UNITED STATES PATENT AND TRADEMARK OFFICE
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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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`Case No.: IPR2017-00747
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`U.S. Patent 9,078,905
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`Issue Date: July 14, 2015
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`Title: Bioeffective Krill Oil Compositions
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`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE PURSUANT
`TO 37 C.F.R. § 42.23(b)
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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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`
`Case No.: IPR2017-00747
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`U.S. Patent 9,078,905
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`Issue Date: July 14, 2015
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`Title: Bioeffective Krill Oil Compositions
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`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE PURSUANT
`TO 37 C.F.R. § 42.23(b)
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`Inter Partes Review Case No.: IPR2017-00747
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`U.S. Patent No. 9,078,905
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`TABLE OF CONTENTS
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`3.
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`4.
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`5.
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`INTRODUCTION ............................................................................................... 1
`I.
`II. CLAIMS 1-20 WOULD HAVE OBVIOUS ....................................................... 3
`A.
`The Teachings Of Sampalis I, Tanaka I And Fricke Render
`Claims 1-4, 6, 9-10, 12, 15-16 And 18 Obvious ................................... 3
`1.
`Fricke II Did Not Directly Measure Ether Phospholipids .......... 4
`2.
`A POSITA Would Have Known That Fricke II’s Method
`Was Inaccurate And Obsolete ..................................................... 6
`Variability In Krill And The Components Of Krill Oil Were
`Well Studied And Understood .................................................... 9
`Possible PAF Activity Does Not Teach Away From The
`Challenged Claims ....................................................................13
`Ether Phospholipids Were Recognized To Provide
`Health Benefits ..........................................................................18
`Claim 5 Is Obvious In View Of Sampalis I, Tanaka I, Fricke
`And Randolph ......................................................................................25
`Claims 7-8, 11, 13-14, 17 And 19 Are Obvious In View Of
`Sampalis I, Tanaka I, Fricke And Bottino...........................................26
`III. CONCLUSION ................................................................................................27
`IV. CERTIFICATE OF COMPLIANCE ...............................................................29
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`C.
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`Inter Partes Review Case No.: IPR 2017-00747
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`I.
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`INTRODUCTION
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`U.S. Patent No. 9,078,905
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`In its response (Paper 14), Patent Owner does not dispute that Sampalis I
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`(Exhibit 1012), Tanaka I (Exhibit 1014), Fricke (Exhibit 1010), Randolph (Exhibit
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`1011) and/or Bottino (Exhibit 1007) teach and disclose each element of the claims
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`of the ‘905 patent. Instead, Patent Owner presents two unpersuasive arguments
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`that challenged claims 1-20 would not have been obvious in view of the teachings
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`of one or more of these references. Both arguments are inapt.
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`First, Patent Owner mistakenly asserts that, because certain ether
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`phospholipids could be precursors of compounds with Platelet Activating Factor
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`(PAF) activity, a POSITA would have been deterred from encapsulating a krill oil
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`composition having greater than about 3% ether phospholipids as recited in the
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`challenged claims. (Paper 14, pp. 4-5).
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`Second, Patent Owner, relying upon anomalous data from Fricke II,
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`erroneously argues that a POSITA would not have combined the teachings of the
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`above-identified references because they disclose different extraction techniques
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`and use krill that purportedly may have different chemical make-ups (e.g.,
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`percentages of ether phospholipids), and because there is “no reasonable way to
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`predict the content of oil extracted from a natural biomass.” (Paper 14, pp. 5-6).
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`Each of Patent Owner’s arguments is unavailing. First, it was well-known
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`that the ether phospholipids associated with PAF activity are structurally different
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`than the ether phospholipids found in krill and krill oil. As a result, a POSITA
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`would not have been dissuaded from encapsulating a krill oil composition having
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`greater than about 3% ether phospholipids. Second, a POSITA could have known
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`that the values Patent Owner pulls from Fricke II are clearly anomalies that would
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`not be relied on. Additionally, any seasonable or geographic fluctuations in the
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`chemical make-up of krill have been extensively studied, were well known, and
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`have been quantified in the prior art. Further, a POSITA would have known that
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`conventional extraction techniques could be modified resulting predictable changes
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`to the resulting krill oil composition.
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`The challenged claims would have been obvious to a POSITA in view of the
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`prior art combinations set forth in the in the Institution Decision (e.g., Paper 9, pp.
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`10-16) because a POSITA: (a) would have been motivated to encapsulate an
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`effective amount of a krill oil containing from about 3% to 15% ether
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`phospholipids because of the known health benefits associated with phospholipids
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`and associated omega-3s; (b) would have known that the phospholipids in krill and
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`its attendant phosphatidylcholine and ether phosphatidylcholine sub-components,
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`as well as triglycerides, were present within predictable and known ranges; and (c)
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`would have known that conventional extraction techniques could be modified to
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`take into account any seasonal or geographic fluctuations in the starting krill
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`material resulting in predictable changes in the composition of the resulting krill
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`oil. As a result, a POSITA in would have possessed a reasonable expectation of
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`obtaining krill oil compositions as recited in the challenged claims.1
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`II. CLAIMS 1-20 WOULD HAVE OBVIOUS
`A. The Teachings Of Sampalis I, Tanaka I And Fricke Render
`Claims 1-4, 6, 9-10, 12, 15-16 And 18 Obvious
`Patent Owner maintains that a POSITA would not have combined the
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`teachings of Sampalis I (Exhibit 1012) (Neptune’s encapsulated NKO krill oil
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`product), Tanaka I (Exhibit 1014) (krill phospholipids having approximately 23%
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`ether phospholipids) and Fricke (krill oil having 7.8% ether phospholipids and 20-
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`50% triglycerides). First, Patent Owner erroneously asserts that Frick II (Exhibit
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`2006) purportedly shows that the ether phospholipid content disclosed in Fricke
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`was not 7.8%, as detailed by Dr. Tallon (Tallon Dec. (Exhibit 1006), ¶ 98), but was
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`1In support of its arguments, Petitioner relies upon its Petition (Paper No. 2),
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`Tallon Dec. (Exhibit 1006) and Tallon Reply (Exhibit 1086).
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`at most only 0.6%. (Paper 14, pp. 16, 23-25). Next, Patent Owner maintains that,
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`because certain ether phospholipids are precursors to compounds exhibiting PAF
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`activity, a POSITA would not encapsulate a krill oil composition having greater
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`than about 3% ether phospholipids. Both of Patent Owner’s arguments are
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`misplaced.
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`Fricke II Did Not Directly Measure Ether Phospholipids
`1.
`Fricke II analyzed 1-O-alkylglycerolipids present in two samples of
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`Antarctic krill by first separating the total lipid extract into phospholipids and
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`neutral lipids using thin layer chromatography. The phospholipid fraction was
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`then hydrolyzed enzymatically. The resulting phospholipid and neutral lipid
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`fractions were first converted to free alkylglycerols and then to isopropylidene
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`derivatives of the alkylglycerols, which were finally quantified. (Exhibit 2006, pp.
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`1-2). (Tallon Reply (Exhibit 1086), ¶ 63).
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`Importantly, the ether lipid values reported by Fricke II are not direct
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`measurements of the ether phospholipids present in the krill. Rather, the
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`compound quantified, 1-O-alkyleglycerol, is a degraded or deacylated version of
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`the original ether lipids that has no phospholipid head group and no acyl group on
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`the sn-2 position. Consequently, 1-O-alkyleglycerol has a significantly smaller
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`molecular mass than the ether phospholipids present in krill and krill oil. (Tallon
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`Reply (Exhibit 1086), ¶ 67).
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`Fricke II’s method requires successive degradation of the natural ether
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`phospholipid into a glycerolipid with only the ether linked fatty acid remaining,
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`and then further to an isopropylidene derivative. There are numerous steps during
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`this successive degradation in which losses of the final quantifiable compound
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`could occur including, but not limited to, limited selectivity of the phospholipase
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`conversion. Thus, the content of ether phospholipids in the original sampled krill
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`oil will necessarily be greater than the mass of 1-O-alkylglycerol measured by
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`Fricke II. (Tallon Reply (Exhibit 1086), ¶ 67). This explains why Fricke II’s
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`reported ether phospholipid levels are significantly lower than the typical range of
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`krill ether lipid levels observed by Dr. Tallon and reported in more recent analyses
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`by others, and demonstrates that Fricke II’s values are anomalies that a POSITA
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`would not rely upon. (Tallon Reply (Exhibit 1086), ¶ 69). Even Patent Owner’s
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`expert Dr. Hoem admits that he has not observed krill oils with such low levels of
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`ether phospholipid. (Exhibit 1090, 108:12-23).
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`Further, Patent Owner and Dr. Hoem refer only to the 1-O-alkylglycerolipid
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`values reported in Fricke II, and incorrectly propose those values represent the
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`ether phospholipid content of the analyzed sample. (Paper 14, p. 25; Exhibit 2001,
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`¶ 35). As described above, the values reported by Fricke II only quantify the
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`deacylated glycerolipid content, not the original acylated ether phospholipids from
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`which they were derived. (Tallon Reply (Exhibit 1086), ¶ 67).
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`Contrary to Patent Owner’s argument, a POSITA would have understood
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`that the ether phospholipid levels reported in Fricke II are anomalies that are
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`significantly lower than the typical ether lipid content observed in krill. (Tallon
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`Reply (Exhibit 1086), ¶¶ 67-69, 76).
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`2.
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`A POSITA Would Have Known That Fricke II’s
`Method Was Inaccurate And Obsolete
`Fricke II’s results were reported more than 10 years before the priority date
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`of the ‘905 patent. By 2006, additional results were available to a POSITA using
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`modern, more accurate analytical techniques, including the direct quantification of
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`the ether phospholipids using 31P-NMR spectroscopy (Catchpole (Exhibit 1009),
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`p. 0014; Tallon Dec. (Exhibit 1006), ¶ 90) or analysis of the main ether lipid
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`AAPC by directly quantifying partially hydrolyzed 1-O-alkyl-2-lyso glycerol
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`phosphatidylcholine levels. (Tanaka I (Exhibit 1014), p. 0002; Tallon Dec.
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`(Exhibit 1006), ¶¶ 130-31). (Tallon Reply (Exhibit 1086), ¶¶ 71-74, 79).
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`A POSITA would have a compelling reason to rely upon the results obtained
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`using a more precise analytical technique, such as NMR, and disregard Fricke II’s
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`outdated and imprecise method which failed to directly measure ether phospholipid
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`content or differentiate between ether phospholipids and other possible sources of
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`ether lipids in the samples analyzed. (Tallon Reply (Exhibit 1086), ¶ 71).
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`In contrast to Fricke II’s indirect method, the enhanced accuracy of NMR
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`results is highlighted by an article co-authored by Dr. Hoem which acknowledges
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`that NMR is the preferred method for analyzing the components of krill oil.
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`(Exhibit 1079), pp. 0001, 0003-0004, 0011). (Tallon Reply (Exhibit 1086), ¶¶ 72-
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`73). In particular, the article studied “the usefulness of the combination of 31P, 1H
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`and 13C nuclear magnetic resonance (NMR) spectroscopies to characterize krill oil
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`profile. . . . The method was characterized by high sensitivity, accuracy, and
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`reproducibility.” (Exhibit 1079, Abstract, p. 0001) (emphasis added). The authors
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`concede that 31P-NMR provides a direct, sensitive, and selective method of
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`analysis, allowing phospholipids to be analyzed in their natural intact state, without
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`the additional uncertainty of chemical modification steps that convert them into
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`another form for analysis. This analytical technique also directly responds to the
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`presence of the characteristic phosphorous nucleus that is present in the
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`phospholipids, making the results much more reliable and accurate. (Tallon Reply
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`(Exhibit 1086), ¶¶ 72-74).
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`Tanaka I (Exhibit 1014) also describes a direct and more precise technique
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`for measuring krill ether phospholipids. With Tanaka I, phosphatidylcholine (ether
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`and non-ether phosphatidylcholine) is hydrolyzed to the lyso-form of
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`phosphatidylcholine, in which the acyl fatty acid has been removed leaving the
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`ether-bonded fatty acid and the phospholipid group still attached. This molecule,
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`1-O-alkyl-2-lyso-GPC, is an ether phospholipid. The analysis in Tanaka I is then
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`directly carried out on the ether phospholipid by quantifying the amount of lipid-
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`phosphate present. (Exhibit 1014, p. 0002; Tallon Dec. (Exhibit 1006), ¶¶ 130-31).
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`This is in contrast to Fricke II where the ether phospholipid is further degraded to
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`an ether glycerolipid which contains only the ether linked fatty acid attached to the
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`residual glycerol group. (Tallon Reply (Exhibit 1086), ¶ 79).
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`A POSITA would have undoubtedly recognized that the ether phospholipid
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`level disclosed in Fricke II was both internally inconsistent and artificially low
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`because Fricke II utilized an obsolete and inaccurate analytical method that
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`indirectly tries to quantify ether phospholipids. (Tallon Reply (Exhibit 1086), ¶¶
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`63-69). Accordingly, and consistent with Dr. Tallon (Tallon Dec. (Exhibit 1006), ¶
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`98), a POSITA would have recognized that Fricke II’s results are anomalies and
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`would have no bearing on a POSITA’s motivation to combine. (Tallon Reply
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`(Exhibit 1086), ¶¶ 76, 78).
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`3.
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`Variability In Krill And The Components Of Krill Oil
`Were Well Studied And Understood
`Patent Owner’s argument that the extraction methods used and the chemical
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`make-up of the starting krill material could unpredictably influence the profile of
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`the resulting krill lipids is baseless. (Paper 14, pp. 16-18). Instead, possible
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`variations in the resulting krill oil caused by extraction techniques or any seasonal
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`or geographic fluctuations in the composition of natural krill was predictable and
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`well understood by a POSITA. Thus, despite the availability of a variety of
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`conventional extraction techniques and possible variations in krill, a POSITA
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`would have possessed a reasonable expectation of obtaining a krill oil composition
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`falling within the ranges recited in the challenged claims with little or no
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`experimentation. (Tallon Dec. (Exhibit 1006), ¶¶ 32, 194). (Tallon Dep. (Exhibit
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`2008), 64:11-65:22, 66:19-67:8, 68:7-23). (Tallon Reply (Exhibit 1086), ¶¶ 86,
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`108-09).
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`Lipid extraction techniques were predictable and well understood by a
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`POSITA, and the ability of various conventional solvent systems to dissolve
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`different krill lipid components was well studied and documented. (Tallon Dec.
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`(Exhibit 1006), ¶¶ 82-92, 144-150). For example, the extraction method in Folch
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`(Exhibit 1017) has been used since the 1960’s to produce an essentially complete
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`extract of all lipid components, including the triglycerides, phospholipids, and
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`carotenoids and associated fatty acids. (Tallon Reply (Exhibit 1086), ¶ 102).
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`Likewise, solvent extraction techniques using supercritical CO2 and
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`supercritical CO2 with a polar entrainer were also well-known. A POSITA would
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`have also appreciated that extraction conditions could be modified to predictably
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`extract different lipid components, and that different fractions could be extracted
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`separately or blended with other fractions to arrive at a desired krill oil
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`composition. (Tallon Reply (Exhibit 1086), ¶ 103).
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`Patent Owner also mistakenly asserts that the content of krill oil could not be
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`predicted because of possible fluctuations in the chemical make-up of natural krill.
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`(Paper 14, pp. 5-6, 22-23). Contrary to this assertion, a POSITA would have been
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`well aware of numerous studies detailing how the lipid content and components of
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`these lipids may fluctuate based upon the species of krill or where and when the
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`krill is caught. For example, Bottino (Exhibit 1007) reported an analysis of the
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`fatty acid profiles of freshly harvested Euphausia superba from 3 different
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`locations, and noted the “remarkable similarity in the fatty acid compositions of the
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`samples collected from the three stations (Table I).” (Exhibit 1007, p. 0002
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`(emphasis added). (Tallon Dec. (Exhibit 1006), ¶ 115; Tallon Reply (Exhibit
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`1086), ¶ 87).
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`Likewise, Grantham provided data on ranges and average compositions,
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`including even some compositional differences between krill of different gender.
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`(Exhibit 1032, pp. 0011-24). (Tallon Reply (Exhibit 1086), ¶ 88). By 1998,
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`numerous publications had reported the lipid distribution in Euphausia superba,
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`and disclosed the overall high phospholipid, and in particular high
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`phosphatidylcholine content found in krill. (Tallon Reply (Exhibit 1086), ¶ 89).
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`Similarly, Mayzaud studied the relative influence of geographical
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`differences on lipid content and reported that the mean lipid percentage of
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`Euphausia superba fell within a defined, narrow range of 1.9% to 3.1% by wet
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`weight of krill (Exhibit 1084, p. 0006), and within this range were “similar
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`concentrations of triglycendes or PC or PE.” (Exhibit 1084, p. 0011). (Tallon
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`Reply (Exhibit 1086), ¶ 90).
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`Thus, a POSITA would have known that Euphausia superba had from
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`approximately 2-3% lipids by wet weight, of which 30-50% by weight was
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`phosphatidylcholine. (Tallon Reply (Exhibit 1086), ¶ 91). Further, it would have
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`been a routine matter for a POSITA, if necessary, to vary either the location or
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`season in which the krill is caught, or to modify conventional processing
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`techniques. The POSITA would have appreciated that the results of these
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`modifications would be predictable as the range of lipids and phospholipids in krill
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`was well-known and, therefore would have a reasonable expectation of obtaining
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`the krill oil composition as recited in the challenged claims. (Tallon Reply
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`(Exhibit 1086), ¶¶ 92, 107-09).
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`Patent Owner’s arguments regarding possible differences in harvesting,
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`storage, and pre-processing methods, such as heat treatment to denature enzymatic
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`activity, are equally misplaced. (Paper 14, pp. 22-23). Any resulting differences
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`were also well studied, predictable and, understood by a POSITA. (Tallon Reply
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`(Exhibit 1086), ¶¶ 93-101). Similarly, a POSITA would have recognized that
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`different extraction techniques could have been predictably modified to take into
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`account any seasonal or geographic fluctuations in the composition of the natural
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`krill starting material to obtain a krill oil composition as recited by the claims of
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`the ‘905 patent. (Tallon Reply (Exhibit 1086), ¶¶ 107-08).
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`4.
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`Possible PAF Activity Does Not Teach Away
`From The Challenged Claims
`Predicated entirely on the “opinion” offered by Dr. Hoem, Patent Owner
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`asserts that a POSITA would not be motivated to encapsulate an effective amount
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`of krill oil containing “high” ether phospholipid levels because of concerns
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`regarding the possible formation of PAF. (Paper 14, pp. 4-5, 8-9, 14, 18-21).2 In
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`advancing this “teaching away” argument, Patent Owner blindly points to three
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`publications that reference PAF and PAF-like compounds: Prescott (Exhibit
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`2003); Zimmerman (Exhibit 2002); and Tanaka I (Exhibit 1014). (Paper 14, pp. 8-
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`2 Dr. Hoem’s “opinion” regarding PAF activity was copied verbatim from the
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`Declaration of Finn Myhren filed earlier in a proceeding in Australia. Compare
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`Exhibit 2001, ¶ 31 with Exhibit 1088, ¶ 25. When questioned, Dr. Hoem could not
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`explain why his “opinion” was identical to that proffered earlier by Dr. Myhren.
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`(Exhibit 1090, 71:6-72:10). Patent Owner’s PAF discussion, Paper 14, pp. 8-9,
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`also appears to have been literally copied from that same Australian Declaration.
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`9; Exhibit 2001), ¶ 31).3 Patent Owner’s “teaching away” argument fails in several
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`crucial respects.
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`First, although PAF is an ether phospholipid, it is structurally different than
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`any of the ether phospholipids found in krill and krill oil. In particular, PAF is an
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`alkyl acyl phospholipid where the acyl component is an acyl group (an ethyl group
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`having a single carbon atom bonded through a carbonyl). In contrast, ether
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`phospholipids in krill and krill oil, and as recited in the ‘905 patent, possess much
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`longer acyl chains ranging from 14-25 carbon atoms, and as a result do not exhibit
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`PAF signaling activity. (Tallon Reply (Exhibit 1086), ¶¶ 20, 22). For example,
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`Table 23 of the ‘905 patent reports that acyl groups in krill oil AAPC range in
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`length from 14 to 24 carbon atoms. (Tallon Reply (Exhibit 1086), ¶¶ 23-24).
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`However, PAF activity only exists if the acyl group is substantially shorter, in the
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`range 1-4 carbon atoms. This fact is confirmed by Prescott:
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`The PAF receptor recognizes the sn-1 ether bond of PAF, its
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`short sn-2 acetyl residue, and the choline head group; alteration
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`3 Neither Patent Owner nor Dr. Hoem direct Petitioner or the Board to any
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`passage(s) in the 29-page Prescott publication or the 8-page Zimmerman article.
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`of any of these structures greatly decreases signaling through
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`the PAF receptor. Extension of the sn-2 acetyl residue by one
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`methylene is without consequence, but extension by two
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`methylenes decreases activity by a factor of 10- to 100-fold,
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`depending on the assay. Extension beyond this results in the
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`loss of signaling through the PAF receptor. (Exhibit 2003, p.
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`13) (notations deleted) (emphasis added). (Exhibit 2003, p. 13)
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`(notations deleted) (emphasis added).
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`Prescott teaches that ether phospholipids having longer acyl groups, such as
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`those present in krill and krill oil, would not exhibit PAF activity.4 (Tallon Reply
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`(Exhibit 1086), ¶ 25). Prescott undermines Dr. Hoem’s premise and subverts
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`Patent Owner’s “PAF teaching away” argument.
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`Second, Tanaka I, Zimmerman and Prescott only address artificially
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`oxidized lipid products that may have PAF-like behavior, but draw no connection
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`between the oral administration of ether phospholipids and in-vivo signaling
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`4 Dr. Hoem agreed that PAF activity increases significantly as the acyl group
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`becomes significantly shorter. (Exhibit 1090, 39:19-22).
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`behavior. For example, Tanaka I simply “investigated the PAF-like lipids formed
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`U.S. Patent No. 9,078,905
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`during peroxidation of PCs from hen egg yolk, salmon roe, sea urchin eggs, and
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`krill in an [in vitro] FeS04/EDTA/ascorbate system” (Exhibit 1014, p. 0001)
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`(emphasis added). Tanaka I concluded that “the occurrence of PAF-like lipids in
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`some stored foods is still speculative and requires further investigation.” (Exhibit
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`1014, p. 0005). (Tallon Reply (Exhibit 1086), ¶¶ 26, 28). While Tanaka I
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`describes artificial oxidation of the natural AAPC present in krill, the presence of
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`PAF-like lipids is very small even under artificial chemically induced oxidation.
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`(Prescott (Exhibit 2003), pp. 0013-14); Tanaka I, (Exhibit 1014), p. 0005). (Tallon
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`Reply (Exhibit 1086), ¶ 31). Additionally, Zimmerman refers only to artificially
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`generated oxidation products, and does not relate to oral administration of natural
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`ether phospholipids and the activity of the potential degradation products that is
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`being described. (Tallon Reply (Exhibit 1086), ¶ 30). Further, Prescott observed:
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`Oxidation of complex lipids in reduced systems has defined
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`potential oxidation pathways and products, but whether such
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`oxidizing conditions exist in vivo is problematic, given the
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`unstable nature of the reactive intermediates and the potential of
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`metabolism of the oxidation products. (Exhibit 2003, p. 14)
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`U.S. Patent No. 9,078,905
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`(emphasis added).
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`Tellingly, Dr. Hoem could not recall any publication associating the oral
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`administration of ether phospholipids with PAF. (Exhibit 1090, 35:4-9, 35:22-
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`36:11).
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`Third, it was recognized that PAF-like lipids have lower activity than PAF
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`itself because they are only mimicking the functionality of PAF. Every deviation
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`from the true PAF molecule rapidly decreases the activity, and after a slight
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`deviation, PAF-like activity ceases completely. (Tallon Reply (Exhibit 1086), ¶¶
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`25, 29). For example, Prescott states: “alteration of any of these structures greatly
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`decreases signaling through the PAF receptor . . . .” (Exhibit 2003, p. 13).
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`Finally, Prescott indicates that the PAF signaling system is “tightly
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`controlled” and is subject to “rapid degradation” by extracellular and intracellular
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`acetylhydrolases. (Exhibit 2003, p. 2). Thus, oral administration of ether
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`phospholipids does not contribute to the process described by Prescott. (Tallon
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`Reply (Exhibit 1086), ¶ 31). Further, PAF-like lipids are rapidly degraded by the
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`body’s natural mechanisms, given the unstable nature of the reactive intermediates
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`and the potential of metabolism of the oxidation products. Likewise, Zimmerman
`17
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`Inter Partes Review Case No.: IPR 2017-00747
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`observes “[t]he biological activities of PAF are regulated by several precise
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`U.S. Patent No. 9,078,905
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`mechanisms that, together, constrain and control its action in physiologic
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`inflammation.” (Exhibit 2004, p. 1). (Tallon Reply (Exhibit 1086), ¶ 30).
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`The “PAF publications” relied upon by Patent Owner only describe
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`artificially oxidized lipid products that may exhibit some PAF-like behavior, but
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`draw no connection between oral administration of ether phospholipids and in-vivo
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`signaling behavior. (Tallon Reply (Exhibit 1086), ¶¶ 26-27, 30). This, combined
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`with the low activity of the degradation products compared with true PAF, their
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`low concentration, the proliferation of different degradation products of which the
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`majority have no PAF-like activity, and the body’s natural metabolization to
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`remove them from the body, would not have discouraged a POSITA from
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`encapsulating an effective amount of a krill oil composition containing from about
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`3% to 15% ether phospholipids. (Tallon Reply (Exhibit 1086), ¶ 32).
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`5.
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`Ether Phospholipids Were Recognized To
`Provide Health Benefits
`Because of “PAF concerns,” Patent Owner asserts that a POSITA would not
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`have chosen to encapsulate krill oil with “enhanced,” “substantial” or “high” ether
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`phospholipid levels. (Paper 14, pp. 5, 9, 20). Contrary to Patent Owner’s
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`Inter Partes Review Case No.: IPR 2017-00747
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`assertion, a POSITA would have been aware that krill oil compositions with
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`U.S. Patent No. 9,078,905
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`“enhanced,” “substantial” or “high” ether phospholipid levels, including then-
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`existing commercial krill oil products, exhibited a variety of health benefits.
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`For example, it was known that ether phospholipids exhibited health benefits
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`through their enhanced delivery of DHA to the brain: “DHA-containing ether
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`phospholipid species and DHA-containing lysophospholipid species can be
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`delivered smoothly into the brain as carriers of DHA, resulting in the uptake of free
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`DHA after brain phospholipase hydrolyses of the phospholipids species . . . .”
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`(Chen (Exhibit 1072), p. 0011, 0018-0019 (claims 26-37)). (Tallon Reply (Exhibit
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`1086), ¶¶ 33-34).
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`Similarly, Catchpole discloses that phospholipids conferred “a number of
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`health benefits.” (Exhibit 1009, p. 0024; Tallon Dec. (Exhibit 1006), ¶¶ 91-92, 193,
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`214). (Tallon Reply (Exhibit 1086), ¶¶ 35, 60). Likewise, Breivik describes
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`processes for producing krill oils having a phospholipid content from 30% to in
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`excess of 90%, and teaches that phospholipids are useful in “medical products,
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`health food and human nutrition,” and that “[o]mega-3 fatty acids bound to marine
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`phospholipids are assumed to have particularly useful properties.” (Breivik I
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`(Exhibit 1035), 0002-0003; Breivik II (Exhibit 1037), 1:14-19; Breivik III (Exhibit
`19
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`1036), 1:9-14). (Tallon Reply (Exhibit 1086), ¶¶ 45-49). In fact, Dr. Tallon made
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`U.S. Patent No. 9,078,905
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`recommendations regarding the beneficial properties of phospholipids, including
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`ether phospholipids, in a report predating the priority date of the ‘905 patent,
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`notwithstanding his awareness of the possible role PAF plays in inflammation.
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`(Tallon Reply (Exhibit 1086), ¶ 61).
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`Table 22 of the ‘905 patent reports that phospholipids constitute 30% of
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`Neptune’s prior art NKO krill oil product, and of that fraction, 8.2% are ether
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`phospholipids. (Exhibit, 1001, 33:15-37, p. 0041). Thus, Patent Owner represents
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`that the NKO product has 2.46% ether phospholipids based on a total phospholipid
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`content of 30% ([7.0% AAPC + 1.2% LAAPC] x 0.30). (Tallon Reply (Exhibit
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`1086), ¶ 52). In fact, during the prosecution of the ‘905 patent, Patent Owner used
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`this same rationale to argue that the NKO product has 2.46% ether phospholipids.
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`(Response to Office Action (Exhibit 1026), p. 0250).
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`However, three of the provisional applications that the ‘905 patent claims
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`priority include “Table 17” that was inexplicably omitted from the ‘905 patent’s
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`non-provisional application. (‘072 Provisional (Exhibit 1002), p. 0036; ‘058
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`Provisional (Exhibit 1004), p. 0034; ‘483 Provisional, (Exhibit 1005), p. 0036). In
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`Table 17, reproduced below, Patent Owner represented that NKO’s total
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`U.S. Patent No. 9,078,905
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`phospholipids was 42.96%, not 8.2% as disclosed in Table 22.5
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`The Table 17 data deleted from the ‘905 patent combined with the
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`information provided in Table 22 demonstrates that Neptune’s NKO product had
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`an ether phospholipid level of 3.52% ([7.0% AAPC + 1.2% LAAPC] x 0.4296).
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`(Tallon Reply (Exhibit 1086), ¶ 53). Dr. Hoem admitted Patent Owner’s
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`representations of the ether phospholipid content of NKO (i.e., 2.46-3.52%) would
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`be considered “substantial or high” when considering PAF. (Exhibit 1090, 61:2-
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`12).
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`5 Table 16 of the provisional applications characterized the NKO product as “the
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`closest prior art krill oil.” Table 16 of the ‘905 patent replaced “the closest prior
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`art krill oil” with “NKO krill oil.”
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`Inter Partes Review Case No.: IPR 2017-00747
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`U.S. Patent No. 9,078,905
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`Assuming arguendo that the ether phospholipids found in krill and krill oil
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`exhibited some PAF activity, which they do not, Patent Owner’s “teaching away”
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`argument is completely refuted by the development and marketing of krill oil
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`products, such as Neptune’s NKO krill oil, which by Dr. Hoem’s own admission
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`contain “substantial or high” levels of ether phospholipids. For example, in
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`reporting the results of a study involving Neptune’s NKO krill oil product, Bunea
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`disclosed that “[k]rill oil has a unique bimolecular profile of phospholipids
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`naturally rich in omega-3 fatty acids and diverse antioxidants significantly
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`different from the usual profile of fish oils. The existence of phospholipids in
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`combination with long-chain omega-3 fatty a
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