Paper No. ____
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`AGILA SPECIALTIES INC. and MYLAN LABORATORIES LIMITED,
`Petitioner
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`v.
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`CEPHALON, INC.,
`Patent Owner
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`_____________________________
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`Patent No. 8,791,270
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`_____________________________
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`DECLARATION OF SAMUEL H. YALKOWSKY, PH.D.
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`AGILA ET AL - EXHIBIT 1002
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`I.
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`II.
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`TABLE OF CONTENTS
`TABLE OF CONTENTS
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`QUALIFICATIONS ........................................................................................... 1
`QUALIFICATIONS ......................................................................................... .. 1
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`SCOPE OF WORK ............................................................................................ 3
`SCOPE OF WORK .......................................................................................... ..3
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`III. OVERVIEW OF THE ’270 PATENT .................................................................... 3
`III.
`OVERVIEW OF THE ’270 PATENT .................................................................. ..3
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`IV. FILE HISTORY OF THE ’270 PATENT .............................................................. 11
`IV.
`FILE HISTORY OF THE ’270 PATENT ............................................................ .. 1 1
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`V.
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`FILE HISTORY OF THE ’190 PATENT .............................................................. 12
`FILE HISTORY OF THE ’ 190 PATENT ............................................................ .. 12
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`VI. LEGAL STANDARDS ..................................................................................... 12
`VI.
`LEGAL STANDARDS ................................................................................... .. 12
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`VII. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ 15
`VII.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...................................... .. 15
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`VIII. CLAIM CONSTRUCTION ................................................................................ 16
`VIII.
`CLAIM CONSTRUCTION .............................................................................. .. 16
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`IX. THE STATE OF THE ART................................................................................ 18
`THE STATE OF THE ART .............................................................................. .. 18
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`X.
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`CERTAIN REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`CERTAIN REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’270 PATENT .................................................................... 26
`FEATURES OF THE ’270 PATENT .................................................................. ..26
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`XI. CONCLUDING STATEMENTS .......................................................................... 73
`XI.
`CONCLUDING STATEMENTS ........................................................................ ..7 3
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`XII. APPENDIX – LIST OF EXHIBITS ................................................................... 74
`XII.
`APPENDIX — LIST OF EXHIBITS ................................................................. ..74
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`-i-
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`I, Samuel H. Yalkowsky, declare as follows:
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`I.
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`QUALIFICATIONS
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`1. My name is Samuel H. Yalkowsky. I am currently a Professor in the
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`Department of Pharmaceutical Sciences at The University of Arizona. I have been
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`a member of the faculty of this department since 1982. Prior to this I was a
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`research scientist at the Upjohn Company in their Pharmaceutical Research Unit.
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`2.
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`I received a B.S. in Pharmacy from Columbia University in 1965, and
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`a Ph.D. in Pharmaceutical Chemistry from the University of Michigan in 1969.
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`3. While at Upjohn, I developed the marketed formulations of Xanax®
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`tablets and Halcion® tablets. I also worked on a Xanax® injectable formulation. I
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`formulated the first prostaglandin to be used in humans and received a patent for
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`my formulation.
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`4. My research expertise lies in the relationship between chemical
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`structure and physiochemical properties, especially the solubility and stability of
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`organic compounds, and solubilization in aqueous media. I have extensive
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`experience with pharmaceutical formulations, including the use of organic co-
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`solvents in drug formulations and the optimization of formulations for the freeze-
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`drying (lyophilization) of pharmaceuticals.
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`5.
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`I developed the General Solubility Equation, GSE, which is the state
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`of the art technique for estimating the solubility of organic compounds in water. I
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`also developed an in vitro technique for evaluating whether or not a formulation is
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`likely to precipitate when it is injected into blood or intravenous solutions. This
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`technique is used by many pharmaceutical companies. I also provide a formulation
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`evaluation service to the industry. In addition, I have developed novel dosage
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`forms of highly insoluble drugs and formulations to improve dissolution of
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`important solutes from soil.
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`6. My research has been funded by such organizations as the National
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`Cancer Institute, the Environmental Protection Agency, the Department of
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`Defense, and the pharmaceutical industry.
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`7.
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`I have authored or co-authored more than 260 scientific publications,
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`including peer-reviewed journal articles. Two of my publications have been
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`awarded the Ebert Prize for the best scientific paper in the Journal of
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`Pharmaceutical Sciences. I have authored, co-authored, or edited eight books
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`dealing with solubility and solubilization of drugs. I am presently Editor-in-Chief
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`of the AQUASOL database, a comprehensive collection of solubility data for
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`organic compounds.
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`8.
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`I have also contributed to more than 40 symposia, conferences, short
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`courses, and lectureships, including invited presentations both in The United States
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`and across the world, including: the APhA Academy of Pharmaceutical Sciences,
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`the American Association of Pharmaceutical Scientists, the American Chemical
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`Society, and the Pharmaceutical Society of Great Britain.
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`9.
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`I have received numerous honors and awards, and am an inventor or
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`co-inventor on five United States patents relating to drug formulations.
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`10.
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`I have taught courses at the University of Arizona for over 30 years in
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`which students studied physiochemical properties, and solubility.
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`11.
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` For the last ten years I have taught a short course titled Solubility and
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`Solubilization at the College of Pharmacy, attracting scientists from across the
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`country.
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`12. A summary of my education, experience, publications, awards and
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`honors, patents, publications, and presentations is provided in my CV, a copy of
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`which is submitted separately. Ex. 1003.
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`II.
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`SCOPE OF WORK
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`13.
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`I understand that a petition is being filed with The United States
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`Patent and Trademark Office for Inter Partes Review of U.S. Patent No. 8,791,270
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`(hereinafter, “the ’270 patent,” Ex. 1001). I have been retained by the Petitioner as
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`a technical expert to provide analysis and opinions regarding the ’270 patent. I
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`have reviewed the ’270 patent and relevant sections of its prosecution history in
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`The United States Patent and Trademark Office. Ex. 1004. I have also reviewed
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`and considered various other documents in arriving at my opinions, and cite them
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`in this declaration. For convenience, documents cited in this declaration are listed
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`in the Appendix in Section XII.
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`14.
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`I am compensated at the rate of $1000/hour for my work. I have no
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`financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’270 PATENT
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`15. The ’270 patent is entitled “Bendamustine Pharmaceutical
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`Compositions.” I have been advised that the ’270 patent issued from U.S. Patent
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`Application No. 13/969,724 (the ’724 application), filed on August 19, 2013,
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`which is a continuation of U.S. Patent Application No. 13/719,409, filed on
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`December 19, 2012, now U.S. Patent No. 8,895,756, which in turn is a
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`continuation of U.S. Patent Application No. 13/654,898, filed on October 18, 2012,
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`now U.S. Patent No. 8,461,350, which in turn is a continuation of U.S. Patent
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`Application No. 11/330,868, filed on January 12, 2006, now U.S. Patent No.
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`8,436,190 (hereinafter “the ’190 patent”), which claims priority to U.S. Provisional
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`Patent Application No. 60/644,354 (hereinafter “the ’354 provisional,” Ex. 1018),
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`filed on January 14, 2005.
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`16. The ’270 patent is generally directed to pharmaceutical compositions
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`of bendamustine or bendamustine hydrochloride, including reconstituted
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`compositions thereof. For example, independent claim 1 of the ’270 patent recites
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`the following:
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`1. A pharmaceutical composition that has been reconstituted from a
`lyophilized preparation of bendamustine or bendamustine
`hydrochloride, said composition containing not more than about 0.9%
`(area percent of bendamustine) of HP1:
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`17. Dependent claim 2 refers to independent claim 1 and describes that
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`the amount of HP1 is measured at time zero after reconstitution. Dependent claims
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`3-6 refer to claims 1 and 2 and describe further limitations to the amount of HP1 in
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`the composition.
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`18. Claim 7 of the ’270 patent is an independent claim and recites the
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`following:
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`7. A pharmaceutical composition of bendamustine hydrochloride,
`containing less than or equal to 4.0% (area percent of bendamustine)
`of bendamustine degradants.
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`19. Dependent claim 8 refers to claim 7 and describes further limitations
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`to the amount of bendamustine degradants. Dependent claim 9 refers to claim 8
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`and describes that the pharmaceutical composition has been reconstituted from a
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`lyophilized preparation of bendamustine hydrochloride. Dependent claims 10-12
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`refer to claim 9 and describe limitations to the amount of HP1 in the
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`pharmaceutical composition at time zero after reconstitution.
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`20. Dependent claim 13 refers to claim 10 and describes limitations to the
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`amount of Formula IV at time zero after reconstitution:
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`21. Dependent claims 14 and 15 depend from claims 7 and 8, respectfully,
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`and describe that the pharmaceutical composition is a lyophilized composition.
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`Dependent claims 16-18 refer to claim 7 and describe limitations to the amount of
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`HP1 in the composition. Dependent claim 19 refers to claim 7 and describes
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`limitations to the amount of Formula IV in the composition.
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`22. Dependent claim 20 refers to claim 7 and describes a method of
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`treating cancer in a patient comprising administering the pharmaceutical
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`composition to the patient. Dependent claims 21-23 refer to claim 20 and describe
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`specific types of cancer.
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`23.
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`In the Background of the Invention of the ’270 patent, it is
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`acknowledged that bendamustine was produced and marketed as a drug product
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`long prior to January 14, 2005:
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`Bendamustine was initially synthesized in 1963 in the German
`Democratic Republic (GDR) and was available from 1971 to 1992 in
`that location under the name Cytostasan®. Since that time, it has been
`marketed in Germany under the tradename Ribomustin®. It has been
`widely used in Germany to treat chronic lymphocytic leukemia,
`Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, and
`breast cancer.
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`Due to its degradation in aqueous solutions (like other nitrogen
`mustards), bendamustine is supplied as a lyophilized product. The
`current lyophilized formulation of bendamustine (Ribomustin®)
`contains bendamustine hydrochloride and mannitol in a sterile
`lyophilized form as a white powder for intravenous use following
`reconstitution.
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`Ex. 1001, col. 2, ll. 1-15.
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`24. Thus, according to the specification of the ’270 patent, and as further
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`confirmed by prior art product information for Ribomustin® (see, e.g., Ex. 1007;
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`Ex. 1005; Ex. 1014, these exhibits described below), lyophilized compositions
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`comprising bendamustine hydrochloride were known in the art for many years
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`prior to January 14, 2005. Id. Product information for Ribomustin® was published
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`in the Rote Liste 2003 (Ex. 1005 at 0003), a drug reference manual published
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`yearly in Germany that serves as the German equivalent to the Physician’s Desk
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`Reference in The United States. The Rote Liste 2003 states that the drug
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`formulation comprises bendamustine hydrochloride and mannitol. Id. The
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`Ribomustin® product is also described in Birgit Maas et al., Stability of
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`Bendamustine Hydrochloride in Infusions, 49 PHARMAZIE 775 (1994) (hereinafter
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`“Maas,” Ex. 1007 at 0006), and is also documented on page 56 of the Ribomustin®
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`Product Monograph, which states on its first page “updated 01/2002.” Ex. 1014.
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`25.
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`In the Detailed Description of the Invention of the ’270 patent, the
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`applicant states that the alleged invention is an improvement upon the
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`reconstitution properties and impurity profile of the prior art Ribomustin® drug
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`product:
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`The invention provides stable, pharmaceutically acceptable
`compositions prepared from bendamustine. In particular, the invention
`provides formulations for the lyophilization of bendamustine HCl.
`The lyophilized powder obtained from such formulations is more
`easily reconstituted than the presently available lyophilized powder of
`bendamustine. Further, the lyophilized products of the present
`invention have a better impurity profile than Ribomustin® with respect
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`to certain impurities, in particular HP1, bendamustine dimer, and
`bendamustine ethylester, prior to reconstitution, upon storage of the
`lyophilate, or following reconstitution and admixture.
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`Ex. 1001, col. 12, ll. 27-37.
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`26. The applicant further discloses testing the use of water/alcohol
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`solutions in pre-lyophilization formulations of bendamustine hydrochloride:
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`Because of its instability in aqueous solutions due to hydrolysis with
`water, bendamustine requires lyophilization in order to make a
`product suitable for pharmaceutical use. However . . . the use of
`aqueous solutions during the compounding and fill processes for
`bendamustine and other nitrogen mustards can result in degradation of
`the drug product. Consequently, the effect of various alcohols on the
`degradation of bendamustine was evaluated to determine if
`formulations could be found that would allow longer fill-finish times,
`provide lyophilate powders that could be reconstituted more quickly
`than the current Ribomustin® formulation, and/or provide lyophilized
`preparations of bendamustine with a better impurity profile with
`respect to certain impurities, e.g., HP1, and BM1 dimer than
`Ribomustin®.
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`Ex. 1001, col. 20, ll. 44-61.
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`27. According to this excerpt from the ’270 patent, the applicant
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`improved upon the existing drug product by evaluating the effects of various
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`alcohols, including tertiary butyl alcohol (TBA), on pre-lyophilization
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`formulations of bendamustine hydrochloride. Based on this evaluation, the
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`applicant concluded “TBA was found to be the best stabilizer of the six alcohols
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`tested.” Ex. 1001, col. 31, ll. 62-63. In my opinion, and as explained in further
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`detail below, the use of TBA (tertiary butyl alcohol, also known as tert-butyl
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`alcohol, tert-butanol and t-butanol) to reduce degradation of bendamustine in
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`aqueous environments prior to lyophilization would have been obvious to
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`individuals of ordinary skill in the art prior to and at the time of the filing of the
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`earliest priority application of the ’270 patent, i.e., January 14, 2005.
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`28.
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`In the Examples of the ’270 patent, the applicant disclosed that the
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`prior art Ribomustin® product contained amounts of degradants specified in many
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`of the ’270 claims. In particular, Table 13 of the ’270 patent provides impurity
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`profiles for batches of Ribomustin®:
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`Batch Bendamustine
`(HCl)
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`03H08
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`98.14
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`03H07
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`97.67
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`02K27
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`96.93
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`Ribomustin® Impurity Profile using HPLC Method 3
`Percent Areaa
`[area percent of bendamustine]b
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`Degradantsc HP1 BM1EE BM1 Dimer BM1DCE Total Sum of
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`1.65
`1.07
`0.21
`0.34
`0.03
`[1.09]
`[0.21]
`[0.35]
`[0.03]
`[1.68]
`2.07
`1.5
`0.2
`0.33
`0.04
`[1.54]
`[0.20]
`[0.34]
`[0.04]
`[2.12]
`2.48
`0.93
`0.29
`1.18
`0.08
`[0.96]
`[0.30]
`[1.22]
`[0.08]
`[2.56]
`1.91
`1.24
`0.19
`0.46
`0.02
`[1.27]
`[0.19]
`[0.47]
`[0.02]
`[1.95]
`a) As in Table 13. b) Bracketed values as explained below. c) Tabulated from Table 13
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`03C08
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`97.61
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`Adapted from Table 13 of the ’270 patent. Ex. 1001, col. 30, ll. 35-45; see also the
`’354 provisional (Ex. 1018) at 41.
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`29. The data provided in Table 13 of the ’270 patent are expressed as “%
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`Area” of an HPLC chromatogram. Ex. 1001, col. 30, ll. 35-45. In contrast, the
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`’270 patent claims recite amounts of bendamustine degradants expressed as “area
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`percent of bendamustine,” which is defined in the ’270 patent specification as “the
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`amount of a specified degradant, e.g., HP1, relative to the amount of bendamustine
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`as determined, e.g., by HPLC.” Id. at col. 12, ll. 10-13. To facilitate comparison,
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`the values provided in Table 13 of the ’270 patent are also shown in brackets as
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`“area percent of bendamustine” (i.e., amount of degradant relative to amount of
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`bendamustine expressed as a percent) in the annotated table provided above.
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`30. Table 13 of the ’270 patent discloses that Ribomustin® product
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`contains “about 0.9% (area percent of bendamustine) of HP1.” Id. at col. 30, ll. 35-
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`45. The ʼ270 reported in Table 13 that Ribomustin® Batch 02K27 contained
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`0.93% area of HP1, which equals 0.96% area percent of bendamustine of HP1. See
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`annotated table 13 above, adapted from Ex. 1001, col. 30, ll. 35-45. Batch 02K27
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`of the prior art Ribomustin® product therefore contained “about” 0.9% area percent
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`of bendamustine of HP1, differing by only 0.06%.
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`31. The amounts disclosed in Table 13 of the ’270 patent also demonstrate
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`that each of the batches of Ribomustin® contained less than 4.0% (area percent of
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`bendamustine) of bendamustine degradants (Ex. 1001, col. 20, ll. 35-45), with
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`batches containing 1.68-2.56% (area percent of bendamustine) of degradants. See
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`annotated Table 13, above, adapted from Ex. 1001, col. 30, ll. 35-45. The amounts
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`disclosed in Table 13 of the ’270 patent further demonstrate that each batch of
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`Ribomustin® contained less than 0.5% (area percent of bendamustine) of
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`bendamustine ethyl ester, with batches containing 0.19-0.30% (area percent of
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`bendamustine) of this impurity. Id. “BM1EE” refers to bendamustine ethyl ester,
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`also referred to in the ’270 patent as “Formula IV.” Ex. 1001, col. 20, ll. 35-45.
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`IV. FILE HISTORY OF THE ’270 PATENT
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`32.
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`It is my understanding that a Notice of Allowance of the ’270 claims
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`was mailed on June 9, 2014. In the Reasons for Allowance, the examiner states
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`that the addition of a solvent stabilizes the formulation such that no more than
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`0.5% of bendamustine ethyl ester is formed:
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`[T]he prior art teaches a formulation of bendamustine and mannitol to
`be lyophilized. The prior art also teach a combination of mannitol,
`tertiary-butyl alcohol, water, and an anti-neoplastic agent can be
`lyophilized. 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).
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`Ex. 1004 at 0024.
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`33. No other reasons for allowance of the ’270 claims are provided in the
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`Notice of Allowance. Id. As described above, only two claims of the ’270 patent,
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`claims 13 and 19, describe any limitation to the amount of bendamustine ethyl
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`ester (referred to therein as Formula IV), and no other claims of the ’270 patent
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`refer to or depend from claim 13 or from claim 19. Thus, the reasons for
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`allowance provided by the examiner relate to an aspect of the applicant’s
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`disclosure that is only recited in two of the 23 claims of the ’270 patent. As
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`discussed above, Ribomustin® product contained less than 0.5% bendamustine
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`ethyl ester, well prior to January 14, 2005. As described in detail below, the use of
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`TBA/water solutions to minimize the degradation of water-unstable drugs was
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`known in the art prior to January 14, 2005. See, e.g., Ex. 1006, described below.
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`V.
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`FILE HISTORY OF THE ’190 PATENT
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`34. The ʼ270 patent claims priority to the ʼ190 patent. It is my
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`understanding that during the prosecution history of the ’190 patent, an
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`Amendment was filed by the applicant on November 19, 2010, and in the remarks
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`accompanying this Amendment, applicant argued:
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`Prior to the invention, bendamustine was historically lyophilized from
`a solution of ethanol, water, mannitol, and bendamustine. As
`described in the specification, bendamustine ethyl ester is a degradant
`formed when bendamustine reacts with ethyl alcohol.
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`Ex. 1017 at 0367.
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`35. Thus, according to the applicant, prior to their alleged invention and
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`prior to January 14, 2005, bendamustine was known to be lyophilized from a
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`solution containing ethanol, water, mannitol, and bendamustine.
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`VI. LEGAL STANDARDS
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`36.
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`I understand that a claim is not patentable under 35 U.S.C. §102, for
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`lack of novelty, if each and every element of the claim is found, either expressly or
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`inherently described, in a single prior art reference.
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`37.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. §103, for obviousness, if the differences between the invention and the
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`prior art are such that the subject matter as a whole would have been obvious at the
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`time the invention was made to a person having ordinary skill in the art to which
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`the subject matter pertains.
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`38.
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`I have been instructed that, a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`39.
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`I understand that a claim can be found to be obvious if all the claimed
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`elements were known in the prior art and one skilled in the art could have
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`combined the elements as claimed by known methods with no change in their
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`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art.
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`40.
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`I understand that hindsight must not be used when comparing the
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`prior art to the invention for obviousness. Thus, a conclusion of obviousness must
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`be firmly based on the knowledge and skill of a person of ordinary skill in the art at
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`the time the invention was made, without the use of post-filing knowledge.
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`41.
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`I understand that in order for a claimed invention to be considered
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`obvious, there must be some supporting rationale for combining cited references as
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`proposed.
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`42.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. Obviousness may be
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`demonstrated by showing that it would have been obvious to combine the
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`teachings of more than one item of prior art. In determining whether a piece of
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`prior art could have been combined with other prior art or with other information
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`within the knowledge of one of ordinary skill in the art, the following are examples
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`of approaches and rationales that may be considered: combining prior art elements
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`according to known methods to yield predictable results; simple substitution of one
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`known element for another to obtain predictable results; use of a known technique
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`to improve similar methods or products in the same way; applying a known
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`technique to a known method or product ready for improvement to yield
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`predictable results; applying a technique or approach that would have been
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`“obvious to try” (choosing from a finite number of identified, predictable solutions,
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`with a reasonable expectation of success); known work in one field of endeavor
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`may prompt variations of it for use in either the same field or a different one based
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`on design incentives or other market forces if the variations would have been
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`predictable to one of ordinary skill in the art; or some teaching, suggestion, or
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`motivation in the prior art that would have led one of ordinary skill to modify the
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`prior art reference or to combine prior art reference teachings to arrive at the
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`claimed invention.
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`43.
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`I also understand that “secondary considerations” may be considered
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`when in evidence to rebut a conclusion of prima facie obviousness where
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`appropriate.
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`44.
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`I understand that such secondary considerations include: (i)
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`commercial success of a product due to the merits of the claimed invention; (ii) a
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`long-felt, but unsatisfied need for the invention; (iii) failure of others to find the
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`solution provided by the claimed invention; (iv) deliberate copying of the invention
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`by others; (v) unexpected results achieved by the invention; (vi) praise of the
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`invention by others skilled in the art; (vii) lack of independent simultaneous
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`invention within a comparatively short space of time; and (viii) teaching away
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`from the invention in the prior art. Secondary considerations are relevant where
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`there is a connection, or relationship, between the evidence and the claimed
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`invention.
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`VII. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
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`45.
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`I have been advised that “a person of ordinary skill in the relevant
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`field” is a hypothetical person who is presumed to have known the relevant art at
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`the time of the invention. A person of ordinary skill in the art is also a person of
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`ordinary creativity. I have been advised that the relevant timeframe for assessing
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`validity of claims of the ’270 patent is the time prior to January 14, 2005. Unless
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`otherwise specifically noted, all of my opinions expressed herein regarding a
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`person of ordinary skill in the art apply to a person of ordinary skill in the art prior
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`to January 14, 2005.
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`46. By virtue of my education, experience, and training, I am familiar with
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`the level of skill in the art of the ’270 patent prior to January 14, 2005. In my
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`opinion, a person of ordinary skill in the relevant field as of January 14, 2005
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`would typically have an advanced degree (e.g., a Ph.D.) in pharmaceutics,
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`pharmaceutical chemistry, medicinal chemistry, or a related field, or could have
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`less education but considerable professional experience in one or more of these
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`fields.
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`47.
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`In particular, one of ordinary skill in the art would likely have some
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`combination of the following skills and experience: (i) experience with drug
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`lyophilization; (ii) experience designing and preparing liquid drug formulations;
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`(iii) experience designing and preparing formulations of drugs that are unstable in
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`water; (iv) the ability to understand work presented or published by others in the
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`field, including the publications discussed in this declaration.
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`VIII. CLAIM CONSTRUCTION
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`48.
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`I have been advised that, in the present proceeding, the ’270 patent
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`claims are to be given their broadest reasonable interpretation in view of the
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`specification and this standard differs from the standard used in district court
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`patent litigation proceedings. I also understand that, at the same time, absent some
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`reason to the contrary, claim terms are typically given their ordinary and
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`accustomed meaning as would be understood by one of ordinary skill in the art. I
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`have followed these principles in my analysis throughout this declaration.
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`49.
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`I have been informed that in determining what is encompassed by the
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`term “about,” one must consider the context of the term as it is used in the
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`specification and claims of the patent. Claims 1, 8, 10-13, and 16-19 of the ’270
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`patent recite the term “about” with respect to amounts of bendamustine degradants,
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`expressed as “area percent of bendamustine” (as determined by HPLC) in a
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`“pharmaceutical composition.” In view of the ’270 patent specification, the term
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`“about” can reasonably be viewed as accommodating for an amount of variability
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`typical to the analytical methods employed. The specification of the ’270 patent
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`acknowledges that “slight variability” can be observed between different HPLC
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`methods. See, e.g., Ex. 1001, col. 25, ll. 32-34. The specification of the ’270
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`patent also identifies variability in the amount of each degradant observed across
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`different batches of a pharmaceutical product. See, e.g., id. at col. 30, ll. 35-45; see
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`also id. at fig. 6, showing variability of the baseline within a single HPLC run.
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`Variability can be due to a number of factors, including sample preparation,
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`column temperature, flow rate, and integration protocols, as well as variability
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`between different HPLC methods (id. at col. 25, ll. 32-34), and across samples or
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`batches (id. at col. 30, ll. 35-45), sources that are well known to persons of
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`ordinary skill familiar with HPLC. In the context of the ’270 patent, a person of
`
`ordinary skill in the art would consider the broadest reasonable interpretation of the
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`term “about” to accommodate for each of these sources of variability. Thus, for
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`example, one of ordinary skill in the art would construe the claim term “about
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`0.9% (area percent of bendamustine)” to include “0.96% (area percent of
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`bendamustine),” an amount differing by only 0.06%. This amount of variability
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`-17-
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`(e.g., 0.06%) would reasonably be expected in HPLC analysis of pharmaceutical
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`compositions as described in the ’270 patent specification, and thus falls within the
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`scope of the term “about,” as recited in the ’270 patent claims.
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`50.
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`In light of the specification of the ’270 patent, I consider both
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`“lyophilized preparation” and “lyophilized composition” to mean “solid material
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`obtained by lyophilization, i.e., freeze-drying of an aqueous solution.” See Ex.
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`1001, col. 9, ll. 212-13. I consider “pharmaceutical composition” to mean “a
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`composition intended for use as a pharmaceutical.” I consider “area percent of
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`bendamustine” to mean “the amount of a specified degradant relative to the
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`amount of bendamustine, expressed as a percent.” See id. at col. 12, ll. 10-12. In
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`light of the specification, I consider “bendamustine degradants” to mean
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`“monohydroxy bendamustine (HP1), bendamustine dimer (BM1 Dimer),
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`bendamustine ethyl ester (BM1EE), BM1DCE or a combination thereof.” See id. at
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`col. 21, l. 3-col. 22, l. 10, col. 30, ll. 35-45. I also consider “time zero after
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`reconstitution” to mean “30 minutes or less after reconstitution,” as the
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`specification of the ’270 patent describes measuring amounts of bendamustine
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`degradants in units of hours. See, e.g., id. at col. 21, ll. 20-29. I have followed
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`these definitions in my analysis throughout this declaration.
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`IX. THE STATE OF THE ART
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`51. Below I describe some of the relevant aspects of what was generally
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`known in the art as of January 14, 2005.
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`52. Bendamustine was reportedly first synthesized in 1963 and was
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`originally developed under the tradename Cytostasan®. Ex. 1010 at 782. Its
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`clinical use as an anticancer agent dates back to 1969, when it was first
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`administered to patients with myeloma. Ex. 1011 at 639. Chemically,
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`“[b]endamustine is a bifunctional alkylating agent consisting of a purine and amino
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`acid antagonist (a benzimidazole ring) and an alkylating nitrogen mustard moiety.”
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`Ex. 1012 at 632. For convenience, the structure of bendamustine is shown below:
`
`
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`53. The use of bendamustine in Germany for the treatment of Hodgkin’s
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`disease, Non-Hodgkin’s lymphoma, multiple myeloma, chronic lymphocytic
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`leukemia, and breast cancer was well known in the art prior to January 14, 2005, as
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`disclosed, e.g., by Julia A. Barman Balfour & Karen L. Goa, Bendamustine, 61
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`DRUGS 631 (2001) (hereinafter “Barman Balfour,” Ex. 1012 at 637). Ribomustin®
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`was known in the art to be a lyophilized formulation containing bendamustine
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`hydrochloride and mannitol. See, e.g., Ex. 1007; Ex. 1005; Ex. 1014, these
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`exhibits are described in detail below; see also Ex. 1001, col. 2, ll.