Case IPR2016-00098
`
`Declaration of Bernard Olsen, 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 IPR2016-00098
`
`Patent No. 8,791,270
`
`
`
`DECLARATION OF BERNARD OLSEN 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 1017-0001
`
`

`
`Case ]PR20l6-00098
`
`Declaration of Bernard Olsen, 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 ................................................. ..3
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ........................ ..5
`
`IV. BACKGROUND .............................................................................................. ..5
`
`A. Overview of the ‘27O Patent .................................................................. ..5
`
`B. Overview of the Prosecution History of the ‘27O Patent ..................... .. 10
`
`V. OVERVIEW OF HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
`(HPLC) ........................................................................................................... .. l 1
`
`VI. LEVEL OF ORDINARY SKILL IN THE PERTINENT ART ..................... ..l4
`
`VII. BROADEST REASONABLE CONSTRUCTION ....................................... ..l4
`
`VIII.UNDERSTANDING OF THE LAW ............................................................ .. l 5
`
`IX. DETAILED INVALIDITY ANALYSIS ....................................................... ..l7
`
`A.
`
`Summary of Opinions .......................................................................... ..l7
`
`B. Ground 1: Claims 1-20 Are Obvious Over Maas In View of Teagarden.
`.............................................................................................................. ..l9
`
`1. Background on Maas ...................................................................... .. l9
`
`2. Background on Teagarden .............................................................. ..2O
`
`3. Motivation for Combining Maas and Teagarden ........................... ..2l
`
`4. Maas and Teagarden Disclose All Elements of Claims 1-20. ........ ..24
`
`(a) Claim 1 .................................................................................... ..24
`
`(b) Claim 2 .................................................................................... .31
`
`(c) Claim 3 .................................................................................... ..33
`
`FRESENIUS KABI 1017-0002
`
`

`
`Case ]PR2O 1 6-00098
`
`Declaration of Bernard Olsen, 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
`
`(d) Claim 4 .................................................................................... ..34
`
`(e) Claim 5 .................................................................................... ..34
`
`(1) Claim 6 .................................................................................... ..35
`
`(g) Claim 7 .................................................................................... ..36
`
`(h) Claim 8 .................................................................................... ..38
`
`(i) Claim 9 .................................................................................... ..38
`
`(j) Claim 10 .................................................................................. .39
`
`(k) Claim 11 .................................................................................. ..39
`
`(1) Claim 12 .................................................................................. ..4O
`
`(m) Claim 13 .................................................................................. ..41
`
`(n) Claim 14 .................................................................................. ..42
`
`(0) Claim 15 .................................................................................. ..43
`
`(p) Claim 16 .................................................................................. ..43
`
`(q) Claim 17 .................................................................................. ..44
`
`(r) Claim 18 .................................................................................. ..44
`
`(r) Claim 19 .................................................................................. ..45
`
`(s) Claim 20 .................................................................................. ..46
`
`3. Maas and Teagarden Disclose All Elements of Claims 1-20 Under
`An Inherency Theory. ..................................................................... ..46
`
`C. Ground 2: Claims 13 and 19 Are Obvious Over Maas in View of Gust
`
`and Teagarden. ..................................................................................... ..54
`
`1. Background on Gust ....................................................................... ..54
`
`2. Maas, Teagarden, and Gust Disclose All Elements of Claims 13 and
`19... .................................................................................................. ..55
`
`iii
`
`FRESENIUS KABI 1017-0003
`
`

`
`Case ]PR20l6-00098
`
`Declaration of Bernard Olsen, 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
`
`(a) Claim 13 .................................................................................. ..55
`
`(b) Claim 19 .................................................................................. ..57
`
`D. Ground 3: Claims 20-23 Are Obvious Over Maas in View of Teagarden
`and the Ribomustin® Product Monograph. .......................................... ..5 9
`
`1. Background on the Ribomustin® Product Monograph ................... ..59
`
`2. Maas, Teagarden, and the Ribomustin Product Monograph®
`Disclose All Elements of Claims 20-23. ........................................ ..6l
`
`(a) Claim 20 .................................................................................. ..6l
`
`(b) Claim 21 .................................................................................. ..62
`
`(c) Claim 22 .................................................................................. ..62
`
`(d) Claim 23 .................................................................................. ..63
`
`E. Ground 4: Claims 1-23 Are Obvious Over the Admitted Prior Art in the
`
`‘270 Patent in View of Teagarden. ...................................................... ..64
`
`X. SUPPLEMENTATION .................................................................................. ..65
`
`XI. CONCLUSION .............................................................................................. ..66
`
`iv
`
`FRESENIUS KABI 1017-0004
`
`

`
`Case ]PR2016-
`
`Declaration of Bernard Olsen, 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
`
`I, Bernard Olsen, 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 am being compensated
`
`for my time in connection with this IPR at my standard consulting rate of $400 per
`
`hour. My compensation is in no way dependent on the outcome of this matter.
`
`2.
`
`I have been asked to provide my opinions regarding whether claims 1-
`
`23 of the ‘270 patent are invalid, as anticipated by the prior art, or would have been
`
`obvious to a person having ordinary skill in the art at the time of the alleged
`
`invention.
`
`3.
`
`The ‘270 patent issued on July 29, 2014, from U.S. Patent Application
`
`No. 13/969,724 (“the ‘724 Application”), filed on August 19, 2013. Exhibit 1001,
`
`the ‘270 patent. The face of the patent indicates Jason Edward Brittain and Joe
`
`Craig Franklin as the named inventors. The ‘270 patent is a continuation of U.S.
`
`Patent Application No. 13/719,409,
`
`filed December 19, 2012, which is a
`
`continuation of U.S. Patent Application No. 13/654,898, filed on October 18, 2012,
`
`which issued as U.S. Patent No. 8,461,350 (“the ‘350 patent”), which is a
`
`continuation of U.S. Patent Application No. 11/330,868, filed on January 12, 2006,
`
`which issued as U.S. Patent No. 8,436,190 (“the ‘190 patent”).
`
`FRESENIUS KABI 1017-0005
`
`

`
`4.
`
`In preparing this Declaration, I have reviewed the ‘270 patent, the file
`
`history of the ‘270 patent, and numerous prior art references from the time of the
`
`alleged invention.
`
`5.
`
`I have been advised and it is my understanding that patent claims in
`
`an IPR are given their broadest reasonable construction in view of the patent
`
`specification, file history, and the understanding of one having ordinary skill in the
`
`relevant art at the time of the purported invention.
`
`6.
`
`In forming the opinions expressed in this Declaration, I relied upon
`
`my education and experience in the relevant field of the art, and have considered
`
`the viewpoint of a person having ordinary skill in the relevant art, as of 2005. My
`
`opinions directed to the invalidity of claims 1-23 of the ‘270 patent are based, at
`
`least in part, on the following prior art publications:
`
` Reference
`
`Date of Public Availability
`
`Maas, Stability of
`Bendamustine Hydrochloride
`in Infusions, 49 PHARMAZIE
`775 (1994)
`
`Maas was published in 1994, and the
`German language original and
`certified English translation are
`attached as Exhibit 1004 to the IPR.
`
`Teagarden, Practical aspects
`of lyoplzilization using non—
`aqueous co—solvent systems, 15
`EUR. J. PHARM. SCI. 115
`
`(March 2002)
`
`Teagarden was published in March
`2002, and is attached as Exhibit 1005
`to the IPR.
`
`Gust, Investigations on the
`Stability ofBendamustin, a
`
`Gust was published in 1997, and is
`
`FRESENIUS KABI 1017-0006
`
`

`
`attached as Exhibit 1006 to the IPR.
`
`Cytostatic Agent of the
`Nitrogen Mustard Type, 1.
`Synthesis, Isolation, and
`Characterization ofReference
`Substances, 128 MONATSHEFT
`
`FUR CHEMIE 291 (1997)
`
`The Ribomustin® Product
`Monograph, 2002
`
`The Ribomustin® Product Monograph
`was published in
`2002,
`and is
`attached as Exhibit 1007 to the IPR.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS
`
`7.
`
`I am currently an independent phannaceutical consultant in Wake
`
`Forest, North Carolina.
`
`I received my Ph.D.
`
`in analytical chemistry from the
`
`University of Wisconsin-Madison.
`
`I also have an undergraduate degree in
`
`chemistry from Nebraska Wesleyan University.
`
`8.
`
`After receiving my doctorate, I worked in the pharmaceutical industry
`
`for twenty-nine years at Eli Lilly and Company, where I achieved the rank of
`
`Senior Research Fellow. At Eli Lilly, I held a variety of senior research positions
`
`in the areas of analytical and bioanalytical development and chemistry.
`
`9.
`
`I have supported the development and/or manufacture of more than
`
`twenty-five marketed products.
`
`I have extensive experience in the development
`
`and use of high-perfonnance liquid chromatography (HPLC) methods. For over
`
`twenty years, on nearly a daily basis, I performed hands-on development and
`
`analysis using HPLC, employing seven different modes of HPLC, These analyses
`
`FRESENIUS KABI 1017-0007
`
`

`
`included determination of purity and impurities in drug substances, drug products,
`
`intermediates, and starting materials to generate development information and for
`
`quality control purposes.
`
`10.
`
`I have been involved in many activities within the scientific
`
`community.
`
`I am a member of the American Chemical Society (Analytical
`
`Division) and the American Association of Pharmaceutical Scientists (AAPS). In
`
`2010, I was elected as a Fellow of the AAPS. For ten years, I have served on the
`
`United States Pharmacopeia as an expert committee member for monograph
`
`development and, in 2010 and 2015, was elected to chair an expert committee.
`
`I
`
`am a reviewer
`
`for
`
`the Journal of Chromatography A and the Journal of
`
`Pharmaceutical and Biomedical Analysis.
`
`I am also on the Editorial Advisory
`
`Board of the Journal of Pharmaceutical and Biomedical Analysis. From 2007 to
`
`2010, I served as an adjunct professor in the Department of Industrial and Physical
`
`Pharmacy at Purdue University.
`
`11.
`
`I have delivered over eighty-three external presentations, including
`
`many invited presentations at international venues. Many of my conference and
`
`workshop presentations have been on the development or use of high-perfonnance
`
`liquid chromatography (HPLC) methods.
`
`I have also authored or co-authored
`
`fifty-one publications, including nine invited papers, eight book chapters, and an
`
`edited book. Many of these publications have directly focused on topics and
`
`FRESENIUS KABI 1017-0008
`
`

`
`techniques in analytical chemistry, including over twenty papers on HPLC. The
`
`book I co-edited was on hydrophilic interaction chromatography, a form of HPLC.
`
`12. A more detailed description of my background and qualifications is
`
`provided in my curriculum vitae (attached hereto as Exhibit A). A list of other
`
`cases in which I have testified as an expert at trial or by deposition during the
`
`previous four years is attached as Exhibit B.
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION
`
`13.
`
`In addition to my general knowledge, education, and experience, I
`
`considered the materials listed in Exhibit C in forming my opinions.
`
`IV. BACKGROUND
`
`A.
`
`Overview of the ‘270 Patent
`
`14.
`
`The ‘270 patent was filed on August 19, 2013, and issued on July 29,
`
`2014. According to the Abstract,
`
`the ‘270 patent
`
`is directed generally to
`
`“pharmaceutical
`
`formulations
`
`of
`
`lyophilized
`
`bendamustine
`
`suitable
`
`for
`
`pharmaceutical use.” Exhibit 1001 at Abstract.
`
`15.
`
`The ‘270 patent acknowledges that pharmaceutical formulations of
`
`bendamustine hydrochloride were previously known and used in Germany.
`
`Id. at
`
`2:1-10.
`
`In particular, formulations such as Cytostasan® and Ribomustin® had
`
`“been widely used in Germany to treat chronic lymphocytic leukemia, Hodgkin’s
`
`disease, non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer.”
`
`Id. at
`
`215-10.
`
`The ‘270 patent also acknowledges that nitrogen mustards such as
`
`5
`
`FRESENIUS KABI 1017-0009
`
`

`
`bendamustine hydrochloride “are subject to degradation by hydrolysis.” Id. at
`
`1:45-50.
`
`16.
`
`The ‘270 patent asserted that its improvement over this established
`
`prior art was a “better impurity profile than Ribomustin® with respect to certain
`
`impurities, in particular HP1 .
`
`.
`
`. and bendamustine ethylester .
`
`.
`
`.
`
`.” Id. at 12:31-
`
`38. The ‘270 patent, as issued, includes the following claims:
`
`been
`has
`composition that
`1. A pharmaceutical
`of
`lyophilized
`preparation
`reconstituted
`from a
`said
`bendamustine
`or bendamustine hydrochloride,
`composition containing not more than about 0.9% (area
`percent of bendamustine) of HP1:
`
`2:11?! .r
`
`5‘
`
`<_:n
`
`‘no/W
`I \ {%fi.
`""\
`
`xi“:
`
`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).
`
`FRESENIUS KAB|1017-0010
`
`

`
`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%
`(area
`percent
`of bendamustine)
`of bendamustine
`degradants.
`
`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:
`
`FRESENIUS KAB|1017-0011
`
`

`
`I‘~m:m;l;t W’
`
`if i
`
`~r.1‘z.’:Is€.z=r:.1‘£«l;t..‘§{,-..
`R
`Wo<>./45-}
`
`E
`
`14. The pharmaceutical composition of claim 7, wherein
`the
`pharmaceutical
`composition
`is
`a
`lyophilized
`composition.
`
`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:
`
`{'1
`
`K1
`
`T«.:x:sLaz¥s1§‘r’
`
` ‘£X3£'I-¥j.‘i-§
`
`FRESENIUS KAB|1017-0012
`
`

`
`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-Hodgl<in’s lymphoma, multiple myeloma, or
`breast cancer.
`
`22. The method according to claim 20, wherein the
`cancer is chronic lymphocytic leukemia.
`
`23. The method according to claim 20, wherein the
`cancer is non-Hodgkin’s lymphoma.
`
`17.
`
`There appears to be some inconsistency between Cephalon’s assertion
`
`with respect to alleged improved impurity levels and the specification of the ‘270
`
`patent.
`
`In particular, Table 13 of the ‘270 specification includes the following
`
`impurity data for Ribomustin®:
`
`TABLE 13
`
`R.ibom11s'tine Impliirty Profile using HPLC Method 3
`“.4:
`
`Batch
`
`Benda1nL1stine {IICI} 3
`
`97.61
`
`[I3 Hails
`
`133 Ht}?
`
`02142‘?
`
`EIBCEJS
`
`98.14
`
`916?
`
`96.93
`
`Exhibit 1001 at Table 13. As shown above, a number of the claims (e. g., claims 7,
`
`8, 13-15, and 19) appear to encompass the impurity profile for Ribomustin® rather
`
`9
`
`FRESENIUS KABI 1017-0013
`
`

`
`than “improve” the impurity level.
`
`B.
`
`Overview of the Prosecution History of the ‘270 Patent
`
`18.
`
`As noted above, the application that matured into the ‘270 patent was
`
`filed on August 19, 2013. Cephalon received Track One (accelerated) review from
`
`the Patent Office.
`
`19.
`
`Claims 1-23 were issued without any substantive rejections over the
`
`prior art. Moreover,
`
`the Examiner’s reasons for allowance appear
`
`to be
`
`inconsistent with the claims themselves:
`
`The prior art suggests using a combination of mannitol and tertiary-
`
`butyl alcohol with bendamustine to produce a formulation to be
`
`lyophilized. However, Applicant has unexpectedly found that the
`
`addition of a solvent stabilizes the formulation such that bendamustine
`
`degradation is negligible
`
`(no more
`
`than 0.5% formation of
`
`bendamustine ethyl ester).
`
`Exhibit 1003 at 0300.
`
`In particular, these stated reasons for allowance appear to
`
`apply only to the claims reciting the bendamustine ethyl ester degradant (2 out of
`
`23 claims). Moreover, the Examiner’s reasons for allowance do not acknowledge
`
`that a number of the claims appear to encompass the Ribomustin® impurity profile
`
`that Cephalon sought to distinguish during prosecution.
`
`10
`
`FRESENIUS KAB|1017-0014
`
`

`
`V.
`
`OVERVIEW OF HIGH PERFORMANCE Llg QUID
`CHROMATOGRAPHY {HPLC g
`
`20. High-performance liquid chromatography (HPLC) is a technique used
`
`in the pharmaceutical, biomedical, and chemical sciences for the separation,
`
`identification, and quantitation of components in samples. The diagram below
`
`provides a generalized depiction of how HPLC worksl
`
`chromatogram
`
`
`
`Column
`
`1 i
`
`Stationary Phase
`
`O .
`
`1.
`U
`
`53”"9'°
`Solution
`
`P“""P
`
`Detector
`
`‘NE Ste
`
`Mobile
`
`Phase
`
`‘
`
`21. HPLC is performed by passing a liquid called the “mobile phase”
`
`through a tube (or “column”) that
`
`is packed with solid particles called the
`
`“stationary phase.” A small Volume of the sample to be analyzed is prepared in a
`
`solution and introduced into the flowing mobile phase. A high pressure pump
`
`moves the sample and mobile phase through the column containing the stationary
`
`phase particles. The liquid exiting the column (called the “eluate”) is passed
`
`1 The diagrams in this declaration are modified graphics from the website of Waters
`Corporation, an analytical instrument company:
`http://www.waters.com/waters/naV.htm?cid=l 004905 5.
`
`ll
`
`FRESENIUS KABI 1017-0015
`
`

`
`through a detector. A “chromatogram” is generated based on the data from the
`
`detector.
`
`I discuss each of these steps in more detail below.
`
`22.
`
`The components of the sample will
`
`interact differently with the
`
`stationary phase as they are carried through the column by the mobile phase. The
`
`interactions will differ because they depend on the chemical nature of each
`
`component, as well as the chemical nature of the stationary phase and mobile
`
`phase being used, among other variables. These different interactions provide the
`
`basis for separating the components in the sample.
`
`23.
`
`In a given mobile phase, components that interact more strongly with
`
`the stationary phase will take longer to pass through the column than components
`
`that have weaker interactions. Some components may not emerge from the column
`
`at all. As the mobile phase flows through the column, the components of the
`
`sample travel at different speeds, and separate to different degrees depending on
`
`their chemical interactions with the column.
`
`24. A detector analyzes the components of the sample that leave the other
`
`end of the column in the eluate. There are many types of HPLC detectors. For
`
`example, some detectors are based on measuring the absorption of ultraviolet light
`
`by the sample components in the eluate. Other types of detectors use refractive
`
`index, fluorescence, electrical conductivity, mass spectrometry, or evaporative
`
`light scattering. Depending on the detection method and the properties of the
`
`12
`
`FRESENIUS KAB|1017-0016
`
`

`
`sample components, some sample components in the eluate may not be detected.
`
`Components also will not be detected if they do not emerge from the column under
`
`the HPLC conditions used.
`
`25.
`
`The detector provides a response as each component passes out of the
`
`end of the column. The level of detector response generally depends on the
`
`amount of material passing through it.
`
`CD1 U m n
`
`Detector
`
`.'_-‘.tat:ic:rr1ar1.r Phase-
`
`B5555--lune
`
`26.
`
`The detector is often connected to a computer that records the level of
`
`detector response (as compared to a baseline level) over time. The data output of
`
`HPLC is usually a chromatogram, which the computer generates by plotting the
`
`level of detector response over time as the components pass through the detector.
`
`In other words, the horizontal axis of the chromatogram corresponds to time. The
`
`vertical axis corresponds to the detector response level. The chromatogram often
`
`appears as a series of “peaks.” As components pass through the detector, the
`
`13
`
`FRESENIUS KABI 1017-0017
`
`

`
`magnitude of the detector response typically rises and falls, forming peaks on the
`
`chromato gram.
`
`VI.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART
`
`27.
`
`I have been advised that
`
`there are multiple factors relevant
`
`to
`
`determining the level of ordinary skill in the pertinent art, including the educational
`
`level of active workers in the field at the time of the invention, the sophistication of
`
`the technology, the type of problems encountered in the art, and the prior art
`
`solutions to those problems.
`
`28.
`
`It is my opinion that a person having ordinary skill in the relevant art
`
`at the time of invention would have a Ph.D. in pharmaceutics, analytical chemistry,
`
`or a related field, with at least three years of practical experience in formulating
`
`and/or analyzing pharmaceutical formulations.
`
`VII. BROADEST REASONABLE CONSTRUCTION
`
`29.
`
`I have been advised 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”
`
`l4
`
`FRESENIUS KAB|1017-0018
`
`

`
`“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”
`
`30.
`
`I have asked to apply several alternative constructions with respect to
`
`certain terms. For “pharmaceutical composition that has been reconstituted,” I will
`
`also analyze that
`
`term under the alternative constructions of “pharmaceutical
`
`composition that has been dissolved in a solvent and that is suitable for medical
`
`administration” and “pharmaceutical composition that has been dissolved in a
`
`solvent.”
`
`31. With respect to “time zero after reconstitution,” I understood that
`
`“soon after dissolution in a solvent or diluent” has been understood to refer to “the
`
`first measurement taken as soon as reasonably practicable” after reconstitution.
`
`I
`
`will analyze under the alternative construction of “30 minutes or less after
`
`reconstitution.”
`
`VIII. UNDERSTANDING OF THE LAW
`
`32.
`
`I understand that prior art to the ‘270 patent includes patents and
`
`printed publications that predate the January 14, 2005 priority date.
`
`33.
`
`I understand that a claim is invalid if it is anticipated or obvious.
`
`l5
`
`FRESENIUS KAB|1017-0019
`
`

`
`Anticipation of a claim requires that every element of a claim be disclosed
`
`expressly or inherently in a single prior art reference, as claimed.
`
`I understand that
`
`a prior art reference need only have the same level of disclosure as the asserted
`
`patent to be anticipatory.
`
`34.
`
`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.
`
`I understand that a claim may be obvious in light of one or more prior
`
`art references.
`
`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.
`
`7
`I understand that the concept of “inherency’ can be used in an
`
`obviousness analysis.
`
`35.
`
`I further understand that certain other factors should be considered to
`
`determine if they support or rebut the obviousness of a claim.
`
`I understand that
`
`such secondary considerations include, among other things, commercial success of
`
`the patented invention, skepticism of those having ordinary skill in the art at the
`
`time of invention, unexpected results of the invention, any long-felt but unsolved
`
`need in the art that was satisfied by the alleged invention, the failure of others to
`
`make the alleged invention, praise of the alleged invention by those having
`
`ordinary skill in the art, and copying of the alleged invention by others in the field.
`
`16
`
`FRESENIUS KABI 1017-0020
`
`

`
`I understand that
`
`there must be a nexus—a connection—between any such
`
`secondary considerations and the alleged invention.
`
`IX. DETAILED INVALIDITY ANALYSIS
`
`36.
`
`I have been asked to provide an opinion as to whether claims 1-23 of
`
`the ‘270 patent are invalid in view of the prior art. The discussion below provides
`
`a detailed invalidity analysis of how the prior art references identified in Section I
`
`anticipate and/or render obvious claims 1-23 of the ‘270 patent.
`
`37.
`
`As part of my obviousness analysis, I have considered the scope and
`
`content of the prior art, and whether any differences between the alleged invention
`
`and the prior art are such that the subject matter, as a whole, would have been
`
`obvious to a person having ordinary skill in the art at the time of the alleged
`
`invention. I have also considered the level of ordinary skill in the pertinent art in
`
`performing my analyses.
`
`38.
`
`I describe in detail below the scope and content of the prior art, as
`
`well as any differences between the alleged invention and the prior art, on an
`
`element-by-element basis for claims 1-23 of the ‘270 patent.
`
`39.
`
`The prior art I describe below includes disclosure of all limitations
`
`recited in claims 1-23 of the ‘270 patent.
`
`A.
`
`Summagy of Opinions
`
`40.
`
`In summary, it is my opinion that:
`
`17
`
`FRESENIUS KABI 1017-0021
`
`

`
`0 The combination of Maas and Teagarden disclose all elements of claims
`
`1-20 and therefore renders those claims obvious. Moreover, as I explain
`
`below, Maas and Teagarden are fully and logically combinable and one
`
`of skill in the art would have been motivated to combine them,
`
`0 The combination of Maas, Teagarden, and Gust disclose all elements of
`
`claims 13 and 19 and therefore renders those claims obvious. Moreover,
`
`as I explain below, Maas, Teagarden, and Gust are fully and logically
`
`combinable and one of skill in the art would have been motivated to
`
`combine them,
`
`0 The combination of Maas, Teagarden, and the Ribomustin® Product
`
`Monograph disclose all elements of claims 1-20 and therefore renders
`
`those claims obvious. Moreover, as I explain below, Maas, Teagarden,
`
`and the Ribomustin® Product Monograph are fully and logically
`
`combinable and one of skill in the art would have been motivated to
`
`combine them, and
`
`0 The combination of the admitted prior art
`
`in the ‘27O patent and
`
`Teagarden disclose all elements of claims 1-23 and therefore renders
`
`those claims obvious. As I explained above, the admitted Ribomustin®
`
`prior art and Teagarden are fully and logically combinable and one of
`
`skill in the art would have been motivated to combine them.
`
`18
`
`FRESENIUS KABI 1017-0022
`
`

`
`41.
`
`Below I describe in detail how each of the references or combinations
`
`of references anticipates and/or renders obvious the alleged invention of claims 1-
`
`23 of the ‘270 patent in view of the teachings of the prior art, as well as the
`
`knowledge of one having ordinary skill in the art at the time of the purported
`
`invention.
`
`B.
`
`Ground 1: Claims 1-20 Are Obvious Over Maas In View of
`
`Teagarden.
`
`1.
`
`Background on Maas
`
`42. Maas published in 1994, and teaches an HPLC analysis of the
`
`Ribomustin® formulation. Maas recognizes that Ribomustin® was known to be “an
`
`effective chemotherapeutic drug in the treatment of malignant diseases,” and that
`
`“[b]endamustine is very unstable in aqueous solution.” Exhibit 1004 at 0004.
`
`Maas further recognized that “monohydroxy bendamustine” was formed upon
`
`hydrolysis of Ribomustin®, and specifically observes this “monohydroxy” product
`
`in her HPLC chromatogram. Exhibit 1004 at 0005.
`
`43. Although certain data (such as data reflected in the tables) in Maas is
`
`“normalized,” the HPLC chromatogram in Maas shows the total amount of
`
`detectable degradant present in Maas at the time the chromatogram was taken,
`
`including HPl.
`
`Exhibit 1004 at 0005. As I explain below,
`
`I believe the
`
`chromatogram in Maas is reflective of “time zero after reconstitution” regardless of
`
`which construction is applied.
`
`19
`
`FRESENIUS KABI 1017-0023
`
`

`
`2.
`
`Background on Teagarden
`
`44.
`
`Teagarden published in the European Journal of Pharmaceutical
`
`Sciences in March 2002. Therefore, I have been advised that it qualifies as prior
`
`art with respect to the ‘270 patent.
`
`45.
`
`Teagarden specifically identifies using tert-butyl alcohol (“TBA”) in
`
`the pre-lyophilization solution for water-unstable drugs. Exhibit 1005 at 0003,
`
`(CC
`0004. Teagarden explains that the use of organic solvents such as TBA can