`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`RIMFROST AS
`Petitioner,
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`v.
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`AKER BIOMARINE ANTARCTIC AS
`Patent Owner.
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`Case IPR2018-00295
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`U.S Patent No. 9,320,765
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`Patent Owner’s Sur-Reply to Petitioner’s Reply
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`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`RIMFROST EXHIBIT 1133 Page 0001
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`TABLE OF CONTENTS
`Introduction ........................................................................................... 1
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`There is no motivation to combine the references ................................ 2
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`I.
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`II.
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`A.
`The ranges from Fricke and Catchpole are not interchangeable ..................2
`B.
`The prior art teaches away from increasing ether phospholipids ................7
`III. No reasonable expectation of success ................................................... 9
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`IV. Conclusion ........................................................................................... 10
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`CERTIFICATE OF SERVICE ......................................................................... i
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`RIMFROST EXHIBIT 1133 Page 0002
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`I.
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`Introduction
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`When assessing obviousness, the claimed subject matter must be considered
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`as a whole. Pre-AIA 35 U.S.C. 103(a). The pending claims require specific
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`amounts of each of ether phospholipids (>3%), total phospholipids (30-60%) and
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`triglycerides (20-50%) among other components. Petitioner alleges that these are
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`natural components of krill that could be extracted within predictable ranges by
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`modifying conventional techniques. Petitioner’s Reply (“Pet. Reply”), Paper 19 at
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`2. To arrive at the claimed composition, Petitioner takes the triglyceride and total
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`phospholipid ranges from Fricke and the ether phospholipid range from Catchpole.
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`However, the krill oils described in those references were extracted by very
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`different techniques. Id. at 6. Fricke utilized a non-selective Folch extraction
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`which is intended to extract total lipids, including both neutral and polar lipids,
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`from the source material. Ex. 1010 at 0001. Catchpole utilized a two-step
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`supercritical fluid extraction. Ex. 1009 at 0024. In the first step, neat CO2 is used
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`to selectively extract neutral lipids. Id. In the second step, catchpole using CO2 in
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`combination with ethanol to selectively extract polar lipids. Id. As will be shown
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`by the evidence below, the rationale advanced by Petitioner to explain why the
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`ranges for total phospholipids and triglycerides from Fricke can be simply
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`combined with the ether phospholipid range from Catchpole is fatally flawed.
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`Thus, a person having ordinary skill in the art (POSITA): 1) would not combine
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`1
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`RIMFROST EXHIBIT 1133 Page 0003
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`the cited to arrive at the claimed krill oil with specific claimed levels of
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`components; and 2) recognize there is no reasonable expectation of success in
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`obtaining a composition with the claimed components.
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`II.
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`There is no motivation to combine the references
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`A.
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`The ranges from Fricke and Catchpole are not interchangeable
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`Petitioner alleges that “[b]ased on the teaching of Catchpole in view of
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`Fricke, it clearly would have been well within the ability of a POSITA to obtain a
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`krill oil composition” with the defined amounts of ether phospholipids, total
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`phospholipids and triglycerides. Pet. Reply at 6, citing Tallon Decl. Ex. 1086
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`¶¶49&25-50. In ¶40-46 of his Reply Decl. (Ex. 1086), Dr. Tallon states that
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`Extract 2 of Catchpole must contain a significant proportion of triglycerides and
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`purports to calculate the triglyceride content of Extract 2 of Catchpole by applying
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`the triglyceride and other neutral lipid ranges from Fricke. However, evidence
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`obtained from cross-examination of Dr. Tallon demonstrates that this rationale for
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`combination is fatally flawed and further demonstrates why a POSITA would not
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`be motivated to combine Catchpole and Fricke (or the other cited references).
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`Example 18 of Catchpole teaches a two-step extraction process. In Step 1,
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`the starting freeze-dried krill material was “extracted continuously with
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`supercritical CO2” until “no further extract was contained.” Ex. 1009, p. 0024. A
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`2
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`RIMFROST EXHIBIT 1133 Page 0004
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`total of 650 g of that extract (Extract 1) was obtained and reported to contain
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`“substantially all neutral lipids” and “no phospholipids.” Id. In Step 2, the residual
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`powder, containing the phospholipids and lacking neutral lipids, was then
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`extracted with CO2 and 11% ethanol to provide Extract 2 which has an alleged
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`ether phospholipid content of 4.8%.
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`Petitioner argues that Extract 2 must contain triglycerides and that “Patent
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`Owner’s suggestion that the initial extraction in the Example 18 process would
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`have removed all triglycerides lacks foundation and is wrong.” Pet. Reply at 8,
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`citing Tallon Dec. Ex. 1086 ¶¶37,25-46. This is incorrect.
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`First, Catchpole itself clearly teaches that the “feed material can be
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`processed using pure CO2 before the co-solvent is introduced to remove much or
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`all of neutral lipids.” Ex. 1009, p. 11, l. 23-24. In a general description of the
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`process, Catchpole further teaches the extractions are “optionally carried out using
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`only CO2 until all of the compounds soluble in CO2 only, such as neutral lipids,
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`were extracted.” Id., p. 13, l. 2-22. Thus, Catchpole clearly teaches that the Step 1
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`extraction can remove all neutral lipids, including triglycerides. This is consistent
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`with Example 18 which indicates that Step 1 was continued until no further extract
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`was obtained.
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`Second, evidence obtained during cross-examination of Dr. Tallon
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`establishes that when his methodology for calculation of the triglyceride content
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`3
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`RIMFROST EXHIBIT 1133 Page 0005
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`of Extract 2 is applied to the Step 1 extraction of the freeze-dried starting material,
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`that all of the neutral lipids were extracted from the freeze-dried krill starting
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`material. As a result, Extract 2 could not have contained the claimed range of
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`triglycerides as it contained no neutral lipids.
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`In ¶40-46 of his Reply Decl. (Ex. 1086), Dr. Tallon purports to calculate the
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`triglyceride content of Extract 2 of Catchpole by applying the triglyceride and
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`other neutral lipid ranges from Fricke. Dr. Tallon concludes that “a POSITA would
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`have known, based on the lipid composition disclosed by Fricke, that the other
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`compounds disclosed by Catchpole in extract 2 would consist of at least 32 to 37%
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`triglycerides . . . .” Tallon Decl. Ex. 1086 at ¶46.
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`However, during cross examination, Dr. Tallon admitted that the triglyceride
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`and neutral lipid amounts provided in Fricke could also be used to estimate the
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`amount of neutral lipids in the krill feed material. Ex. 2020, p. 33, l. 4 – p. 34. l. 4.
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`During the deposition, Dr. Tallon calculated the amount of neutral lipids expected
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`to be in the freeze-dried krill starting material used in Example 18 of Catchpole.
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`Id., p. 38, l. 10 – p. 47, l. 18. Dr. Tallon calculated the average neutral lipid content
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`for the 1977 and 1981 krill lipid samples to be 53.8%. Id., 46, l. 7-18. Example 18
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`of Catchpole provides that krill feed material weighed 5619.9 grams and contained
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`21.4% lipids. Ex. 1009 at p. 24, l. 3-4. Dr. Tallon calculated that the starting feed
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`material contained 1203 grams of lipid, including both neutral lipids and
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`4
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`RIMFROST EXHIBIT 1133 Page 0006
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`phospholipids. Ex. 2020, p.42, l. 21 - p. 43, l. 17. This 1203 grams of total lipids
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`can then be multiplied by the 53.8% average neutral lipid content of Fricke to
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`estimate the amount of neutral lipids present in the krill feed material. As
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`confirmed by Dr. Tallon, this amount is 647 grams, which is approximately 650
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`grams. Id., p.47, l. 14-18.
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`Using Dr. Tallon’s rationale for calculating triglycerides in Extract 2 based
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`on the ranges in Fricke, the starting feed material in Example 18 is estimated to
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`contain about 650 grams of neutral lipids. Example 18 reports that 650 grams of
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`neutral lipids were removed during the first step of the extraction with neat CO2 (a
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`neutral solvent). Ex. 1009, p. 24, l. 8. Thus, a POSITA would conclude that Extract
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`2 could not contain the claimed range of triglycerides because all of the neutral
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`lipids, including triglycerides, were removed during the first extraction step. This
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`is consistent with the teaching of Catchpole that the first extraction step with CO2
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`removes “much or all” of the neutral lipids. Ex. 1009, p. 11, l. 23-24.
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`The 53.7% “other compounds” in Extract 2 of Example 18 of Catchpole are
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`unknown, but it would appear to a POSITA using Dr. Tallon’s rationale and the
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`teachings of Catchpole that the first neat CO2 extractions step removed all of the
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`neutral lipids, including triglycerides. Thus, a POSITA would not combine the
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`ether phospholipid content in Extract 2 of Catchpole with the triglyceride content
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`of Fricke when Fricke’s extracts were obtained by a completely different method.
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`5
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`RIMFROST EXHIBIT 1133 Page 0007
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`Furthermore, it would be obvious to a POSITA that to provide the claimed
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`range of 20-50% triglycerides, triglycerides would need to be added to Extract 2
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`which would necessarily dilute or decrease the ether phospholipid content to
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`substantially less than 4.8%. In fact, since the claims specify a range of total
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`phospholipids of 30-60%, then the neutral lipid content of the krill oil would be at
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`least 40%. Adding 40% neutral lipids to Extract 2 of Catchpole would reduce the
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`ether phospholipid content to (.60)(4.8%) = 2.88%. Thus, Catchpole does not teach
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`the claimed range of ether phospholipids and cannot be modified in view of the
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`other combined references to provide the claimed range of ether phospholipids in
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`conjunction with the claimed range of triglycerides. This argument applies both to
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`the independent claims which require greater than 3% ether phospholipids and
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`with even more force to the dependent claims which require greater than 4% or 5%
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`ether phospholipids (i.e., claims 9-24 and 33-48) which are both much higher than
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`2.88%.
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`It must be noted that since Fricke analyzed the total lipid content of krill, it is
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`more appropriate to apply the ranges from Fricke to the freeze-dried krill feed
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`material used in Example 18 than it is to Extract 2 because Extract 2 was derived
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`from material that had been pre-treated with neat CO2 to remove neutral lipids.
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`The krill analyzed in Fricke was not pretreated to remove neutral lipids. Thus, it is
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`not appropriate to use the triglyceride levels reported in Fricke to determine the
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`6
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`RIMFROST EXHIBIT 1133 Page 0008
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`triglyceride levels that would be present in Extract 2 as confirmed by the analysis
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`provided above. A POSITA would not combine or modify the references as
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`suggested by Petitioner.
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`Finally, Petitioner relies on Tanaka II as evidence that Extract II of Fricke
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`contained triglycerides because “a POSITA would have recognized that a
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`subsequent extraction using CO2 and ethanol would produce an extract that
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`included triglycerides not removed during the initial extraction.” Pet. Reply at 9,
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`citing Ex. 1015, p. 0004; see also Tallon Decl. Ex. 1086 ¶32. However, the
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`experiments described at p. 0004 of Tanaka and discussed in ¶32 of the Tallon
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`Reply Decl. that produce an extract containing 75% triglycerides did not utilize a
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`pre-extraction step with neat CO2 to remove neutral lipids as admitted by Dr.
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`Tallon when cross-examined. Tallon Depo., Ex. 2020, p. 7, l. 11-25. Thus, it is no
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`surprise that those extracts contained triglycerides as they had not been removed in
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`a first step with neat CO2.
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`B. The prior art teaches away from increasing ether phospholipids
`The prior art as a whole teaches away from increasing the ether phospholipid
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`content of krill oil. Petitioner alleges that this argument is identical to the argument
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`presented in IPR2017-00745 and -00746. Pet. Reply at 14. This is incorrect as
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`Patent Owner has presented new evidence intended to address deficiencies noted
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`by the Board in those cases. As noted by Petitioner, the Board in IPR-00745 (Ex.
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`7
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`RIMFROST EXHIBIT 1133 Page 0009
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`1103) found that “PAF and the PAF-like compounds . . . are structurally and
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`functionally distinct from the ether phospholipids present in Catchpole’s krill
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`extract which do not exhibit PAF-like behavior . . . .” Pet. Reply at 16. Patent
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`Owner has provided substantial additional evidence in the proceeding that
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`addresses the issues noted by the Board. In particular, it is the peroxidation of ether
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`lipids, especially from krill, after ingestion that is of concern. Hoem Decl., Ex.
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`2001, ¶55.
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`As admitted by Dr. Tallon, the references cited by Patent Owner “describe
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`the possible formation of peroxidation products from dietary ether phospholipids,
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`and that some of said peroxidation products are similar enough to PAF to trigger
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`the same inflammatory effects.” Tallon Reply Decl., Ex. 1086, ¶73. During his
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`deposition, Dr. Tallon admitted that dietary ether phospholipids could influence
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`the lipid composition of LDL particles in the blood. Ex. 2020, p. 120, l. 2-7. Dr.
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`Tallon further admitted that peroxidation of ether phospholipids can generate
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`compounds with PAF-like activity. Id., p. 102, l. 18 - p.103, l. 19. Dr. Tallon
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`further admitted that Marathe (Ex. 1094) demonstrates that peroxidated ether lipids
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`in LDL particles can generate an inflammatory response in an in vivo model.
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`Tallon Depo., Ex. 2020, p. 117, l. 1 - p.118, l. 9. Together, this evidence clearly
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`establishes the link between ingestion of ether phospholipids and inflammatory
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`8
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`RIMFROST EXHIBIT 1133 Page 0010
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`responses in vivo. A POSITA would understand the prior art as a whole to teach
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`away from increasing the amount of ether phospholipids in krill oil.
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`Petitioner’s reliance on Patent Owner’s GRAS statement (Ex. 1089) as
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`evidence that there is no teaching away is also baseless. Pet. Reply at 21-23.
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`Aker’s GRAS statement was submitted in December 2010, approximately 32
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`months after the March 28, 2008 filing date of the initial regular U.S. application
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`in the priority chain. The GRAS statement specifically refers to human safety
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`studies using Aker’s Superba krill oil that were published in 2009 and 2010,
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`specifically Maki et al. and Ulven et al. See Ex. 1089 at 0018-19. As admitted by
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`Dr. Tallon, these studies demonstrated that administration of Patent Owner’s
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`Superba krill oil had “no effect or a beneficial effect on inflammation as measured
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`by markers of inflammation.” Tallon Reply Decl., Ex. 1086, ¶115. Aker’s GRAS
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`statement has no bearing on whether the prior art taught away from the claimed
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`invention prior to its priority date and supports the fact that Patent Owner did
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`establish safety of its krill oil after that date and as reflected in the GRAS
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`statement.
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`III. No reasonable expectation of success
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`The evidence presented above also demonstrates that the combined
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`references do not provide a reasonable expectation of success in arriving at the
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`claimed compositions. As discussed above, since Extract 2 of Catchpole did not
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`RIMFROST EXHIBIT 1133 Page 0011
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`contain neutral lipids including triglycerides, it would be necessary to dilute
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`Extract 2 with neutral lipids in order to arrive at the claimed compositions. This
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`dilution would reduce the ether phospholipid content of Extract 2 to 2.88% which
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`is below the claimed levels. The combined references do not provide any teaching,
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`suggestion or evidence that the ether phospholipid content of krill oil can be
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`increased to beyond 4.8%. In fact, Dr. Tallon confirmed that the highest level of
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`ether phospholipids obtained in Catchpole was the 4.8% in Example 18. Tallon
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`Depo., Ex. 2020, p. 88, l.12 - p. 89, l. 3. There is no oil with higher levels that
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`could be diluted to provide an oil with the claimed values for ether phospholipids
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`and triglycerides. As above, this argument applies with even more force to the
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`dependent claims which require greater than 4% or 5% ether phospholipids (i.e.,
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`claims 9-24 and 33-48) which are both much higher than 2.88%.
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`IV. Conclusion
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`For the foregoing reasons, Patent Owner submits that the Petition should be
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`denied.
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`Dated: January 18, 2019 Respectfully submitted,
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`/David A. Casimir / Reg. No. 42,395
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`10
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`RIMFROST EXHIBIT 1133 Page 0012
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`IPR2018-00295
`U.S. Patent No. 9,320,765
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`CERTIFICATE OF SERVICE
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`The undersigned hereby certifies that on this 18th day of January 2019, a
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`copy of the foregoing Patent Owner’s Sur-Reply to Petitioner’s Reply was
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`served in its entirety electronically (as consented to by Petitioner) to the attorneys
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`of record as follows:
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`James F. Harrington
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`Reg. No. 44,741
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`Hoffmann & Baron, LLP
`jfhdocket@hbiplaw.com
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`Ronald J. Baron
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`Reg. No. 29,281
`Hoffman & Baron, LLP
`rjbdocket@hbiplaw.com
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`765ipr@hbiplaw.com
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`Michael I. Chakansky
`Reg. No. 31,600
`Hoffman & Baron, LLP
`micdocket@hbiplaw.com
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`John T. Gallagher
`Reg. No. 35,516
`Hoffman & Baron, LLP
`jtgdocket@hbiplaw.com
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`By: /David A. Casimir/
`David A. Casimir, Ph.D.
`Registration No. 42,395
`Counsel for Patent Owner
`CASIMIR JONES, S.C.
`2275 Deming Way
`Suite 310
`Middleton, Wisconsin 53562
`(608) 662-1277
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`i
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`RIMFROST EXHIBIT 1133 Page 0013
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