`
`Teagarden taught one of ordinary skill in the art that the use of a tert-
`
`butanol / water co-solvent system “produced a greater than 40-fold increase in
`
`solubility compared to that in pure water” with at least one formulation. See Exh.
`
`1008 at 0003, § 2 (aplidine).
`
`52.
`
`Teagarden taught one of ordinary skill in the art that the use of a tert-
`
`butanol / water co-solvent system “slowed solution state degradation by a factor of
`
`approximately 4-5.” See Exh. 1008 at 0004, § 3 (trecetilide fumarate).
`
`53.
`
`Teagarden taught one of ordinary skill in the art that lyophilization
`
`was costly. See Exh. 1008 at 0005, § 4.2 (“The freeze-drying process is a unit
`
`operation which typically involves a long and expensive process”).
`
`16
`
`FRESENIUS KABI 1012-0019
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`E. Maas
`
`54. Maas was published in 1994, and the German language original and
`
`certified English translation are attached as Exhibit 1009 to the IPR.
`
`55. Maas perfonned decomposition experiments with reconstituted
`
`Ribomustin®. See Exh. 1009 at 0004.
`
`56. Maas repeatedly emphasized the known instability of bendamustine
`
`hydrochloride in aqueous solution, explaining that “[b]endamustine is very
`
`unstable in an aqueous solution.” See Exh. 1009 at 0004. Maas further taught one
`
`of ordinary skill in the art that “rapid hydrolysis” occurred in “aqueous
`
`bendamustine hydrochloride solutions.” Exh. 1009 at 0005.
`
`F.
`
`Sullivan
`
`57.
`
`Sullivan was filed in 1996, and is attached as Exhibit 1010 to the IPR.
`
`5 8.
`
`Sullivan taught one of ordinary skill in the art that economic
`
`considerations may dictate vials with smaller diameters because “[s]maller vials
`
`can be packed together more closely, fill up the horizontal area of a shelf [in a
`
`lyophilization chamber] better, and leave less empty [space] between the vials”).
`
`See Exh. 1010, col. 14,11. 14-22.
`
`G.
`
`DeLuca
`
`17
`
`FRESENIUS KABI 1012-0020
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`59. DeLuca was published in 1992, and is attached as Exhibit 1011 to the
`
`IPR.
`
`60. DeLuca taught one of ordinary skill in the art that the solids content in
`
`a prelyophilization solution should be between about 5%-30% (optimally 10%-
`
`15%). See Exh. 1011 at 0006 (teaching that “the need for a suitable filler or
`
`bulking agent is often indicated” and listing mannitol as an appropriate material “to
`
`improve the physical characteristics of the finished cake”).
`
`61. DeLuca taught one of ordinary skill in the art that a lower solids
`
`content would accelerate drying, but that too low a solids content could result in an
`
`undesirable, brittle lyophilized cake subject to collapse. See Exh. 1011 at 0006
`
`(“So compromises and trade-offs are often necessary”).
`
`62. DeLuca taught one of ordinary skill in the art that “[t]he depth of fill
`
`in a container is critical” and “[w]hile this depends on the volume of the container,
`
`a rule of thumb has been 1 to 2 cm in depth but never exceed one-half the capacity
`
`of the container.” See Exh. 1011 at 0006.
`
`IX. DETAILED ANALYSIS
`
`63.
`
`I have been asked to provide an opinion as to whether one of ordinary
`
`skill in the art at the time of the purported invention would have been motivated to
`
`combine the teachings of (1) the Ribomustin® Product Monograph, Alexander or
`
`18
`
`FRESENIUS KABI 1012-0021
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`Sauerbier, or (2) the Ribomustin® Product Monograph, Alexander or Sauerbier
`
`and Teagarden; or (3) the Ribomustin® Product Monograph, Alexander or
`
`Sauerbier, Teagarden and DeLuca, or (4) Maas and the Ribomustin® Product
`
`Monograph, Alexander or Sauerbier and Teagarden, and whether such a person
`
`would have had a reasonable expectation of success in obtaining a lyophilized
`
`formulation of bendamustine hydrochloride and mannitol with more desirable cake
`
`characteristics, a faster reconstitution time, and/or a better impurity profile than
`
`Ribomustin®.
`
`64.
`
`As part of my analysis, I considered the scope and content of the prior
`
`art as well as the level of ordinary skill in the pertinent art in perfonning my
`
`analyses.
`
`A.
`
`Summagy of Opinion
`
`65.
`
`In summary, it is my opinion that:
`
`0 The Ribomustin® Product Monograph discloses almost all the
`
`elements of the ’75 6 patent claims;
`
`0 One of ordinary skill in the art would have been motivated to combine
`
`the teachings of the Ribomustin® Product Monograph, Alexander,
`
`Sauerbier, Teagarden, DeLuca and Maas,
`
`0 One of ordinary skill in the art would have a reasonable expectation of
`
`19
`
`FRESENIUS KABI 1012-0022
`
`

`
`Case ]PR20l6-O01 ll
`
`Declaration of Michael J. Akers, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,895,756
`
`success in obtaining a lyophilized fonnulation of bendamustine
`
`hydrochloride and mannit