Case IPR2016-
`
`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. 8,791,270
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FRESENIUS KABI USA, LLC,
`Petitioner
`
`V.
`
`CEPHALON, INC.,
`Patent Owner
`
`Case IPR20 16
`
`Patent No. 8,791,270
`
`
`
`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. 8,791,270
`
`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 1013-0001
`
`
`
`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. 8,791,270
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FRESENIUS KABI USA, LLC,
`Petitioner
`
`V.
`
`CEPHALON, INC.,
`Patent Owner
`
`Case IPR20 16
`
`Patent No. 8,791,270
`
`
`
`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. 8,791,270
`
`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 1013-0001
`
`
`
`Case IPR2016
`
`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. 8,791,270
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... ..l
`
`II. BACKGROUND AND QUALIFICATIONS ................................................. ..l
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ........................ ..6
`
`IV. OVERVIEW OF THE ‘270 PATENT ............................................................ ..7
`
`V. LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .................... ..lO
`
`VI. BROADEST REASONABLE CONSTRUCTION ....................................... ..lO
`
`VII. UNDERSTANDING OF THE LAW ............................................................ ..ll
`
`VIII.SCOPE AND CONTENT OF THE PRIOR ART ......................................... .13
`
`A. Maas, Stability ofBendamustine Hydrochloride in Infusions, 49
`PHARMAZIE 775 (1994) ................................................................... .13
`
`B. Teagarden, Practical aspects of lyoplzilization using non—aqueous co-
`solvent systems, 15 EUR. J. PHARM. SCI. 115 (March 2002) .......... ..l4
`
`IX. DETAILED ANALYSIS ............................................................................... ..l5
`
`A.
`
`Summary of Opinion ........................................................................... ..l6
`
`B. A Person of Ordinary Skill in the Art Would Have Been Motivated to
`Combine Maas with Teagarden. .......................................................... ..l6
`
`C. A Person of Ordinary Skill in the Art Would Have Had a Reasonable
`Expectation of Success in Lowering Degradant Levels Based on the
`Teachings of Maas and Teagarden, ..................................................... ..l9
`
`X.
`
`SUPPLEMENTATION ................................................................................. ..2l
`
`XI. CONCLUSION .............................................................................................. ..22
`
`ii
`
`FRESENIUS KABI 1013-0002
`
`
`
`Case IPR2016-
`
`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. 8,791,270
`
`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. 8,791,270 (“the ‘270 patent”).
`
`I have been asked to
`
`provide my opinions regarding the motivation to combine certain prior art
`
`references from the perspective of a person having 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 1968.
`
`I received my Ph.D. in Phannaceutics from the University of Iowa in
`
`1972.
`
`I have over 40 years’ experience in phannaceutical formulation and
`
`development, with a special focus on formulation of lyophilized and parenteral
`
`products.
`
`4.
`
`From 1974-1977,
`
`I was the Senior Scientist and Head of the
`
`FRESENIUS KABI 1013-0003
`
`
`
`Preformulation Research Section of Alcon Laboratories. At Alcon; I personally
`
`participated in the formulation 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
`
`(“Baxter”). At Baxter; I was the leader of the Baxter Lyophilization Center of
`
`Excellence; and personally participated in the formulation of approximately 10
`
`FRESENIUS KABI 1013-0004
`
`
`
`lyophilized compounds.
`
`I also provided technical training and offered over 20
`
`lectures on various sterile products.
`
`7.
`
`I have taught extensively in the fields 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 pharmaceutical 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--
`
`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,
`
`FRESENIUS KABI 1013-0005
`
`
`
`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 of Parenteral Science
`
`and Technology,
`
`(1980-2010),
`
`Pharmaceutical Manufacturing, (1982-86); Pharmaceutical Technology, (1983-
`
`present),
`
`Interpharm Press,
`
`(1991-2000), Pharmaceutical Development and
`
`Technology,
`
`(1996-present);
`
`AAPS
`
`PharmSci,
`
`(1999-present);
`
`AAPS
`
`PharmaSciTech, (2001-present), and Journal of Pharmaceutical 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, K. E.,
`
`Lachman, L., Lieberman, H. A., eds., Marcel Dekker, New York, 1992, pp. 17-58,
`
`“Parenteral Preparations,” Akers, MJ, Remington ’s Pharmaceutical Sciences, 215‘
`
`ed., Lipponcott Williams & Wilkins, Philadelphia, 2005, pp. 802-836, and
`
`Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity
`
`Testing, 3nd edition, revised and expanded, Akers, MJ, Larrimore, D, and Guazzo,
`
`DM, Marcel Dekker, Inc., New York, 2002, 430 pages.
`
`11.
`
`I have been invited to lecture internationally on pharmaceutical
`
`FRESENIUS KABI 1013-0006
`
`
`
`technologies, including lyophilisation 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 Jarrnan).
`
`12.
`
`I have consulted with 67 pharmaceutical companies throughout my
`
`career. Many of these consultancy arrangements concern pharmaceutical
`
`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.
`
`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 Pharmacoepia. With respect to AAPS, I was
`
`the Co-Chairman and Founder of the Sterile Products Group. With respect to the
`
`Parenteral Drug Association,
`
`I served for several years as co-chair of the
`
`FRESENIUS KABI 1013-0007
`
`
`
`Lyophilization Validation Task Force with Ed Trappler. With respect to the
`
`United States Pharmacoepia, I served on the expert committee on parenterals from
`
`2005-2009.
`
`14. A more detailed description of my background, qualifications can be
`
`found in my curriculum vitae (attached hereto as Exhibit A).
`
`I have not testified at
`
`trial or deposition in the past four years.
`
`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
`
`information in forming 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.
`
`FRESENIUS KABI 1013-0008
`
`
`
`IV. OVERVIEW OF THE ‘270 PATENT
`
`20.
`
`The ‘270 patent was filed on August 19, 2013, and issued on July 29,
`
`2014. As issued, the ‘270 patent contains 23 claims:
`
`been
`has
`that
`composition
`1. A pharmaceutical
`of
`preparation
`lyophilized
`reconstituted
`from a
`said
`bendamustine
`or bendamustine hydrochloride,
`composition containing not more than about 0.9% (area
`percent of bendamustine) of HP1:
`
`rrofi
`/f
`
`3”‘
`
`=:::.
`
`1 .1
`
`.
`
`42:)
`
` c:I-I.
`A
`
`V
`
`2. The pharmaceutical composition of claim 1, wherein
`the amount of HP1 is measured at
`time zero after
`
`reconstitution of said lyophilized preparation.
`
`3. The pharmaceutical composition of claim 1, wherein
`the amount of HP1 is not more than 0.5% (area percent
`of bendamustine).
`
`4. The pharmaceutical composition of claim 2, wherein
`the amount of HP1 is not more than 0.5% (area percent
`of bendamustine).
`
`5. The pharmaceutical composition of claim 1, wherein
`the amount of HP1 is not more than 0.4% (area percent
`of bendamustine).
`
`6. The pharmaceutical composition of claim 2, wherein
`the amount of HP1 is not more than 0.4% (area percent
`of bendamustine).
`
`composition of bendamustine
`7. A pharmaceutical
`hydrochloride, containing less than or equal
`to 4.0%
`
`7
`
`FRESENIUS KABI 1013-0009
`
`
`
`percent
`(area
`degradants.
`
`of bendamustine)
`
`of bendamustine
`
`8. The pharmaceutical composition of claim 7, containing
`between about 2.0% and 4.0% (area percent of
`bendamustine) of bendamustine degradants.
`
`9. The pharmaceutical composition of claim 8, wherein
`the pharmaceutical composition has been reconstituted
`from a
`lyophilized
`preparation
`of bendamustine
`hydrochloride.
`
`claim 9,
`composition of
`10. The pharmaceutical
`containing not more than about 0.9% (area percent of
`bendamustine) of HP1 at time zero after reconstitution.
`
`claim 9,
`composition of
`11. The pharmaceutical
`containing not more than about 0.5% (area percent of
`bendamustine) of HP1 at time zero after reconstitution.
`
`claim 9,
`composition of
`12. The pharmaceutical
`containing not more than about 0.4% (area percent of
`bendamustine) of HP1 at time zero after reconstitution.
`
`composition of claim 10,
`13. The pharmaceutical
`containing not more than about 0.5% (area percent of
`bendamustine) of a compound of Formula IV at time zero
`after reconstitution:
`
`FE!,l'T.T1K1l£l TV
`
`fit
`
`iT'£)€}CTI»l3£T‘lI3.
`R
`a:?:’/A‘v/ \ NW
`
`1
`
`14. The pharmaceutical composition of claim 7, wherein
`the
`pharmaceutical
`composition
`is
`a
`lyophilized
`composition.
`
`FRESENIUS KABI 1013-0010
`
`
`
`15. The pharmaceutical composition of claim 8, wherein
`the
`pharmaceutical
`composition
`is
`a
`lyophilized
`composition.
`
`claim 7,
`composition of
`16. The pharmaceutical
`containing not more than about 0.9% (area percent of
`bendamustine) of HP1.
`
`claim 7,
`composition of
`17. The pharmaceutical
`containing not more than about 0.5% (area percent of
`bendamustine) of HP1.
`
`claim 7,
`composition of
`18. The pharmaceutical
`containing not more than about 0.4% (area percent of
`bendamustine) of HP1.
`
`claim 7,
`composition of
`19. The pharmaceutical
`containing not more than about 0.5% (area percent of
`bendamustine) of a compound of Formula IV:
`
`K‘
`
`Fanrinails. W’
`
`m~z"3«:“I~1‘_i:;‘-H3.
`
`20. A method of treating cancer in a patient comprising
`administering
`to
`the
`patient
`a
`pharmaceutical
`composition of bendamustine hydrochloride according to
`claim 7.
`
`21. The method according to claim 20, wherein the
`cancer
`is chronic lymphocytic leukemia, Hodgkin’s
`disease, non-Hodgkin’s lymphoma, multiple myeloma, or
`breast cancer.
`
`22. The method according to claim 20, wherein the
`cancer is chronic lymphocytic leukemia.
`
`FRESENIUS KABI 1013-0011
`
`
`
`23. The method according to claim 20, wherein the
`cancer is non-Hodgkin’s lymphoma.
`
`21.
`
`I understand that Cephalon argued that the distinction between its
`
`invention and the prior formulations of bendamustine hydrochloride (such as the
`
`Ribomustin® and Cytostastan® formulations described in the specification) was a
`
`“better impurity profile than Ribomustin® with respect to certain impurities,
`
`in
`
`particular HP1 .
`
`.
`
`. and bendamustine ethylester .
`
`.
`
`. .” Id. at 12:31-38.
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART
`
`22.
`
`It is my opinion that a person having 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 Fresenius has proposed the following constructions
`
`under the broadest reasonable interpretation:
`
`Term
`
`Broadest Reasonable Construction
`
`“pharmaceutical composition”
`
`“a composition that is made under
`conditions such that it is suitable for
`
`administration to humans”
`
`“pharmaceutical composition that has
`been reconstituted”
`
`“[pharmaceutical composition] (as
`construed above) that has been
`dissolved in a solvent or diluent”
`
`10
`
`FRESENIUS KABI 1013-0012
`
`
`
`“area percent of bendamustine”
`
`“the amount of a specified degradant
`relative to the amount of bendamustine”
`
`“bendamustine degradants”
`
`“chemical compounds resulting from a
`change in chemical structure of
`bendamustine”
`
`'
`'
`CC '
`time zero after reconstitution
`
`77
`
`CC
`
`'
`'
`'
`soon after dissolution in a solvent or a
`
`diluent”
`
`VII. UNDERSTANDING OF THE LAW
`
`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 ‘270 patent.
`
`25.
`
`I understand that a claim is invalid if it is obvious. Obviousness
`
`requires that the claim be obvious from the perspective of a person having 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 a person having 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 a person of ordinary skill in the art to combine a piece
`
`ll
`
`FRESENIUS KABI 1013-0013
`
`
`
`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
`
`described in another prior art reference, to the same or a different field
`
`based on design incentives or other market forces;
`
`o 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, a
`
`person of ordinary skill in the art must only have only a “reasonable expectation of
`
`12
`
`FRESENIUS KABI 1013-0014
`
`
`
`success,” and not “absolute predictability.”
`
`VIII. SCOPE AND CONTENT OF THE PRIOR ART
`
`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 ‘270 patent issued from an application filed in
`
`August 2013, but that it claims priority to a provisional application filed in January
`
`of 2005.
`
`I have been advised that both Maas and Teagarden (discussed below) are
`
`prior art to the ‘270 patent.
`
`A. Maas, Stzzbilitz ofBe11d221m1st1'11e Hzdrocbloride 1'11 Infusions, 49
`PHARMAZIE 775 (1994)
`
`30. Maas was published in 1994, and the German language original and
`
`certified English translation are attached as Exhibit 1004 to the IPR. Maas
`
`discloses Ribomustin®, which it teaches is a “lyophilized dry substance” that is an
`
`“effective chemotherapeutic drug in the treatment of malignant diseases.” Exhibit
`
`1004 at 0004.
`
`31. Maas repeatedly emphasizes the known instability of bendamustine
`
`hydrochloride in aqueous solution, explaining that “[b]endamustine is very
`
`unstable in an aqueous solution.” Id. Maas further teaches that “rapid hydrolysis”
`
`occurs in “aqueous bendamustine hydrochloride solutions” (id. at 0005), and
`
`13
`
`FRESENIUS KABI 1013-0015
`
`
`
`teaches a tgo (time at 10% degradation of drug product) of 9 hours at room
`
`temperature. Id. at 0004.
`
`32. Maas
`
`further
`
`teaches
`
`using
`
`High-Performance
`
`Liquid
`
`Chromatography (“HPLC”)
`
`to analyze and characterize the stability of the
`
`Ribomustin® formulation “immediately after dilution.” Id. at 0005. The Maas
`
`HPLC chromatogram identifies two degradants “immediately after dilution”—the
`
`“monohydrolysis product” and an additional “unknown” synthesis. Id.
`
`B.
`
`Teagarden, Practical zzsgects ofIz0QI11'I1'z22t1'011 using 11011-aqueous
`co-solventszstems, 15 EUR. J. PHARM. SCI. 115 {March 2002)
`
`33.
`
`Teagarden was published in 2002, and is attached as Exhibit 1005 to
`
`the IPR.
`
`34.
`
`Teagarden discloses known uses and benefits of “nonaqueous co-
`
`solvent systems” (z'.e., mixtures of water with an organic solvent)
`
`for
`
`the
`
`lyophilization of pharmaceutical formulations.
`
`35.
`
`Teagarden explains that “[t]here are many reasons why it may be
`
`beneficial
`
`to both product quality and process optimization to select
`
`a
`
`lyophilization process which employs a strictly organic or organic /water co-
`
`solvent system.” Id. at 0001. These advantages include that such a solvent system:
`
`[I]ncreases rate of sublimation and decreases drying time, increases
`chemical stability of the pre-dried bulk solution, increases chemical
`stability of the dried product, facilitates manufacture of bulk solution
`by increasing drug wettability and solubility in solution,
`improves
`
`l4
`
`FRESENIUS KABI 1013-0016
`
`
`
`reconstitution characteristics (e.g. decreases reconstitution time), and
`enhances sterility assurance for pre-dried bulk solution.
`
`Id.
`
`36.
`
`Teagarden further teaches that
`
`the “organic solvent can have a
`
`profound effect on the chemical stability. Those drug candidates which are very
`
`labile in aqueous solutions may require the added stability to achieve an acceptable
`
`level of degradation during manufacture.” Exhibit 1005 at 0003.
`
`37.
`
`Teagarden specifically discloses that freeze-drying unstable drugs
`
`from a TBA/water solution “significantly reduced” the degradation rate, sometimes
`
`“by a factor of approximately 4-5.”
`
`Id. at 0003, 0004.
`
`Further, Teagarden
`
`instructs that “[t]his type of effect would be expected to be observed for many
`
`other drug products [that] are degraded in the presence of water.” Id. at 0004.
`
`IX. DETAILED ANALYSIS
`
`38.
`
`I have been asked to provide an opinion as to whether a person of
`
`ordinary skill in the art at the time of the purported invention would have been
`
`motivated to combine the teachings of Maas with Teagarden, and whether such a
`
`person would have a reasonable expectation of success in lowering degradant
`
`levels based on this combination. As part of my analysis, I have considered the
`
`scope and content of the prior art, and whether a person of ordinary skill in the art
`
`would have been motivated to combine the teachings of Maas and Teagarden.
`
`39.
`
`As part of my analysis, I have also considered the level of ordinary
`
`l5
`
`FRESENIUS KABI 1013-0017
`
`
`
`skill in the pertinent art in performing my analyses.
`
`A.
`
`Summary of Opinion
`
`40.
`
`In summary, it is my opinion that:
`
`0 Maas and Teagarden are readily combinable;
`
`0 A person of skill in the art would have been motivated to combine
`
`them, and
`
`0 A person of skill in the art would have a reasonable expectation of
`
`success in lowering degradant levels based on that combination;
`
`B.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Combine Maas with Teagarden.
`
`41.
`
`Below is my analysis supporting my opinion that a person of ordinary
`
`skill in the art at the time of the purported invention would have been motivated to
`
`combine the teachings of Maas with Teagarden. In my opinion, Maas and
`
`Teagarden are fully and logically combinable.
`
`42. Maas teaches that “[b]endamustine (Ribomustin®)
`
`is an effective
`
`chemotherapeutic drug in the treatment of malignant diseases,” and further
`
`discloses injecting bendamustine hydrochloride solutions “immediately following
`
`their preparation.” Exhibit 1004 at 0004, 0005. Maas teaches reconstituting
`
`bendamustine hydrochloride in an aqueous solution to form a pharmaceutical
`
`composition, by “dissolv[ing] in 10 mL of water for injection and then diluted to
`
`100 mL with 0.9% NaCl solution .
`
`.
`
`.
`
`.” Id. at 0006.
`
`16
`
`FRESENIUS KABI 1013-0018
`
`
`
`43. At the time of the purported invention, a person of ordinary skill
`
`would have been aware that bendamustine, being a nitrogen mustard, is highly
`
`reactive and unstable in aqueous solutions. See Exhibit 1001 at 1:45-50 (“Once in
`
`aqueous solutions, nitrogen mustards are subject to degradation by hydrolysis .
`
`.
`
`.
`
`7’).
`
`Indeed, Maas specifically discloses: “Bendamustine is very unstable in an
`
`aqueous solution.” Exhibit 1004 at 0004.
`
`44. Maas discloses that the “chemical stability (tgo) of the [bendamustine]
`
`cytostatic (0.25 mg/mL) in 0.9% sodium chloride is 120 h at 4°C and 9 h at 23°C.”
`
`Id. at 0004. Reading these results, a person of ordinary skill in the art would be
`
`motivated to prolong the stability of bendamustine pharmaceutical compositions.
`
`In particular, 9 hours at room temperature is a fairly short tgo for a drug product,
`
`and would require preparation of the drug product near the point of infusion into
`
`the patient.
`
`45. A person of ordinary skill in the art would have further appreciated
`
`that the degradants present in bendamustine formulations greatly influenced the
`
`stability of bendamustine pharmaceutical compositions, and that stability could be
`
`improved by reducing these degradants.
`
`See, e.g.,
`
`id. at 0005 (“The [HPLC]
`
`measurement
`
`results
`
`thus allow us
`
`to determine the relative stability of
`
`bendamustine”), see also,
`
`e. g., Exhibit 1025 at 0001 (describing hydrolysis
`
`degradation in 1969).
`
`17
`
`FRESENIUS KABI 1013-0019
`
`
`
`46. Maas identifies that
`
`the HPLC uncovered two degradants—the
`
`“monohydrolysis product” and an additional “unknown” synthesis degradant.
`
`Exhibit 1004 at 0004, see also Exhibit l0l0 at 0001 (“[T]he drug [Cyostasan]
`
`degrades spontaneously in water solutions yielding two hydrolysis products”).
`
`47.
`
`In my opinion, at the time of the purported invention, a person of
`
`ordinary skill in the art, being aware of the existing bendamustine hydrochloride
`
`product disclosed in Maas, would have been motivated to reduce the degradants in
`
`order to improve stability of the pharmaceutical composition. See, e. g., Exhibit
`
`1004 at 0005 (“Due to the rapid hydrolysis of aqueous bendamustine hydrochloride
`
`solutions, only freshly prepared solutions which must be injected immediately
`
`following their preparation”).
`
`48.
`
`The disclosure in Teagarden would have provided a person of
`
`ordinary skill in the art at the time of the purported invention with the requisite
`
`knowledge to reduce the degradants
`
`existing bendamustine hydrochloride
`
`pharmaceutical composition disclosed in Maas. Additionally, in my opinion, a
`
`person of ordinary skill
`
`in the art would have been motivated to apply the
`
`teachings in Teagarden to Maas.
`
`49.
`
`Teagarden provided a person of ordinary skill
`
`in the art with
`
`numerous reasons to use a strictly organic or organic /water co-solvent system in
`
`the lyophilization process, including, inter alia, decreasing the product’s drying
`
`l8
`
`FRESENIUS KABI 1013-0020
`
`
`
`time, decreasing reconstitution time, increasing the shelf-life of the product, and
`
`enhancing the sterility of the pre-dried bulk solution. Exhibit 1005 at 0001, 0004.
`
`This teaching alone would have motivated a person of ordinary skill in the art to
`
`apply the teachings of Maas to improve the lyophilization process for a
`
`bendamustine pharmaceutical composition.
`
`50. A person of ordinary skill in the art would further be motivated to
`
`apply the teachings of Teagarden to improve stability. Teagarden discloses that the
`
`selection of a solvent may improve the chemical stability of the pre-dried bulk
`
`solution and of the dried product.
`
`Id. Teagarden explains that the stability of
`
`lyophilized formulations can be improved by using TBA to reduce degradants “by
`
`a factor of approximately 4-5 .” Id. at 0004. Maas discloses that bendamustine
`
`pharmaceutical formulations contain degradants, and further discloses that these
`
`degradants pose stability issues. See Exhibit 1004 at 0005.
`
`51.
`
`Further, a person of ordinary skill in the art would have specifically
`
`been motivated to use TBA to improve stability of bendamustine, “[t]he co-solvent
`
`system that has been most extensively evaluated.” See Exhibit 1005 at 0017.
`
`C.
`
`in the Art Would Have Had a
`A Person of Ordinagy Skill
`Reasonable Expectation of Success in Lowering Degradant Levels
`Based on the Teachings of Maas and Teagarden.
`
`52.
`
`In my opinion, a person of ordinary skill in the art would have had a
`
`reasonable expectation of success
`
`in reducing bendamustine hydrochloride
`
`19
`
`FRESENIUS KABI 1013-0021
`
`
`
`degradant levels based on the teachings of Maas and Teagarden.
`
`53.
`
`Teagarden discusses the successful use of TBA/water co-solvents for
`
`at
`
`least five different pharmaceutical compositions,
`
`including for the specific
`
`purpose of improving drug stability.
`
`Id. at 0003, 0004. For example, Teagarden
`
`articulates the successful application of using TBA in pre-lyophilization solutions,
`
`detailing
`
`that
`
`“alprostadil
`
`has
`
`been
`
`successfully
`
`freeze-dried
`
`from a
`
`tertbutanol/water solution. The first-order degradation rate constant of alprostadil
`
`in 20% v/v tert-butanol/water .
`
`.
`
`. was significantly reduced.” Id. at 0003.
`
`54.
`
`Teagarden further specifically teaches that using an organic/water co-
`
`solvent system, such as TBA with water, “would be expected to be observed for
`
`many other drug products [that] are degraded in the presence of water.” Id. at
`
`0004. Ribomustin® is
`
`such a drug product.
`
`See Exhibit 1004 at 0004
`
`(“Bendamustine is very unstable in an aqueous solution”).
`
`55.
`
`Teagarden further teaches that “[u]se of tertiary butyl alcohol as a co-
`
`solvent slowed solution state degradation by a factor of approximately 4-5 ,” and
`
`explains that “[t]he co-solvent system that has been most extensively evaluated
`
`was the tertbutanol/water combination .
`
`.
`
`. Other co-solvent systems .
`
`.
`
`. were more
`
`difficult to use and often resulted in unacceptable freeze-dried cakes.” Exhibit
`
`1005 at 0003, 0031.
`
`20
`
`FRESENIUS KABI 1013-0022
`
`
`
`56.
`
`Because Teagarden specifically acknowledges that using TBA may
`
`decrease degradants by a 4-5 factor, see Exhibit 1005 at 0003, a person of ordinary
`
`skill
`
`in the art would have a reasonable expectation of success to reduce
`
`Bendamustine degradants by a 4-5 factor.
`
`57. Additionally,
`
`I understand that Cephalon has acknowledged that
`
`instead of TBA, “bendamustine was historically lyophilized from a solution of
`
`ethanol, water, mannitol, and bendamustine.” Exhibit 1014 at 0367. Because ethyl
`
`esters are known to be formed by reactions with ethanol, a person of ordinary skill
`
`in the art, would have been motivated to replace ethanol with TBA, and would
`
`have had a reasonable expectation of success that substituting TBA for ethanol
`
`would reduce ethyl ester formation.
`
`5 8. Accordingly, it is my opinion that a person of ordinary skill in the art
`
`would have been both motivated to apply the teachings of Teagarden to Maas, and
`
`further would have had a reasonable expectation of success in reducing degradants
`
`and improving stability.
`
`X.
`
`SUPPLEMENTATION
`
`59.
`
`I may utilize the documents cited and/or listed herein, or portions of
`
`those documents, as exhibits at any hearing or trial in this litigation.
`
`1 may further
`
`prepare and use exhibits that summarize portions of my testimony or key terms or
`
`21
`
`FRESENIUS KABI 1013-0023
`
`
`
`concepts presented therein, or other demonstrative exhibits, at any hearing or trial
`
`in this litigation.
`
`60.
`
`I reserve the right to supplement my testimony and this report in
`
`response to any judicial determinations, in response to the opinions expressed by
`
`the Cephalon’s experts in this proceeding, and/or in light of additional evid
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