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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`AKER BIOMARINE AS
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`Petitioner
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`v.
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`NEPTUNE TECHNOLOGIES AND BIORESOURCES INC.
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`Patent Owner
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`
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`CASE IPR: Unassigned
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`Declaration of Dr. Richard B. van Breemen
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`000001
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`I, Richard B. van Breemen, Ph.D., hereby declare and say:
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`
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`1.
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`I, Dr. Richard B. van Breemen, have been retained by counsel for
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`Petitioner Aker BioMarine AS to provide an expert declaration in this action.
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`2.
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`I have reviewed U.S. Patent 8,278,351 (hereinafter ‘351 patent; Ex.
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`1001) and the claims contained therein. It is my understanding that the ‘351 patent
`
`contains claims to krill extracts (claims 1-23); capsules, tablets, solutions, syrups
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`or suspensions comprising the krill extracts (claims 24-46); foods, beverages or
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`nutritional supplements comprising the krill extracts (claims 47-69); cosmetics
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`comprising the krill extracts (claims 70-93); and Antarctic krill extracts (claim 94).
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`3.
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`As part of my engagement by the Respondents, I have been asked to
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`provide analysis and opinions on the following:
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`• whether certain krill extracts analyzed by Earl L. White on behalf
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`of the Patentee contain the Claimed Phospholipids of the ‘351
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`patent; and
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`• whether any of the Claims of the ‘351 patent are invalid under 35
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`U.S.C. § 102 as anticipated or under 35 U.S.C. § 103 as being
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`rendered obvious.
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`- 2 -
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`000002
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`4.
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`I hold a B.A. degree in Chemistry from Oberlin College (1980) and a
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`Ph.D. in Pharmacology from the Johns Hopkins University School of Medicine
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`(1985).
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`5.
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`From 1986 to 1993, I was an Assistant Professor of Chemistry at
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`North Carolina State University. During that time, I also served as Director of the
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`Mass Spectrometry Laboratory for Biotechnology Research. In 1994, I joined the
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`faculty of the University of Illinois at Chicago (UIC) as an Associate Professor of
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`Medicinal Chemistry at the College of Pharmacy. In 2000, I was promoted to the
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`position of Professor of Medicinal Chemistry and Pharmacognosy at the UIC
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`College of Pharmacy, and I hold that position today.
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`6.
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`Since 1999, I have also worked at the UIC/NIH Center for Botanical
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`Dietary Supplements Research (UIC Botanical Center). The UIC Botanical Center
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`focuses on the study of the safety and efficacy of dietary supplements used by
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`women. I was initially a Co-Director at the UIC Botanical Center when it was
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`founded in 1999, and my primary responsibilities were supplement safety and all
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`analytical aspects of supplements, including chemical standardization. Since 2011,
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`I have been the Director of the UIC Botanical Center. In this role, I have been
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`responsible for extraction and standardization of all botanical supplements for
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`study. Since 1999, we have completed three Phase-1 trials and one Phase-2
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`clinical trial at the UIC Botanical Center.
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`- 3 -
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`000003
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`7.
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`Since 2001, I have also held the administrative position of Assistant to
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`the Director of the Research Resources Center at the University of Illinois at
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`Chicago. In this position, I provide advice regarding campus needs in the area of
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`mass spectrometry, and my laboratory serves as a central campus resource in mass
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`spectrometry.
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`8.
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`Since 2010, I have been the leader of the Mass Spectrometry,
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`Metabolomics and Proteomics Facility (MMPF) for the University of Illinois
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`Cancer Center. MMPF provides analytical mass spectrometry support for cancer
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`researchers for all branches of the University of Illinois. For examples, MMPF
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`supports drug discovery, drug metabolism, pharmacokinetics, and clinical trials.
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`9.
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`I have done analytical work regarding materials of marine origin.
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`Beginning in the 1990s, I performed research on carotenoids that included
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`astaxanthin of marine origin utilizing tandem mass spectrometry (MS/MS). My
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`publications stemming from that work include:
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`• van Breemen RB, Schmitz HH, Schwartz SJ. Fast atom
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`bombardment tandem mass spectrometry of carotenoids. J. Agric.
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`Food Chem. 43, 384-389 (1995); and
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`• van Breemen RB, Dong L, Pajkovic ND. Atmospheric pressure
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`chemical ionization tandem mass spectrometry of carotenoids. Int.
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`J. Mass Spectrom. 312, 163-172 (2012)
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`- 4 -
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`000004
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`From 2006-2011, as a project leader on a program project grant entitled, “Natural
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`inhibitors of carcinogenesis,” from the National Cancer Institute of the National
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`Institutes of Health, I carried out drug discovery research utilizing mass
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`spectrometry focused exclusively on natural products from marine sediment
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`microorganisms. My publications stemming from that work include:
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`• Choi Y, Jermihov K, Nam S-J, Sturdy M, Maloney K, Qiu X,
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`Chadwick LR, Main M, Chen S-N, Mesecar AD, Farnsworth NR,
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`Pauli GF, Fenical W, Pezzuto JM, van Breemen RB. Screening
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`natural products for inhibitors of quinone reductase-2 using
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`ultrafiltration LC-MS. Anal. Chem. 83, 1048-1052 (2011).
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`PMC3034444; and
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`• Kondratyuk TP, Park E-J, Yu R, van Breemen RB, Asolkar RN,
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`Murphy BT, Fenical W, Pezzuto JM. Novel marine phenazines as
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`potential cancer chemopreventive and inflammatory agents. Mar.
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`Drugs, 10, 451-464 (2012). PMC3297008
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`I have also done work in the field of lipid chemistry. For example, between 1990-
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`1995, I carried out early mass spectrometry-based structural studies of
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`phosphatidylinositols (PI) including:
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`000005
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`• van Breemen RB, Wheeler JJ, Boss WF. Identification of carrot
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`inositol phospholipids by
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`fast atom bombardment mass
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`spectrometry. Lipids, 25, 328-334 (1990); and
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`• van Breemen, RB. Structural analysis of phosphatidylinositol from
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`carrot cell membranes by fast atom bombardment and tandem
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`mass spectrometry. In Mass Spectrometry in the Molecular
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`Sciences: A Tutorial, pp. 443-451, ed. by Gross ML. Kluwer
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`Academic Publishers, Dordrecht, 1992. (Invited Contribution)
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`I also published numerous papers regarding the structural characterization and
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`identification of
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`lipophilic carotenoids using high performance
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`liquid
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`chromatography-mass spectrometry (LC-MS) and LC-MS/MS, including:
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`• van Breemen RB, Schmitz HH, Schwartz SJ. Continuous-flow fast
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`atom bombardment liquid chromatography/mass spectrometry of
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`carotenoids. Anal. Chem. 65, 965-969 (1993);
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`• van Breemen RB. Electrospray
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`liquid chromatography-mass
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`spectrometry of carotenoids. Anal. Chem. 67, 2004-2009 (1995);
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`000006
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`• van Breemen RB. Innovations in carotenoid analysis using liquid
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`chromatography/mass spectrometry. Anal. Chem. 68, 299A-304A
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`(1996);
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`• van Breemen RB, Huang C-H, Tan Y, Sander LC, Schilling AB.
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`Liquid chromatography/mass spectrometry of carotenoids using
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`atmospheric pressure chemical ionization. J. Mass Spectrom. 31,
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`975-981 (1996); and
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`• van Breemen RB. Liquid chromatography/mass spectrometry of
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`carotenoids. Pure Appl. Chem. 69, 2061-2066 (1997).
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`10. Since 1986, I have been teaching analytical chemistry and mass
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`spectrometry at the university level, including at the graduate level. In the Fall of
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`1986, I created and taught a course at North Carolina State University entitled,
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`CH527 Mass Spectrometry, which I taught until 1992. In that course I instructed
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`students regarding the theory and application of mass spectrometry. From 1987-
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`1993, I also taught a course called CH525 Physical Methods in Organic Chemistry.
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`In that course I instructed students regarding the structure determination of organic
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`compounds using a variety of spectroscopy data. Since joining the faculty at UIC
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`in 1994, I have taught a course called MDCH 562 Spectroscopy in Medicinal
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`Chemistry. In that course I instruct graduate students regarding the interpretation
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`000007
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`of mass spectra and the structure determination of drugs and natural products using
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`a combination of analytical techniques including nuclear magnetic resonance,
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`infrared spectroscopy, ultraviolet spectroscopy, and mass spectrometry. More than
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`45 graduate students and 19 post-doctoral fellows have graduated from my
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`laboratory, all with advanced training in mass spectrometry.
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`11.
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`I have authored or co-authored more than 250 articles in peer-
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`reviewed journals and have co-authored more than a dozen book chapters,
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`including chapters for texts related to mass spectrometry, food analytical
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`chemistry, and lipid analysis. I am the American Regional Editor of the scientific
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`journal Biomedical Chromatography and am also on the editorial board of Assay
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`and Drug Development Technologies, and I serve as an ad hoc reviewer for
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`approximately 40 scientific journals, reviewing approximately 35 papers each year
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`on average.
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`12. On more than 30 occasions, I have served as an advisor to Federal
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`Government Public Advisory Committees at the National Institutes of Health
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`(NIH) on topics ranging from cancer, complementary and alternative medicine,
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`small business proposals related to biomedical research (SBIR), and shared
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`instrument proposals, including those related to mass spectrometry.
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`13. My research is interdisciplinary and currently focuses on safety and
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`efficacy of botanical dietary supplements and cancer chemoprevention. My
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`000008
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`laboratory at UIC routinely prepares samples for analysis using LC-MS, including
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`specialized biomedical applications of LC-MS. On a daily basis we use high
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`performance liquid chromatography (HPLC) and ultrahigh pressure liquid
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`chromagraphy (UHPLC). On a daily basis, we also extract specimens of
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`botanicals as well as human and animal specimens, including serum, tissue, and
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`urine, in preparation for analysis.
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`14. A more detailed account of my education, work experience,
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`publications, honors, memberships in professional societies, selected speaking
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`engagements, a listing of my previous and present graduate students and
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`postdoctoral research associates, and other qualifications—as well as a list of cases
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`during the last four years in which I have signed a Protective Order, have testified
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`as an expert either at a trial, hearing, or deposition, or have submitted statements /
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`opinions—is listed in my Curriculum Vitae attached as Attachment A to this
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`Declaration.
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`15.
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`I am being compensated at my customary consulting rate of $300 per
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`hour for my time spent on this matter. I am also being reimbursed for reasonable
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`expenses incurred with respect to this matter, and my university is being paid a rate
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`of $162 per hour for access to its LC/MS facilities. My compensation is not
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`contingent on the conclusions I reach in my expert report or the outcome of this
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`litigation.
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`000009
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`16.
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`I have reviewed and considered, in the preparation of this report, the
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`documents in the below table.
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`Exhibit
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`Description
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`No.
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`1001
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`U.S. Pat. No. 8,278,351 to Sampalis (“’351”)
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`1005
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`Certified translation of Ex. 1072: Fisheries Agency, General Report
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`on Research and Development of Techniques in Processing and
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`Utilization of Marine Products, Chapter 6, Development of
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`technology for recovery of valuable substances (astaxanthin) from
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`krill, by Takao Fujita, pp. 273-307 (March 1985) (“Fujita”) ;
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`Certificate of Translation provided as Ex. 1073.
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`1008
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`Canadian Patent No. 1098900, titled Method for the Processing of
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`Krill to Produce Protein, Lipids and Chitin (“Rogozhin”)
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`1031
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`Winther et al., Elucidation of Phosphatidylcholine Composition in
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`Krill Oil Extracted from Euphausia superba, Lipids 46(1):25-36
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`(2011)(“Winther”)
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`1043
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`Expert Witness Report of Dr. Theodore Welch submitted in relation
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`0000010
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`to ITC Investigation No. 337-TA-877 (“Welch”)
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`1051
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`Declaration of Dr. Earl White submitted during prosecution of parent
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`patent U.S. 8,030,348 (“2011 White Decl.”)
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`1054
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`Declaration of Dr. Yeboah submitted during inter partes
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`reexamination of parent patent U.S. 8,030,348 (“Yeboah Reexam
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`Decl.”)
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`1055
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`Supplemental Declaration of Dr. Earl White submitted during inter
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`partes reexamination of parent patent U.S. 8,030,348 (“White Supp.
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`Reexam. Decl.”)
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`1056
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`Declaration of Dr. Shahidi submitted during inter partes
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`reexamination of parent patent U.S. 8,030,348 (Shahidi Reexam.
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`Decl.”
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`1057
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`Declaration of Dr. Tina Sampalis submitted during inter partes
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`reexamination of parent patent U.S. 8,030,348 (Sampalis”)
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`1061
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`April 2, 2012 Response to Office Action, ‘351 patent
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`1062
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`Provisional Application No. 60/307,842 (Priority document for the
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`0000011
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`‘351 patent)
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`1066
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`Declaration of Dr. van Breemen submitted during Ex parte
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`Reexamination of the ‘351 patent (Van Breemen ‘351 Reexam.
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`Decl.”
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`1067
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`Declaration of Dr. van Breemen submitted during Ex parte
`
`Reexamination of the ‘348 patent (van Breemen ‘348 Reexam Decl.”
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`1069
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`U.S. Patent No. 8,030,348
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`
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`17. Additionally,
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`I
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`submitted declarartions during
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`reexamination
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`proceedings concerning the ‘351 Patent and during reexamination proceedings
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`concerning U.S. Patent No. 8,030,348 (the ‘348 patent; Ex. 1069), to which the
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`‘351 patent claims priority (Declaration of Dr. van Breemen submitted during Ex
`
`parte Reexamination of the ‘351 patent; Ex. 1066; (Declaration of Dr. van
`
`Breemen submitted during Inter partes Reexamination of the ‘348 patent; Ex.
`
`1067). The data and analysis in those declarations are incorporated at ¶¶ 90-101
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`below.
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`18. The ‘351 patent discusses certain phospholipid molecules, including
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`phosphatidylcholine
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`(abbreviated
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`as
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`“PC”),
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`phosphatidylethanolamine
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`- 12 -
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`0000012
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`(abbreviated as “PE”), and phosphaditlinositol
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`(abbreviated as “PI”).
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`Phospholipids PC, PE and PI are naturally occurring biochemicals consisting of a
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`glycerol molecule to which is attached a polar group at one end, a fatty acid acyl
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`group in the middle (called the sn-2 position) and another fatty acid acyl group at
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`the other end (called the sn-1 position). The polar group consists of a phosphate
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`group to which is attached a choline, ethanolamine or an inositol group.
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`19. Various analytical chemistry techniques are referred to in this report
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`and in the case materials I have considered for purposes of my analysis. These
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`analytical chemistry techniques including TLC, HPLC, UHPLC, GC, and LC/MS.
`
`20. TLC. Thin Layer Chromatography is a technique used to separate
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`compounds in a mixture. Generally, a compound mixture is applied to a plate or
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`sheet that is coated with an adsorbent material. A solvent is then applied to the
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`plate. As the solvent travels up the plate (through capillary action), the different
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`compounds in the mixture will travel with it while adsorbing to and desorbing from
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`the stationary coat on the plate at different rates, achieving separation. TLC may be
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`used preparatively to separate mixtures of compounds or it may be used
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`qualitatively to characterize a mixture. Although co-chromatography of two
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`compounds during TLC does not provide sufficient chemical information for
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`compound identification, TLC can show that two compounds are not identical.
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`0000013
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`21. HPLC and UHPLC. High performance liquid chromatography
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`(HPLC) and ultrahigh pressure liquid chromatography (UHPLC) are techniques
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`used to separate compounds in mixtures while in solution. Separations occur on a
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`stationary phase (usually silica or chemically derivatized silica) that is packed into
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`a column. Solvent (called the mobile phase) is pumped through the column up at
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`pressures typically up to 6,000 psi (HPLC) or 19,000 psi (UHPLC), and a
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`compound mixture is injected into the flowing of solvent and onto the column. Due
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`to differences in interactions between the stationary phase and the compounds in
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`the mixture such as adsorption, the compound mixture can be separated as it flows
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`through the column such that each compound elutes (is washed out or removed) at
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`a different time. UHPLC typically provides better chromatographic separations and
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`faster separations than can HPLC.
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`22. GC. Gas chromatography is a technique used to separate compounds
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`in mixtures while in the gas phase. Separations occur in a column containing a
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`stationary phase that is either packed into the column or on the inner wall of the
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`column. The compound mixture is injected into a moving stream of gas (usually
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`helium or hydrogen) that carries the compounds into the column. Compounds
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`separate as they partition differently between the stationary phase and the carrier
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`gas and then elute from the column at different times.
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`0000014
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`23. LC-MS
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`and LC-MS/MS.
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` Liquid
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`chromatography-mass
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`spectrometry and LC-tandem mass spectrometry involve the interfacing of HPLC
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`or UHPLC to a mass spectrometer and a tandem mass spectrometer, respectively.
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`Mass spectrometers convert molecules to gas phase ions that are then separated
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`and weighed in an electromagnetic field according to their mass-to-charge
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`properties. High resolution mass spectrometers can weigh ions with such accuracy
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`that the elemental compositions of the ions can be determined. For the
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`measurement of the Claimed Phospholipids in my laboratory, I used a hybrid ion
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`trap time-of-flight (IT-TOF) high resolution mass spectrometer and a triple
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`quadrupole tandem mass spectrometer. Tandem mass spectrometers provide a
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`second dimension of ion characterization by selecting a specific precursor ion,
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`fragmenting it (usually using a gas-phase process called collision-induced
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`dissociation) and then recording all or specific fragment ions that provide structural
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`information about the precursor ion.
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`24. The ‘351 patent is titled “Natural Marine Source Phospholipids
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`Comprising Polyunsaturated Fatty Acids and Their Applications.” The ‘351 patent
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`lists one inventor, Fotini Sampalis. I understand that the ‘351 patent is assigned to
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`Neptune Technologies & Bioressources, Inc.
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`25.
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`It is my understanding that the ‘351 patent contains claims to krill
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`extracts (claims 1-23); capsules, tablets, solutions, syrups or suspensions
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`- 15 -
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`0000015
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`
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`comprising the krill extracts (claims 24-46); foods, beverages or nutritional
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`supplements comprising the krill extracts (claims 47-69); cosmetics comprising the
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`krill extracts (claims 70-93); and Antarctic krill extracts (claim 94). I understand
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`that claims 1, 24, 47, 70 and 94 of the ’351 Patent are independent claims and that
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`claims 2-23 depend on claim 1, claims 25-46 depend on claim 24, claims 48-69
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`depend on claim 47, and claims 71-93 depend on claim 70.
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`26. The common feature of the independent claims (claims 1, 24, 47, 70
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`and 94) is the
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`requirement of a phospholipid of the general formula (I),
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`
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`wherein R1 and R2, each together with the respective
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`carboxyl groups
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`to which each
`
`is attached, each
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`independently represent a docosahexaenoic acid (DHA)
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`or an eicosapentaenoic acid (EPA) residue, and X is —
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`CH2CH2NH3, —CH2CH2N(CH3)3, or
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`0000016
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`.
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`The dependent claims add limitations on other components of the
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`composition such as omega-3 content, polyunsaturated fatty acid content, content
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`of other lipid classes, metal content and antioxidant content.
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`27. Because a phospholipid of general formula I is in each independent
`
`claim, it is also required in each of the dependent claims.
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`28. General formula I comprises the following twelve phospholipids:
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`Phospholipid Class
`
`R1 and R2
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`—CH2CH2NH3
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`(Phosphatidylethanolamine or “PE”)
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`R1: DHA
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`R2: EPA
`
`R1: EPA
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`R2: DHA
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`R1: EPA
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`R2: EPA
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`R1: DHA
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`R2: DHA
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`- 17 -
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`0000017
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`—CH2CH2N(CH3)3
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`(Phosphatidylcholine or “PC”)
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`
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`(Phosphatidylinositol or “PI”)
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`
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`R1: DHA
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`R2: EPA
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`R1: EPA
`
`R2: DHA
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`R1: EPA
`
`R2: EPA
`
`R1: DHA
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`R2: DHA
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`R1: DHA
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`R2: EPA
`
`R1: EPA
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`R2: DHA
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`R1: EPA
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`R2: EPA
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`R1: DHA
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`R2: DHA
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`Throughout my report, I will refer to these twelve phospholipids as the “Claimed
`
`Phospholipids.”
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`0000018
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`29. Claim 1 of the ‘351 Patent states: “[a] krill extract comprising: a
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`phospholipid of the general formula (I),
`
`
`
`wherein R1 and R2, each together with the respective
`
`carboxyl groups
`
`to which each
`
`is attached, each
`
`independently represent a docosahexaenoic acid (DHA)
`
`or an eicosapentaenoic acid (EPA) residue, and X is —
`
`CH2CH2NH3, —CH2CH2N(CH3)3, or
`
`
`
`and wherein
`
`the extract
`
`is suitable
`
`for human
`
`consumption.
`
`30. Claim 24 of the ‘351 Patent is identical to claim 1, except that claim
`
`24 additionally states “[a] capsule, tablet, solution, syrup, or suspension
`
`comprising a krill extract …”
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`0000019
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`31. Claim 47 of the ‘351 Patent is identical to claim 1, except that claim
`
`47 additionally states “[a] food, beverage, energy bar or nutritional supplement…”
`
`32. Claim 70 of the ‘351 Patent is identical to claim 1, except that claim
`
`70 additionally states “[a] cosmetic preparation…”
`
`33. The claims of the ‘351 Patent that depend on claim 1 (claims 2-23),
`
`the claims that depend on claim 24 (claims 25-46), the claims that depend on claim
`
`47 (claims 48-69), and the claims that depend on claim 70 (claims 72-93) (with the
`
`exception of claim 71) mirror each other in the following manner:
`
`Claims
`
`
`
`2, 25,
`
`The extract according to claim [1, 24, 47, 70] wherein the extract has a
`
`48, 72
`
`total phospholipid concentration in an amount of about 40% w/w,
`
`wherein about represents ±10%.
`
`3, 26,
`
`The extract according to claim [1, 24, 47, 70], wherein the extract has a
`
`49, 73
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`total phospholipid concentration in an amount of about 45% w/w,
`
`wherein about represents ±20%.
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`0000020
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`
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`Claims
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`
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`4, 27,
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`The extract according to claim [1, 24, 47, 70], further comprising an
`
`50, 74
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`additional lipid, wherein the additional lipid is selected from the group
`
`consisting of monoglycerides, triglycerides, cholesterols, mixtures
`
`thereof, and free fatty acids.
`
`5, 28,
`
`The extract according to claim [1, 24, 47, 70], wherein the extract has a
`
`51, 75
`
`concentration of free fatty acids of about 5% w/w of the lipids in the
`
`extract.
`
`6, 29,
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`The extract according to claim [1, 24, 47, 70], wherein the extract further
`
`52, 76
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`comprises polyunsaturated fatty acids which comprise at least 15% w/w
`
`of the lipids in the extract.
`
`7, 30,
`
`The extract according to claim [1, 24, 47, 70], wherein the extract further
`
`53, 77
`
`comprises polyunsaturated fatty acids which comprise at least 40% w/w
`
`of the lipids in the extract.
`
`8, 31,
`
`The extract according to claim [1, 24, 47, 70], wherein the extract further
`
`54, 78
`
`comprises polyunsaturated fatty acids which comprise at least 45% w/w
`
`of the lipids in the extract.
`
`
`- 21 -
`
`0000021
`
`
`
`
`
`Claims
`
`
`
`9, 32,
`
`The extract according to claims [6, 29, 52, 76], [7, 30, 53, 77], or [8, 31,
`
`55, 79
`
`54, 78], wherein the polyunsaturated fatty acids are omega-3 fatty acids.
`
`10, 33,
`
`The extract according to claim [1, 24, 47, 70], wherein DHA and EPA
`
`56, 80
`
`comprise at least 32% w/w of the lipids in the extract.
`
`11, 34,
`
`The extract according to claim [1, 24, 47, 70], wherein DHA and EPA
`
`57, 81
`
`comprise at least 35% w/w of the lipids in the extract.
`
`12, 35,
`
`The extract according to claim [1, 24, 47, 70], further comprising a metal.
`
`58, 82
`
`13, 36,
`
`The extract according to claim [12, 35, 58, 82], wherein the metal is zinc,
`
`59, 83
`
`selenium or a mixture thereof.
`
`14, 37,
`
`The extract according to claim [13, 36, 59, 83], wherein the zinc
`
`60, 84
`
`comprises at least 0.005 mg/100 g of the extract and the selenium
`
`comprises less than 3 mg/100 g of the extract.
`
`15, 38,
`
`The extract according to claim [4, 27, 50, 74], wherein the fatty acid
`
`61, 85
`
`composition of the lipids in the extract is about:
`
`
`- 22 -
`
`0000022
`
`
`
`
`
`Claims
`
`
`
`16, 39,
`
`The extract according to claim [15, 38, 61, 85], wherein the total fatty
`
`62, 86
`
`acid composition of all the lipids in the extract is:
`
`17, 40,
`
`The extract according to claim [16, 39, 62, 86], wherein the total fatty
`
`63, 87
`
`acid composition of all the lipids is:
`
`18, 41,
`
`The extract according to claim [4, 27, 50, 74], comprising:
`
`64, 88
`
`19, 42,
`
`The extract of claim [1, 24, 47, 70], wherein one of R1 and R2 is EPA
`
`65, 89
`
`and the other is DHA.
`
`20, 43,
`
`The extract of claim [1, 24, 47, 70], wherein R1 and R2 is EPA.
`
`66, 90
`
`21, 44,
`
`The extract of claim [1, 24, 47, 70], wherein R1 and R2 is DHA.
`
`67, 91
`
`22, 45,
`
`The extract of claim [1, 24, 47, 70], further comprising an antioxidant.
`
`68, 92
`
`
`- 23 -
`
`0000023
`
`
`
`
`
`Claims
`
`
`
`23, 46,
`
`The extract of claim [22, 45, 68, 92], wherein the antioxidant is selected
`
`69, 93
`
`from the group consisting of vitamin A, vitamin E, carotenoid, beta-
`
`carotene, astaxanthin, canthaxanthin, flavonoids, and mixtures thereof.
`
`34. Claim 71 depends on indepdent Claim 70, and recites: “The cosmetic
`
`preparation of claim 70, wherein the topical cosmetic product is one or more of a
`
`moisturizing cream and a sun-block product.”
`
`35. Claim 94 of the ’351 Patent recites:
`
`An Antarctic krill oil extract comprising: a phospholipid
`
`of the general formula (I),
`
`
`
`wherein R1 and R2, each together with the respective
`
`carboxyl groups
`
`to which each
`
`is attached, each
`
`independently represent a docosahexaenoic acid (DHA)
`
`
`- 24 -
`
`0000024
`
`
`
`
`
`or an eicosapentaenoic acid (EPA) residue, and X is —
`
`CH2CH2NH3, —CH2CH2N(CH3)3, or
`
`
`
`the extract is extracted under conditions suitable for
`
`preserving an effective amount of a phospholipid having
`
`two independently selected fatty acid chains within the
`
`same [molecule/phospholipid] selected from EPA and
`
`DHA;
`
`the extract comprises phospholipids in an amount of at
`
`least 40% w/w;
`
`the extract comprises omega-3 fatty acids in an amount
`
`of at least 15% w/w;
`
`the extract comprises astaxanthin and
`
`the extract is suitable for human consumption.
`
`
`
`
`- 25 -
`
`0000025
`
`
`
`
`
`36. The Fisheries Agency, General Report on Research and Development
`
`of Techniques in Processing and Utilization of Marine Products (March 1985) (the
`
`“General Report”) is a publication compiling studies relating to marine products.
`
`Section II of the General Report is focused on the development of krill as a food
`
`product. It contains a Chapter 6 (pp. 273-307) written by Takao Fujita and entitled
`
`“Development of utilization technology of a valuable resource (astaxanthin) in
`
`krill” (the “Fujita Reference”; Ex. 1005).
`
`37. The General Report including the Fujita Reference was published at
`
`least in 1986, fifteen years before the earliest claimed priority date of the Asserted
`
`Patents, and is therefore prior art to all Asserted Claims of the Asserted Patents
`
`under at least 35 U.S.C. § 102(b).
`
`38.
`
`I have reviewed the Expert Witness Report of Theodore F. Welch,
`
`Ph.D Regarding Public Accessibility of Certain References (Welch Expert
`
`Witness Report; Ex. 1043), and I understand that the Fujita Reference has been
`
`publicly accessible at the Ministry of Agriculture, Forestry and Fisheries Library
`
`(“MAFF Library”) in Tokyo, Japan since at least as early as November 1986, at
`
`least because the General Report including the Fujita Reference was indexed,
`
`catalogued, shelved, and publicly searchable by author and title by this date, and
`
`was fully cataloged and searchable by subject heading within a reasonable amount
`
`of time thereafter.
`
`
`- 26 -
`
`0000026
`
`
`
`
`
`39. On Monday, August 19, 2013, I also spoke with Ms. Endou, Ms.
`
`Sugiyama and Mr. Yoshihama (librarians at MAFF), who separately confirmed the
`
`following information for me:
`
`• The General Report including the Fujita Reference is in the MAFF
`
`Library’s collection and has been since at least as early as November
`
`1986;
`
`• The MAFF Library record for the General Report indicates its
`
`accession date at the MAFF Library was November 1986;
`
`
`
`• A stamp appearing on the first page of the table of contents for the
`
`General Report also indicates that its accession date at the MAFF
`
`Library was November 1986;
`
`
`
`• MAFF Library records, including the record for the General Report,
`
`have been electronically searchable since April 2001 by at least
`
`author, keyword, and/or title fields, and searchable by card catalog
`
`since the accession date of the General Report; and
`
`
`
`• The MAFF Library is generally open to the public on weekdays.
`
`
`- 27 -
`
`0000027
`
`
`
`
`
`
`
`40. The General Report discusses research directed toward use of krill for
`
`food products. For example, the Fujita Reference states:
`
`
`
`(Fujita (Ex. 1005) at page 275) Thus, the Fujita Reference discusses methods for
`
`extracting “valuable” components from krill for use in human food products with
`
`the objective that the resulting extracts comply with safety restrictions and
`
`“promot[e] effective utilization of krill.” (Id.)
`
`
`- 28 -
`
`0000028
`
`
`
`
`
`41. Multiple solvent extraction methods are
`
`taught in the Fujita
`
`Reference. The Fujita Reference teaches that among the solvents tested, hexane
`
`was chosen for further study because it was considered safe and appropriate for use
`
`in foods:
`
`In contrast, while the extractability with hexane was somewhat worse,
`
`this solvent is widely utilized in the extraction of vegetable oil, and it
`
`is believed to be the most practical solvent from the standpoint of
`
`safety, price and solvent recovery, etc. Therefore a study was
`
`performed to look at improving the extractability of lipids and
`
`carotenoids through adjustment of the water content.
`
`
`
`(Id., pages 283-284.)
`
`
`
`42. The Fujita Reference teaches at least three different extraction
`
`methods using hexane: (a) extraction with hexane with adjusted water content
`
`(Id., pages 284-285 (extraction test a with hexane with adjusted water content));
`
`(b) extraction with a hexane-ethanol mixture (Id. (extraction test b with
`
`hexane/ethanol)); and (c) a “once-through” extraction with hexane (Id., page 285
`
`(extraction test c)). I tested each of the forgoing three hexane extraction methods
`
`
`- 29 -
`
`0000029
`
`
`
`
`
`to determine if they inherently result in the Claimed Phospholipid. A detailed
`
`description of my processes for creating these krill extracts is set out below.
`
`43. The extraction with hexane with adjusted water content is reported in
`
`the Fujita Reference as follows:
`
`
`
`(Id., p. 285) The Fujita Reference reports results obtained “when performing
`
`extraction with reflux and heating for 1 hour using each of these solvents at an
`
`amount that was five times greater than that of the krill meal.” (Id., pages 282)
`
`44. Accordingly, to test this process, the following steps were performed:
`
`i.
`
`Krill meal used for this experiment was supplied by Aker. The
`
`meal arrived frozen on dry ice and was stored in a 4°C
`
`refrigerator upon receipt until use.
`
`ii.
`
`750 mL of hexane, water corresponding to a meal water content
`
`of 20%, and 150 gram of the krill meal were added to a 2 Liter
`
`round bottom flask. (The moisture content of the meal was
`
`
`- 30 -
`
`0000030
`
`
`
`
`
`4.3%. Accordingly, approximately 24 mL of water was added
`
`to achieve a 20% water content)
`
`iii. A magnetic stir bar was added to the round bottom flask and set
`
`to stir at 50 rpm. Extraction was performed with reflux and
`
`heating for 1 hour at 59°C while stirring the material.
`
`iv.
`
`The material was filtered under reduced pressure using a filter.
`
`v.
`
`The filtration residue was washed three times using 750 mL of
`
`hexane.
`
`vi.
`
`The procedures ii. through v. were repeated to ensure sufficient
`
`oil for analysis.
`
`vii. The filtrate and wash solution from both extractions were
`
`combined in a round bottom flask and the majority of the
`
`hexane was distilled off at 200 Torr and 30°C.
`
`viii. Solvent removal was completed by distillation at 40 Torr and
`
`70°C in order to obtain the oil.
`
`
`- 31 -
`
`0000031
`
`
`
`
`
`Reduced pressures of 40 Torr and 200 Torr, respectively, were obtained using a
`
`vacuum pump equipped with a pressure gauge and bleed valve, and temperatures
`
`of 70°C and 30°C were obtained using a water bath equipped with a thermometer.
`
`45. The Fujita Reference also teaches that hexane/ethanol at a ratio of
`
`79:21 can be substituted for hexane/water. (Id., pp. 284-285.) For example, the
`
`Fujita Reference states:
`
`Next, an intermediate extractor was used to perform manufact
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