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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________
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`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.: IPR2017-00748
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`U.S. Patent 9,028,877
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`Issue Date: July 14, 2015
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`Title: Bioeffective Krill Oil Compositions
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`_______________
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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. IPR2017-00748
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`U.S. Patent No. 9,028,877
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`I.
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`II.
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`TABLE OF CONTENTS
`INTRODUCTION ...........................................................................................1
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`CLAIMS 1-19 OF THE ‘877 PATENT ARE OBVIOUS ..............................4
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`A.
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`B.
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`C.
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`D.
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`E.
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`The Teachings Of Grantham, Fricke And Tanaka Render
`Claims 1-3, 8-9, 11-12 And 17-18 Obvious .........................................4
`1. Fricke II Did Not Directly Measure Ether Phospholipids ............ 5
`2. A POSITA Would Have Known That Fricke II’s Method
` Was Inaccurate And Obsolete ....................................................... 7
`3. Variability In Krill And The Components of Krill Oil Were
` Well Studied And Understood .................................................... 10
`Claims 4-5 And 13-14 Are Obvious In View Of The Teachings
`Found In Grantham, Fricke, Tanaka I and Bottino ............................ 14
`
`Claims 6 And 15 Are Obvious In View Of The Grantham, Fricke,
`Tanaka I And Tanaka II ..................................................................... 16
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`Claims 7 And 16 Are Obvious In View Of Grantham, Fricke,
`Tanaka I And Sampalis I .................................................................... 17
`1. PAF Does Not Teach Away From The Challenged Claims ....... 18
`2. Ether Phospholipids Were Recognized To Provide
` Health Benefits ............................................................................ 24
`Claims 10 and 19 Are Obvious Based Upon The Combination Of
`Grantham, Fricke, Tanaka I and Sampalis II ..................................... 31
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`III. CONCLUSION ............................................................................................. 32
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`IV. CERTIFICATE OF COMPLIANCE............................................................ 34
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`Inter Partes Review Case No. IPR2017-00748
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`I.
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`INTRODUCTION
`Patent Owner does not dispute that it was well-known prior to the filing date
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`U.S. Patent No. 9,028,877
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`of the ‘877 patent that krill quickly spoils, and that methods were available to
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`denature the lipases and phospholipases naturally present in krill responsible for
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`that spoilage. Additionally, Patent Owner fails to contest that conventional
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`extraction techniques could be used to extract oil from a denatured krill product.
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`Instead, Patent Owner presents two unpersuasive arguments that challenged
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`method claims 1-19 would not have been obvious in view the teachings of one or
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`more of the following references: Grantham (Exhibit 1032); Fricke (Exhibit
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`1010); Tanaka I (Exhibit 1014); Tanaka II (Exhibit 1015); Bottino (Exhibit 1007);
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`Sampalis I (Exhibit 1012); and/or Sampalis II (Exhibit 1013). Both arguments are
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`unavailing.
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`First, 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 13, pp. 5, 15-
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`17).
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`Second, Patent Owner mistakenly asserts that claims 7 and 16, which
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`require encapsulation of the extracted krill oil, would have been unobvious
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`because certain ether phospholipids could be precursors of compounds exhibiting
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`Platelet Activating Factor (PAF) activity. This, the Patent Owner claims, would
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`have deterred a POSITA from encapsulating krill oil compositions having
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`“enhanced” or “substantial” ether phospholipid levels. (Paper 13, pp. 6, 9-10, 22-
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`24).
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`Each of Patent Owner’s arguments is unavailing. First, a POSITA would
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`have known that the values Patent Owner pulls from Fricke II are clearly
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`anomalies that could not be relied on. Additionally, any seasonable or geographic
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`fluctuations in the chemical make-up of krill have been extensively studied, were
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`well known, and have been quantified in the prior art. Further, a POSITA would
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`have known that conventional extraction techniques could be modified, resulting
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`in predictable changes to the resulting krill oil composition. Second, it was well-
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`known that the specific ether phospholipids associated with PAF activity are
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`structurally different than the ether phospholipids present in krill and krill oil. As
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`a result, a POSITA would not have been dissuaded from encapsulating krill oil
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`having greater than about 3% ether phospholipids.
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`The challenged claims of the ‘877 patent would have been obvious to a
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`POSITA in view the teachings in the prior art combinations set forth in the in the
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`Institution Decision (e.g., Paper 8, pp. 11-19). A POSITA would have known that
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`(a) the lipases and phospholipases naturally present in krill needed to be
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`deactivated, via denaturation or some other method, to reduce lipid and
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`phospholipid decomposition and prevent spoilage; (b) krill phospholipids and its
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`attendant phosphatidylcholine and ether phosphatidylcholine sub-components, as
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`well as triglycerides, were present within predictable and known ranges; and (c) a
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`variety of conventional extraction techniques could be modified to take into
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`account any seasonal or geographical fluctuations in the natural krill starting
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`material resulting in predictable changes to the resulting krill oil composition.
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`As a result, a POSITA would have possessed a reasonable expectation of
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`extracting oil from a denatured krill product and obtaining krill oil compositions
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`as recited in the challenged claims.1
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`II. CLAIMS 1-19 OF THE ‘877 PATENT ARE OBVIOUS
`A. The Teachings Of Grantham, Fricke And Tanaka Render
`Claims 1-3, 8-9, 11-12 And 17-18 Obvious
`The combined teaching of Grantham (Exhibit 1032) (krill denaturing
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`process using heat), Fricke (Exhibit 1010) (krill oil having 7.8% ether
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`phospholipids and 20-50% triglycerides) and Tanaka I (Exhibit 1015) (krill
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`phospholipids with an ether phospholipid content of 23%) disclose a process to
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`denature krill and extract oil from that denatured krill product as recited in claims
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`1-3, 8-9, 11-12 and 17-18. While these references teach each element of the
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`above-identified claims, Patent Owner mistakenly maintains that Frick II (Exhibit
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`2006) shows that the ether phospholipid content disclosed by Fricke was not 7.8%
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`1 In 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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`as detailed by Dr. Tallon (Tallon Dec, (Exhibit 1006), ¶ 102), but instead is at
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`most only 0.6%. (Paper 13, p. 16-19). Patent Owner, therefore, contends that a
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`POSITA would not have combined the teachings of Grantham, Fricke and Tanaka.
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`Patent Owner’s arguments based upon Fricke II are 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), ¶ 69). 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 by others, and
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`demonstrates that Fricke II’s values are anomalies that a POSITA would not rely
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`upon. (Tallon Reply (Exhibit 1086), ¶ 69). Even Patent Owner’s expert Dr. Hoem
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`admits that he has not observed krill oils with such low levels of ether
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`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 ‘877 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), ¶ 94), 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), ¶¶ 134-35). (Tallon Reply (Exhibit 1084), ¶ 71).
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`A POSITA would have a compelling reason to rely upon the results
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`obtained using a more precise analytical technique, such as NMR, and disregard
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`Fricke II’s outdated and imprecise method which failed to directly measure ether
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`phospholipid content or differentiate between ether phospholipids and other
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`possible sources of ether lipids in the samples analyzed. (Tallon Reply (Exhibit
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`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
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`oil 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,
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`without the additional uncertainty of chemical modification steps that convert
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`them into another form for analysis. (Exhibit 1079, p. 0012). This analytical
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`technique also directly responds to the presence of the characteristic phosphorous
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`nucleus that is present in the phospholipids, making the results much more reliable
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`and accurate. (Tallon Reply (Exhibit 1086), ¶ 74).
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`Tanaka I (Exhibit 1014) also describes a direct and more precise technique
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`of measuring krill ether phospholipid. 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), ¶¶ 134-
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`36). This is in contrast to Fricke II where the ether phospholipid is further
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`degraded to an ether glycerolipid that contains only the ether linked fatty acid
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`attached to the residual glycerol group. (Tallon Reply (Exhibit 1086), ¶ 79).
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`A POSITA would have undoubtedly recognized that Fricke II’s ether
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`phospholipid values were both internally inconsistent and artificially low because
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`Fricke II utilized an obsolete and inaccurate method that indirectly tries to
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`quantify ether phospholipids. (Tallon Reply (Exhibit 1086), ¶¶ 63-69).
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`Accordingly, and consistent with Dr. Tallon (Tallon Dec. (Exhibit 1006), ¶ 102), a
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`POSITA would have recognized that Fricke II’s results are anomalies and have no
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`bearing on a POSITA’s motivation to combine. (Tallon Reply (Exhibit 1086), ¶¶
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`75-77).
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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 13, pp. 17-18). Instead, possible
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`variations in the resulting krill oil caused by particular extraction techniques or
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`seasonal or geographic fluctuations in the composition of natural krill was
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`predictable and well understood by a POSITA. Thus, despite the availability of a
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`variety of conventional extraction techniques, a POSITA would have possessed a
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`reasonable expectation of obtaining a krill oil composition falling within the
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`ranges recited in the challenged claims with little or no experimentation. (Tallon
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`Dec. (Exhibit 1006), ¶¶ 32, 208-18, 238-39, 241-43, 245-55). (Tallon Dep.
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`(Exhibit 2008), 64:11-65:22, 66:19-67:8, 68:7-23). (Tallon Reply (Exhibit 1086),
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`¶ 86, 108-109).
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`Lipid extraction techniques were predictable and well understood, and the
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`ability of various conventional solvent systems to dissolve different krill lipid
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`components were well studied and documented. (Tallon Dec. Exhibit 1006), ¶¶
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`87-96, 137-43). For example, the extraction method in Folch (Exhibit 1017) has
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`been used since the 1960’s to produce an essentially complete extract of all lipid
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`components, including the triglycerides, phospholipids, and carotenoids and
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`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 oil extracted from a
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`denatured krill product could not be predicted because of possible fluctuations in
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`the chemical make-up of natural krill. (Paper 13, pp. 5, 17-19). Contrary to this
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`assertion, a POSITA would have been well aware of numerous studies detailing
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`how the lipid content and components of those lipids may fluctuate based upon the
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`species of krill or where and when the krill is caught. For example, Bottino
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`(Exhibit 1007) reported an analysis of the fatty acid profiles of freshly harvested
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`Euphausia superba from 3 different locations and noted the “remarkable
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`similarity in the fatty acid compositions of the samples collected from the three
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`stations (Table I).” (Exhibit 1007, p. 0002 (emphasis added). (Tallon Dec.
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`(Exhibit 1006), ¶¶ 119-22). (Tallon Reply (Exhibit 1086), ¶ 87).
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`Likewise, Grantham provided data on ranges and average compositions,
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`including even some compositional differences associated with the krill’s 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 present 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 from 1.9% to 3.1% by
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`wet 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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`Accordingly, a POSITA would have expected that Euphausia superba had
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`from 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. (Tallon Reply (Exhibit 1086), ¶ 92). The POSITA would have
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`appreciated that the results of these modifications would be predictable as the
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`range of lipids and phospholipids in krill was well-known, and therefore would
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`have a reasonable expectation of obtaining the krill oil composition as recited in
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`the challenged claims. (Tallon Reply (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 lipases
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`and phospholipases, are equally misplaced. (Paper 13, pp. 18-19). Any possible
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`differences were also well studied, predictable and readily understood by a
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`POSITA. (Tallon Reply (Exhibit 1086), ¶¶ 93-101). Similarly, a POSITA would
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`have recognized that once denatured, a number of conventional extraction
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`techniques could be implemented to predictably take into account any seasonal or
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`geographic fluctuations in the composition of the natural krill starting material so
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`that there would have been a reasonable expectation of obtaining krill oil as
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`recited by the claims of the ‘877 patent.
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`Claims 1-3, 8-9, 11-12, and 17-18 would have been obvious to a POSITA
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`given the teachings of Grantham, Fricke and Tanaka. (Tallon Dec. (Exhibit 1006),
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`¶¶ 199-235). (Tallon Reply (Exhibit 1086), ¶¶ 110-15).
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`B. Claims 4-5 And 13-14 Are Obvious In View Of The Teachings
`Found In Grantham, Fricke, Tanaka I And Bottino
`Claims 4-5 and 13-14 have an additional limitation requiring that the
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`extracted krill oil have from about 20 to 35% omega-3 fatty acids. In a tepid
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`attempt to refute the obviousness of these claims, Patent Owner again relies upon
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`its flawed argument predicated upon Fricke II. (Paper 13, p. 20-21).2 As detailed
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`previously, Patent Owner’s arguments based on Fricke II are inapt. (See supra,
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`pp. 5-10). A POSITA, using known methods to denature krill, would have
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`recognized that a number of conventional extraction techniques could then be
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`modified to take into account any seasonal or geographic fluctuations in the
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`composition of the natural krill starting material causing predictable changes in
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`the composition of the resulting krill oil. (See supra, pp. 10-14).
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`The teachings of Grantham, Fricke, Tanaka I and Bottino render claims 4-5
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`and 13-14 obvious. (Tallon Dec. (Exhibit 1006), ¶¶ 244-46). (Tallon Reply
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`(Exhibit 1086), ¶¶ 116-18).
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`2 Patent Owner proposes that “Bottino’s oil would most likely contain similar
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`levels of ether phospholipids as the Fricke 1984 and 1986 oil. . . .” (Paper 13, p.
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`22). This is nothing more than unsupported attorney argument as Dr.Hoem
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`(Exhibit 2001, ¶ 43) does not opine on the level of ether phospholipids disclosed
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`in Bottino.
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`C. Claims 6 And 15 Are Obvious In View Of The Grantham,
`Fricke, Tanaka I And Tanaka II
`Patent Owner asserts that a POSITA would not combine the teachings of
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`Grantham, Fricke, Tanaka I and Tanaka II, repeating its tired argument that there
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`is “no scientific basis to combine ranges for lipid components produced by
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`different methods and from different starting materials.” (Paper 13, 20-21)3.
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`As noted previously, a POSITA, using known methods to denature krill,
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`would have recognized that a number of conventional extraction techniques could
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`then be modified to take into account any seasonal or geographic fluctuations in
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`the composition of the natural krill starting material causing predictable changes
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`in the composition of the resulting krill oil. (See supra, pp. 10-14).
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`The teachings of Grantham, Fricke, Tanaka I and Tanaka II render claims 6
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`and 15 obvious. (Tallon Dec. (Exhibit 1006), ¶¶ 244-46). (Tallon Reply (Exhibit
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`1086), ¶¶ 119-20).
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`3 Patent Owner mistakenly refers to claims 4-5 and 13-14 in advancing this
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`argument.
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`D. Claims 7 And 16 Are Obvious In View Of Grantham,
`Fricke, Tanaka I And Sampalis I
`Claims 7 and 16 each require encapsulation of the krill oil extracted from
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`the denatured krill product. Patent Owner offers two unpersuasive arguments to
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`refute the obviousness of these claims.
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`First, Patent Owner again asserts “there is no scientific basis” for a POSITA
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`to combine the teachings of Grantham, Fricke, Tanaka I and Sampalis I because
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`the references disclose different extraction techniques and different krill starting
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`material. (Paper 13, pp. 22-23). As detailed previously, a POSITA would have
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`been fully aware that, depending on the starting krill material, conventional
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`extraction techniques could be routinely modified, resulting in predictable changes
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`to the composition of the resulting krill oil. (See supra, pp. 10-14).
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`Patent Owner’s second argument fairs no better. In particular, Patent Owner
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`asserts that a POSITA would not be motivated to encapsulate krill oil having from
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`3-10% ether phospholipids because of concerns that some ether phospholipids are
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`precursors of PAF-like compounds that trigger inflammation. (Paper 13, pp. 9-10,
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`23-26). Patent Owner’s “PAF teaching away” argument is baseless.
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`U.S. Patent No. 9,028,877
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`PAF Does Not Teach Away From The Challenged Claims
`1.
`Predicated entirely on the “opinion” offered by Dr. Hoem,4 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 from about 3% to 10% ether phospholipids because of
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`concerns regarding the possible formation of PAF. (Paper 13, pp. 6, 9, 22-24). 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 products: Prescott (Exhibit 2003);
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`Zimmerman (Exhibit 2002); Tanaka I (Exhibit 1014). (Paper 13, p. 9; Exhibit
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`4 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
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`not explain why his “opinion” was identical to that proffered earlier by Dr.
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`Myhren. (Exhibit 1090, 71:6-72:10). Patent Owner’s PAF discussion, Paper 14,
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`pp. 8-9, also appears to have been literally copied from that same Australian
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`Declaration.
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`Inter Partes Review Case No. IPR2017-00748
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`2001, ¶ 32).5 Patent Owner’s “PAF teaching away” argument fails in several
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`U.S. Patent No. 9,028,877
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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
`
`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 ‘877 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 ‘877 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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`5 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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`U.S. Patent No. 9,028,877
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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
`
`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).
`
`Prescott teaches that ether phospholipids having longer acyl groups, such as
`
`those found in krill and krill oil extracts, would not exhibit PAF activity.6 (Tallon
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`Reply (Exhibit 1086), ¶¶ 20, 22). Prescott refutes Dr. Hoem’s underlying premise
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`and subverts Patent Owner’s “PAF teaching away” argument.
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`6 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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`Inter Partes Review Case No. IPR2017-00748
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`Second, Tanaka I, Zimmerman and Prescott only address artificially
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`U.S. Patent No. 9,028,877
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`oxidized lipid products that may have PAF-like behavior, and draws no
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`connection between the oral administration of ether phospholipids and in-vivo
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`signaling behavior. For example, Tanaka I simply “investigated the PAF-like
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`lipids formed during peroxidation of PCs from hen egg yolk, salmon roe, sea
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`urchin eggs, and krill in an [in vitro] FeS04/EDTA/ascorbate system” (Exhibit
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`1014, p. 0001) (emphasis added). Tanaka I concluded that “the occurrence of
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`PAF-like lipids in some stored foods is still speculative and requires further
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`investigation.” (Exhibit 1014, p. 0005). (Tallon Reply (Exhibit 1086), ¶¶ 26, 28).
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`While Tanaka I describes artificial oxidation of the natural AAPC present in krill,
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`the presence of PAF-like lipids is very small even under artificial chemically
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`induced oxidation. (Prescott (Exhibit 2003), pp. 0013-14). (Tanaka I, (Exhibit
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`1014), p. 0005). (Tallon Reply (Exhibit 1086), ¶ 31). Additionally, Zimmerman
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`refers only to artificially generated oxidation products, and does draw any
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`connection between the oral administration of natural ether phospholipids and the
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`activity of the potential degradation products that is being described. (Tallon
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`Reply (Exhibit 1086), ¶ 30). Moreover, 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
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`of metabolism of the oxidation products. (Exhibit 2003, p. 14)
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`(emphasis added).
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`Tellingly, Dr. Hoem could not recall any publication that associates the ingestion
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`of ether phospholipids with PAF. (Exhibit 1090, 35:4-9, 35:22-36:11).
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`Third, it was recognized that PAF-like lipids have lower activity than PAF
`
`itself because they are only mimicking the functionality of PAF. Every deviation
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`from the true PAF molecule rapidly decreases activity, and beyond 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
`
`decreases signaling through the PAF receptor . . . .” (Exhibit 2003, p. 13).
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`Finally, Prescott teaches 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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`Inter Partes Review Case No. IPR2017-00748
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`phospholipids does not contribute to the process described by Prescott. (Tallon
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`U.S. Patent No. 9,028,877
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`Reply (Exhibit 1086), ¶ 21). 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. (Tallon Reply (Exhibit
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`1086), ¶ 31). Likewise, Zimmerman observes “[t]he biological activities of PAF
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`are regulated by several precise mechanisms that, together, constrain and control
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`its action in physiologic inflammation.” (Exhibit 2004, p. 1). (Tallon Reply
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`(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 dietary intake of ether phospholipids and in-vivo
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`signaling behavior. This, combined with the low activity of the degradation
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`products compared to true PAF, their low concentration, the proliferation of
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`different degradation products of which the majority have no PA
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