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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`RIMFROST AS
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`Petitioner
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`v.
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`AKER BIOMARINE ANTARCTIC AS
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`Patent Owner
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`_______________________
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`Case: IPR2017-00745
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`U.S. Patent No. 9,078,905 B2
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`_______________________
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`REPLY DECLARATION OF DR STEPHEN J. TALLON
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`AKER EXIBHIT 2007 Page 1
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`IPR2017-00745
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`U.S. Patent No. 9,078,905 B2
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`TABLE OF CONTENTS
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`TABLE OF CONTENTS ........................................................................................ 2
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`REPLY DECLARATION OF STEPHEN J. TALLON ....................................... 5
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`Basis for Opinion ................................................................................................... 5
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`Introduction ............................................................................................................ 9
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`Yamaguchi (Exhibit 2002). ..................................................................................15
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`Tanaka I, Prescott, Zimmerman & Platelet Activating Factor (“PAF”) ..............18
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`Chen (Exhibit 1072) .........................................................................................26
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`Bunea (Exhibit 1020) .......................................................................................28
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`Sampalis I (Exhibit 1012) ................................................................................29
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`Enzymotec (Exhibits 1048 and 1049) ..............................................................29
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`Breivik (Exhibits 1035, 1036, 1037) ...............................................................32
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`Neptune Krill Oil (NKO) and Krill Bill NKO (Exhibit 1070, et. al) ..............35
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`Catchpole (Exhibit 1009) .................................................................................38
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`Personal Recommendation ...............................................................................39
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`Fricke II (Exhibit 2006) and Obviousness of Combining Krill Oil Prior Art .....40
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`NMR- The direct method of measuring ether phospholipids. .........................45
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`My Fricke I ether phospholipid calculation was correct .................................48
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`Tanaka I (Exhibit 1014) .......................................................................................49
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`Mayzaud (Exhibit 1084) ......................................................................................50
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`It would be obvious to combine composition ranges from different prior art.....52
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`Krill species and geographical and seasonal variations ...................................54
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`Harvesting, storage and heat treatment ............................................................56
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`Extracting the lipid krill components ...............................................................60
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`‘905 PATENT PETITION GROUNDS ...............................................................64
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`GROUND 1: CLAIMS 1-4 and 9-10 ...................................................................65
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`[CATCHPOLE and SAMPALIS I] .....................................................................65
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`GROUND 2: CLAIM 5 .......................................................................................72
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`[CATCHPOLE, SAMPALIS I and RANDOLPH] .............................................72
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`GROUND 3: CLAIMS 6, 12, 15-16, and 18 .......................................................74
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`[CATCHPOLE, SAMPALIS I and FRICKE I] ...................................................74
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`GROUND 4: CLAIMS 7-8, 13-14, 17, and 19-20 ..............................................80
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`[CATCHPOLE, SAMPALIS I, BOTTINO and FRICKE I] ...............................80
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`GROUND 5: CLAIM 11 .....................................................................................82
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`[CATCHPOLE, SAMPALIS I and BOTTINO ...................................................82
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`CONCLUDING OPINION ......................................................................................83
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`U.S. Patent No. 9,078,905 B2
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`REPLY DECLARATION OF STEPHEN J. TALLON
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`Basis for Opinion
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`1.
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`I have reviewed the Declaration of Dr. Nils Hoem, Exhibit 2001 (“Hoem
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`Dec.”), and the Patent Owner’s Response, Paper 14 (“POR”), and disagree with
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`their conclusions overall and as described in detail in the discussion below.
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`Furthermore, after reviewing the Hoem Dec. Exhibit 2001 and POR Paper 14, I
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`hereby reaffirm my opinion from my earlier Declaration, Exhibit 1006, that all
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`claims of the ‘905 Patent would have been obvious to a POSITA in view of the
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`prior art cited.
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`2.
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`In forming my opinion herein, I have relied on my own education, work
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`experiences and knowledge, my review of the documents referenced in the
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`Declaration of Stephen J. Tallon in IPR2017-00745 (Exhibit 1006), and, in
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`addition to the Hoem Dec. Exhibit 2001 and POR Paper 14, my review of the
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`following documents:
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`a. Yamaguchi, K. et al. “Supercritical Carbon Dioxide Extraction of Oils
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`from Antarctic Krill”, J. Agric. Food Chem. 1986, 34, 904-907 (Exhibit
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`2002).
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`b. Prescott, S. et al. “Platelet-Activating Factor and Related Lipid
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`Mediators”, Annu. Rev. Biochem. 2000. 69:419-445 (Exhibit 2003).
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`c. Zimmerman, G. et al. “The platelet-activating factor signaling system and
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`its regulators in syndromes of inflammation and thrombosis”, pp. 5294-
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`5301, Crit. Care Med 2002, Vol. 30, No. 5 (Suppl) (Exhibit 2004).
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`d. Calder, P. “n-3 Polyunsaturated fatty acids, inflammation, and
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`inflammatory diseases1-3”, Am. J. Clin. Nutr. 2006; 83(suppl):1505S-119S
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`(Exhibit 2005).
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`e. Fricke, H. et al. “1-O-Alkylglycerolipids in Antarctic Krill (Euphausia
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`Superba DANA)”, Comp. Biochem. Physiol. Vol. 85B, No. 1, pp. 131-134,
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`1986 (Fricke II) (Exhibit 2006).
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`f. Deposition of Dr Stephen Tallon (Tallon Dep.) (Exhibits 2007 and 2008).
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`g. Chen, U.S. Patent Application Publication No. US 2008/0021000 A1, for
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`“Mixtures of and Methods of Use for Polyunsaturated Fatty Acid-Containing
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`Phospholipids and Alkyl Ether Phospholipids Species”, filing date July 19,
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`2006, publication date January 24, 2008 (Chen) (Exhibit 1072).
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`h. Enzymotec, GRAS Notice No. GRN 000226 for “Krill-based Lecithin in
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`Food” and “Krill-derived lecithin” https://www.fda.gov/downloads/
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`Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm263930.
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`pdf, dated May 26, 2007 and filed by the FDA May 31, 2007 (Enzymotec)
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`(Exhibit 1048).
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`i. FDA, Agency Response Letter GRAS Notice No. GRN 000226,
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`U.S. Patent No. 9,078,905 B2
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`https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInve
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`ntory/ucm153881.htm, January 3, 2008 (Exhibit 1049).
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`j. Krill Bill Online Purchase Order and Specification Pages from 2006
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`(https://web.archive.org/web/20060715103715/http://www.krillbill.com:80/
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`purchase.htm; https://web.archive.org/web/20060715103809/http://
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`www.krillbill.com/profile.htm) (Krill Bill) (Exhibit 1070).
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`k. Burri, L., et al., “Fingerprinting Krill Oil by 31P, 1H and 13C NMR
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`Spectroscopies”, J Am Oil Chem Soc (2016) 93:1037-1049 (Burri) (Exhibit
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`1079).
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`l. Mayzaud et al, “Changes in lipid composition of the Antarctic krill
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`Euphausia superba in the Indian sector of the Antarctic Ocean: influence of
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`geographical location, sexual maturity stage and distribution among
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`organs” Marine Ecology Progress Series, Vol. 173: 149-162 (1998)
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`(Mayzaud) (Exhibit 1084).
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`m. Breivik, U.S. Patent Application Publication No. US 2010/0143571 A1,
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`“Process for Production of Omega-3 Rich Marine Phospholipids from Krill”
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`(Breivik I) (Exhibit 1035).
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`n. Breivik, U.S. Provisional Patent Application No. 60/859,289, “Processes
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`for production of omega-3 rich marine phospholipids from krill”, filed
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`November 16, 2006 (Breivik ‘289 Provisional, Breivik III) (Exhibit 1036).
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`o. Breivik, WO 2008/060163 A1, “Process for Production of Omega-3 Rich
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`Marine Phospholipids from Krill,” International filing date November 15,
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`2007 (Breivik II) (Exhibit 1037).
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`p. Deposition of Dr. Nils Hoem (Exhibit 1090).
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`q. Aker GRAS [No. GRN 000371], “Notification of GRAS Determination
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`of Krill Oil”, December 14, 2010 (Exhibit 1089).
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`r. Hoem, N., “Composition of Antarctic krill oil and methods for its
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`harvesting, production and qualitative and quantitative analysis”, Aker
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`BioMarine, Newcastle Australia November 2013 (Exhibit 1080).
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`s. Neptune, GRAS Notice [No. GRN 000242] for “High Phospholipid Krill
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`Oil”, dated January 18, 2008 (Exhibit 1075).
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`t. Neptune GRAS Agency Response Letter GRN 000242 (Exhibit 1091).
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`AKER EXIBHIT 2007 Page 8
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`Introduction
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`U.S. Patent No. 9,078,905 B2
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`3.
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`Patent Owner asserts that obviousness is not established on two main
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`grounds. The first ground relates to cited literature on the negative health effects of
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`a specific subset of ether phospholipids, known as Platelet Activating Factor
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`(PAF). Patent Owner suggests that this would teach away from a krill oil which
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`contains krill ether phospholipids in the claimed range. The second ground is that a
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`POSITA would not be able to predict the content of an oil extract by combining
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`prior art elements from different sources that use different samples of krill and
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`different processing methods. I address each of these points, and others raised by
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`Patent Owner, in the following discussion.
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`4.
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`As discussed below, the prior art does not teach away from producing and
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`encapsulating krill oil with high levels of ether phospholipids. To the contrary, the
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`prior art encourages both (i) the use of high levels of phospholipids (with its
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`attendant inherent levels of ether phospholipids) extracted from krill, and (ii) the
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`use of encapsulation as a method for delivering the extracted krill oil for human
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`consumption. Additionally, knowledge of the existence of PAF-like ether
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`phospholipids does not teach away from using krill oil extracts with greater than,
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`for example, about 3% ether phospholipids because, among other reasons, PAF-
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`like lipids are not the same as the ether phospholipids present in krill extracts. PAF
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`contains an acetyl group (one carbon atom) in the sn-2 position of the phospholipid
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`molecule, and PAF activity is very sensitive to this specific group. Krill ether
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`phospholipids contain a much longer acyl group in the sn-2 position (typically 14
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`to 24 carbons). These are not the same compounds as PAF or PAF-like lipids, and
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`have no PAF activity, and the prior art draws no connection between dietary intake
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`of krill ether phospholipids and the production of PAF-like lipids or PAF-like
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`activity.
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`5.
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`Dr. Hoem testified at his deposition that the “high levels” or “substantial
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`levels” of ether phospholipids, which in his opinion, would discourage a POSITA
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`from using oils with said levels of ether phospholipids (see, e.g., Hoem Dec. ¶ 31,
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`p. 21), were essentially “any measurable levels” of ether phospholipids. Hoem
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`Dep. 54:6 – 55:10, especially 58:10-20, Exhibit 1090.
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`6.
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`Neptune krill oil (NKO), a commercial product on sale before the time of the
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`patent application, had, based on Table 22 of the ‘905 Patent, an ether
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`phospholipid which constituted at least 2.46% w/w of the Neptune krill oil. See
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`discussion below, and Hoem Dep., 59:2 – 61:12, Exhibit 1090.
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`7.
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`Dr. Hoem confirmed directly that a 2.46% ether phospholipid content would
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`be “considered a substantial or high level” of ether phospholipids as discussed in
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`his deposition (Exhibit 1090).
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`Right. So you'd roughly get, let's say, 2.46 ether phospholipids.
`Q
`A Yes.
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`Q Now would that be considered a substantial or high level that
`you refer to in your declaration?
`The answer is yes, I guess.
`A
`Q Okay. And the NKO was being sold -- that was a prior product
`that was being sold at the time this application was filed,
`correct?
`A Yes, that's correct.
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`Hoem Dep., 59:2 – 61:12, Exhibit 1090.
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`8.
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`Thus, even though NKO had the substantial or high level of ether
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`phospholipids that Dr. Hoem in his declaration declared a POSITA would be
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`motivated to avoid, a krill oil product (NKO) with these levels was being sold
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`commercially, and was considered generally recognized as safe (“GRAS”). See,
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`e.g., Neptune GRAS (Exhibit 1075) and Neptune GRAS Agency Response Letter
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`(Exhibit 1091). Therefore Neptune had no concern over PAF-like activity of the
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`nature asserted by Patent Owner.
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`9. Moreover, Aker relied on the prior art clinical studies of NKO reported by
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`Sampalis I (Exhibit 1012) to establish that its krill oil product was “safe” in its
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`GRAS Notification to the FDA. This was confirmed by Hoem:
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`Q Okay. So does that refresh your recollection as to whether Aker
`cited to the Sampalis article that we've identified as Exhibit 1012
`to support its claims of safety of krill oil?
`A Definitely. There is no doubt that we did so.
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`See, Hoem Dep., 52:10-16.
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`10. Aker’s GRAS Notification also described that it relied on Sampalis I
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`(Exhibit 1012) to show the safety of its krill oil, demonstrating again that the safety
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`of krill oils containing ether phospholipids was known and accepted at the time.
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`Sampalis et al. (2003) investigated the effects of krill oil on
`premenstrual syndrome (PMS) and dysmenonhoea in 70 female adults
`of reproductive age. The females were randomized to receive either
`krill oil or fish oil. The subjects consumed two 1 g capsules once per
`day with meals during the first month. Subsequently, the subjects
`consumed same dose during the second and third months but for eight
`days prior to menstruation and for two days during menstruation.
`During the course of study, no serious adverse effects were reported.
`Three subjects reported a reduction in the duration of the menstrual
`cycle during the first month of treatment. In subjects receiving krill oil,
`a slight increase in the oiliness of the facial skin was noted. No subjects
`reported gastrointestinal disturbances. However, in fish oil group 64%
`of the participants reported "unpleasant" reflux following consumption.
`The results of this study suggest that krill oil softgels were well
`tolerated.
`Aker GRAS Notification, 2. DATA PERTAINING TO SAFETY, 2.2. Human
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`Studies, p. 0019, Exhibit 1089.
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`11.
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`It is also persuasive that Aker themselves had no real concern about PAF, in
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`that, even though Aker claimed higher levels of ether phospholipids in its krill oil
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`than they report in Neptune krill oil, PAF or PAF-like activity was not explicitly
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`part of or described in Aker’s clinical studies regarding its ‘high level’ ether
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`phospholipids krill oil. Hoem Dep., 100:8-21, Exhibit 1090. In my opinion this is
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`clear evidence that there was no concern about PAF and PAF-like activities in the
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`ingestion of the “high levels” of ether phospholipids in Aker’s krill oil, and in
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`general there was no concern among the POSITAs of the time over the PAF
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`activity described by Patent Owner in the POR. This matches my own independent
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`opinion that POSITA would not have been concerned about PAF-like activity, as
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`described further below.
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`12. Finally, Fricke II’s disclosure of very low ether phospholipid content (ether
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`glycerolipid levels ranging from 0.3% to 0.6% of total lipid, equivalent to an ether
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`phospholipid content of approximately 0.7-1.4%) in Fricke I’s krill samples, is an
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`anomaly. I have not come across any other literature, nor seen analysis in my own
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`experience, supporting such low ether phospholipid values associated with a krill
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`oil extract containing, for example, 40% phospholipids and neither has Dr. Hoem.
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`Hoem Dep., 108:12-23, Exhibit 1090, and see discussion below. Moreover, I stand
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`by my calculation of the amount of AAPC ether phospholipids from the
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`combination of Fricke I and Tanaka I to be 7.8%. See Tallon Dec. ¶ 98, Exhibit
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`1006, pp. 0055-0056. Patent Owner argues that Fricke II discloses a much lower
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`amount for the same extract, and that this is an example of why prior art
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`references, such as Tanaka I and Fricke I, cannot be combined. I disagree with
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`this. In addition to being an anomalous measurement, a POSITA would have been
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`aware of the limitations of the work described by Fricke II and of the availability
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`of more recent analysis using more robust analysis methods. As discussed below,
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`in Fricke II's analysis, the ether phospholipids are degraded to ether glycerolipids,
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`which contain only the ether linked fatty acid attached to the residual glycerol
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`group and do not contain either the phospholipid group or the original acyl fatty
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`acid. In other words, the Fricke II method cannot and does not separately quantify
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`the amounts of ether phospholipid present, or identify any individual ether
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`phospholipids (for example, AAPC, AAPE, LAAPC), because the method converts
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`the ether phospholipid into a degraded form before isolation and quantification.
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`13.
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`It remains my opinion that the claims of the ‘905 Patent are obvious over the
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`combinations of prior art cited in the Grounds asserted by Petitioner because, as
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`has and will be discussed: (a) a POSITA would be motivated in light of the known
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`benefits of high levels of phospholipids and associated omega-3s to encapsulate an
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`effective amount of a krill oil containing greater than about 3% ether phospholipids
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`notwithstanding disclosures of some PAF-like activity of compounds derived from
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`ether phospholipids, none of which were disclosed or claimed in the ‘905 Patent;
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`(b) a POSITA knowing the compositions obtainable from krill via various
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`extraction methods would be motivated to use and adjust, if necessary, one or more
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`of the known successful extraction methods to obtain a krill oil product with the
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`claimed ranges for lipids and other components; and (c) a POSITA would know
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`from the published prior art of krill oil extraction that the natural biological krill
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`starting material provides sources of such things as phospholipids, with its
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`attendant phosphatidylcholine and ether phosphatidylcholine sub-components, as
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`well as triglycerides within measurable, predictable and controllable ranges.
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`Yamaguchi (Exhibit 2002).
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`14.
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`In describing the nature of the invention, patent owner cites to Yamaguchi
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`(Exhibit 2002) as teaching away from including phospholipids in a krill oil because
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`Yamaguchi writes that phospholipids “interfere with the utilization of krill oils”.
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`See, e.g., POR, Paper 14, pp. 7-8; and ¶ 29, Hoem Dec., Exhibit 2001, pp. 19-20.
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`This is a misrepresentation of Yamaguchi’s intent, as Yamaguchi is quite clearly
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`referring to production, by extraction, of an oil product that is intended to only
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`contain neutral or nonpolar lipids, which by its nature must be without
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`“contamination” by polar lipids, e.g.. phospholipids and any of their decomposition
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`products. Yamaguchi, p. 904, Exhibit 2002, p. 1.
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`15. Yamaguchi's comments regarding “excluding phospholipids that interfere
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`with the utilization of krill oil” (Abstract, Yamaguchi, p. 904, Exhibit 2002, p. 1.)
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`are directed to use of the krill oil extract in human foodstuffs, and not as a
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`nutraceutical delivered in a capsule. Basically, Yamaguchi was concerned that
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`because phospholipids are gum-forming compounds, their exclusion provides a
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`krill oil product more suitable as a human foodstuff.
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`16. As Yamaguchi discloses:
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`Organic solvent extraction of oils from raw materials is a well-
`developed technology. However, after the extraction process, further
`purification steps are generally required to remove impurities [e.g., free
`fatty acids] and gum-forming compounds [e.g., phospholipids] from the
`extracted oil, especially in foodstuffs intended for human consumption.
`***
`***
`***
`Lipids of aquatic organisms are general rich in highly unsaturated fatty
`acids and phospholipids, which are readily deteriorated. The Antarctic
`krill, Euphausia superba, possesses an especially high proportion of
`phospholipids (Moti and Hikichi, 1976), which hampers the effective
`utilization of krill oils [due to gumming, etc.]. We applied SC-CO2
`extraction to krill samples and proved that the extracted oils were
`composed solely of nonpolar lipids without contamination by
`phospholipids and their deteriorated lipids.
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`Yamaguchi, p. 904, Exhibit 2002, p. 1 (emphasis and bracketted material added).
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`Yamaguchi makes no representation at all as to the benefits (or otherwise) of
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`including phospholipids in a general krill lipid extract, nor of the benefits (or
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`otherwise) of including phospholipids in a product intended for nutraceutical use.
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`17. Yamaguchi is directed to the use of supercritical carbon dioxide extraction to
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`extract the “nonpolar” lipids from krill samples, in order to separate out the “polar”
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`free fatty acids and phospholipids. As was well known to the POSITA,
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`supercritical carbon dioxide extraction without an entrainer (i.e., neat) will extract
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`the nonpolar lipids and not the polar phospholipids, while supercritical carbon
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`dioxide extraction with an entrainer, e.g., ethanol, is able to extract phospholipids.
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`See, e.g., Tanaka II, p. 417, Exhibit 1015, p. 0001; and Tallon Dec. ¶¶ 135-137,
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`Exhibit 1006, pp. 0075-0076. See also Breivik I, [0025], Exhibit 1035, p. 0005;
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`Breivik II, 5:12-18, Exhibit 1037, p. 0005; Breivik III, 5:5-11, Exhibit 1036, p.
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`0009.
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`18. The term ‘oil’ (as in “krill oil”) in Yamaguchi is used in a different context
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`than its use in the ‘905 Patent. When Yamaguchi refers to “oil” it is referring to the
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`common usage of the term, at the time and still today, meaning an oil containing
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`only neutral lipids. This is clear in Yamaguchi’s description of applying “SC-CO2
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`extraction to krill samples”, resulting in “extracted oils . . . composed solely of
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`nonpolar lipids”, that is without phospholipids. Yamaguchi, p. 904, Exhibit 2002,
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`p. 1. Yamaguchi repeatedly uses the term “lipid” to differentiate between neutral
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`oils and the more general lipid content which includes phospholipids and other
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`lipids. Thus, when Yamaguchi describes manufacture of an “oil”, by definition, the
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`U.S. Patent No. 9,078,905 B2
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`intent is to make a neutral lipid product without polar lipids such as phospholipids.
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`19. When the ‘905 Patent refers to krill oil it is referring to all lipids, polar and
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`neutral, that can be extracted from krill. See Tallon Dec. ¶¶ 35-48, Exhibit 1006.
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`In my Declaration at ¶¶ 35-48, Exhibit 1006, the term “krill oil”, as used in the
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`patent, is construed using the more accurate description “lipids extracted from
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`krill”, to avoid this ambiguity.
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`Tanaka I, Prescott, Zimmerman & Platelet Activating Factor (“PAF”)
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`20. Patent Owner cites 3 publications in reference to PAF1 and PAF-like
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`products; Tanaka I (Exhibit 1014), Prescott (Exhibit 2003), and Zimmerman
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`(Exhibit 2002). See, e.g., POR, Paper 14, pp. 9-10; and Hoem Dec. ¶ 31, Exhibit
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`2001, pp. 20-21. PAF is a distinctive molecular compound that is important in
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`mediation of inflammatory responses. Although PAF is an ether phospholipid it is
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`unrelated to any of the ether lipids present in krill oils, and the ether phospholipids
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`that are present naturally in krill oils have no PAF or PAF-like activity. As was
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`known to the POSITA, PAF is an alkyl acyl phospholipid where the acyl
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`component is an acetyl group (a methyl group, which has a single carbon atom,
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`1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. See Hoem Dec. ¶ 31, Exhibit
`2001, pp. 20-21.
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`bonded through a carbonyl link), whereas the ether phospholipids from krill oil, as
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`U.S. Patent No. 9,078,905 B2
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`described in the ‘905 patent, contain substantially longer acyl chains ranging from
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`14 to 24 carbon atoms, and have no PAF signaling activity.
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`21. As described by Prescott:
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`Several mechanisms regulate the PAF intercellular signaling system.
`These include tightly controlled synthetic pathways, spatial regulation
`of the display and biologic availability of PAF, cell-specific expression
`of the receptor for PAF, homologous and heterologous desensitization
`of the receptor, and rapid degradation of PAF by extracellular and
`intracellular acetylhydrolases.
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`Prescott, p. 420, Exhibit 2003, p. 2. Thus PAF is naturally produced from cellular
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`phospholipids through very regulated pathways and is rapidly degraded. Dietary
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`intake of ether phospholipids does not contribute to this process. Dr. Hoem, in his
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`deposition, could not recall any literature supporting the premise that ether
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`phospholipids can be degraded into PAF-like molecules by digestion. Hoem Dep.
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`35:4-9, Exhibit 1090. Moreover, neither Prescott nor Zimmerman mentioned any
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`harm from ingestion of phospholipids. Hoem Dep. 35:10 - 36:22, Exhibit 1090.
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`22. The Patent Owner’s 3 cited references describe the possible formation of
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`peroxidation products from dietary ether phospholipids, and that some of said
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`peroxidation products are similar enough to PAF to trigger the same inflammatory
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`AKER EXIBHIT 2007 Page 19
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`effects. Once again, the natural alky acyl (ether) phospholipids present in krill oils
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`U.S. Patent No. 9,078,905 B2
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`are not the same as the range of alkyl acyl phosphatidylcholines described in the
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`references as having PAF-like activity. The PAF-like lipids that are described only
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`exist as a byproduct from the natural ether phospholipids by a peroxidation
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`process.
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`23. The natural range of acyl groups in krill oil AAPC have been measured. See
`
`for example, Tanaka I, p. 1390 (Exhibit 1014, p. 0002), who discloses that “GLC
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`analysis found that alkylacyl-GPC from krill had the following fatty acid
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`composition: 14:0 (2.1 %), 16:0 (10.6%), 16:1 (5.2%), 18:0 (4.5%), 18:1, n-9
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`(10.0%), 18:2, n-6 (1.3%), 18:3, n-6 (0.4%), 18:3, n-3 (0.4%), 20:3, n-6 (3.7%),
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`20:3, n-3 (2.9%), 20:4, n-6 (0.3%), 20:5, n-3 (30.8%), 22:6, n-3 (21.8%), unknown
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`(6.0%).” Table 23, ‘905 Patent, 33:42-65 (Exhibit 1001, p. 0041), copied below,
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`also provides the range of acyl groups (carbon range of 14 to 24) for the fatty acid
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`component of AAPC obtained by the method of Example 7 of the ‘905 Patent.
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` In other words, as supported by both Tanaka I and the ‘905 Patent, and as
`24.
`was known to the POSITA, the acyl groups in krill oil AAPC range in length from
`14 to 24 carbon atoms.
`In contrast, PAF-like activity only exists if the acyl group is
`25.
`substantially shorter, typically in the range 1-4 carbon atoms. As Prescott
`describes:
`The PAF receptor recognizes the sn-1 ether bond of PAF, its short sn-
`2 acetyl residue, and the choline head group; alteration of any of these
`structures greatly decreases signaling through the PAF receptor.
`Extension of the sn-2 acetyl residue by one methylene is without
`consequence, but extension by two methylenes decreases activity by a
`factor of 10- to 100-fold, depending on the assay. Extension beyond
`this results in the loss of signaling through the PAF receptor. However
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`AKER EXIBHIT 2007 Page 21
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`introduction of an oxy function allows acceptance of longer sn-2
`residues, just as oxy functions do for the PAF acetylhydrolase (vide
`infra)
`Prescott, p. 431, Exhibit 2003, p. 13 (notations to references omitted). In other words
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`the natural AAPC present in krill has fatty acids groups (C14-C24) well outside the
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`range that have PAF-like activity (C1-C4). While Prescott writes that the
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`introduction of an oxy function allows for longer sn-2 resides, id, these residues are
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`still substantially different to the natural krill AAPC fatty acids, and Prescott is not
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`in any way describing or implying PAF-like activity associated with krill AAPC in
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`its natural form which is a completely different range of C14-C24 compounds, and
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`well outside the range of size and structure described by Prescott as having PAF
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`activity. Instead, Prescott discloses that all of these ‘alterations’ to the true PAF
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`structure rapidly decrease the signaling activity, with the signaling activity rapidly
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`dropping to nothing even after relatively small increases in the size and structure of
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`the attached group beyond the single carbon group representing true PAF.
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`26. Tanaka I describes artificial oxidation of the natural AAPC present in krill,
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`and that some of the compounds produced by this artificial process have some
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`PAF-like activity. This may have been of academic interest to a POSITA, but
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`would not teach away from including any particular level of krill ether
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`phospholipid components in a krill oil. The cited literature describes only
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`artificially oxidized lipid products that may have PAF-like behaviour, and draws
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`22
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`AKER EXIBHIT 2007 Page 22
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`no linkage between dietary intake (ingestion) of ether phophospholipids and in-
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`U.S. Patent No. 9,078,905 B2
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`vivo signaling behaviour.
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`27. As Prescott states:
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`Oxidation of complex lipids in reduced systems has defined potential
`oxidation pathways and products, but whether such oxidizing
`conditions exist in vivo is problematic, given the unstable nature of the
`reactive intermediates and the potential of metabolism of the oxidation
`products.
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`Prescott, p. 432, Exhibit 2003, p. 14 (emphasis added).
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`28. Tanaka I “investigated the PAF-like lipids formed during peroxidation of
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`PCs from hen egg yolk, salmon roe, sea urchin eggs, and krill in an [in vitro]
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`FeS04/EDTA/ascorbate system.” Tanaka I, Abstract, p. 1389, Exhibit 1014, p.
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`0001 (emphasis and material in bracket added). Tanaka I concludes that they have
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`not drawn a link between the formation of these particular peroxidation products
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`and their presence in food products:
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`However, the occurrence of PAF-like lipids in some stored foods is still
`speculative and requires further investigation.
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`Tanaka I, p. 1393, Exhibit 1014, p. 0005. The results reported by Tanaka I apply
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`equally to artificial degradation products of ether phospholipids from general food
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`products such as hen egg yolk, which were and continue to be widely and safely
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`consumed by humans.
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`AKER EXIBHIT 2007 Page 23
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`IPR2017-00745
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`29.
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`U.S. Patent No. 9,078,905 B2
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`It is known that PAF-like lipids have lower activity than PAF itself because
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`they are only mimicking the functionality of PAF, and every deviation from the
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`true PAF molecule rapidly decreases the activity. Beyond a small level of
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`deviation PAF-like activity ceases completely. For example, Prescott states:
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`“alteration of any of these structures greatly decreases signaling through the PAF
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`receptor . . . ”. Prescott, p. 431, Exhibit 2003, p. 13.
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`30. Zimmerman (Exhibit 2004) primarily describes the natural enzymatic
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`regulation of PAF levels in the body. Zimmerman states that: “The biological
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`activities of PAF are regulated by several precise mechanisms that, together,
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`constrain and control its action in physiologic inflammation.” Zimmerman,
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`Abstract, p. S294, Exh
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