`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.: IPR2017-00745
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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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`_______________
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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.: IPR2017-00745
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`U.S. Patent No. 9,078,905
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`I.
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`II.
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`TABLE OF CONTENTS
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`INTRODUCTION ...........................................................................................1
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`CLAIMS 1-20 WOULD HAVE BEEN OBVIOUS .......................................4
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`A.
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`The Teachings Of Catchpole And Sampalis Render
`Claims 1-4 And 9-10 Obvious ..............................................................4
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`B.
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`C.
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`1. Possible PAF Activity Does Not Teach Away
`From The Challenged Claims........................................................ 4
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`2. “High” Levels Of Ether Phospholipids Were
` Recognized As Providing Health Benefits ................................ 10
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`Claims 5 And 11 Are Obvious ........................................................... 17
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`The Teachings Of Catchpole, Sampalis And Fricke Render
`Claims 6, 12, 15-16 And 18 Obvious ................................................ 18
`1. Reasonable Expectation Of Success Does Not Have To Be
`Demonstrates To An Absolute, Scientific Certainty................... 19
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`2. Fricke II Did Not Directly Measure Ether Phospholipids .......... 19
`3. A POSITA Would Have Known That Frick II’s Method
`Was Inaccurate And Non-Representative ................................... 22
`4. Variability In Krill And The Components Of Krill Oil
`Was Studied And Well Understood ............................................ 24
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`D.
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`The Teachings Of Catchpole, Sampalis, Fricke And Bottino
`Render Claims 7-8, 13-14, 17 And 19-20 Obvious ........................... 29
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`III. CONCLUSION ............................................................................................. 29
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`IV. CERTIFICATE OF COMPLIANCE............................................................ 32
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`Inter Partes Review Case No. IPR2017-00745
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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 Catchpole
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`(Exhibit 1009), Sampalis I (Exhibit 1012), Randolph (Exhibit 1011), Fricke
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`(Exhibit 1010) and/or Bottino (Exhibit 1007) teach and disclose each element of
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`the claims of the ‘905 patent. Instead, Patent Owner presents two unpersuasive
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`arguments that challenged claims 1-20 would not have been obvious in view of the
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`teachings of one or more of these references. Neither argument can withstand
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`scrutiny.
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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, p. 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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`Patent Owner tries to buttress its argument by improperly attempting to elevate
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`Petitioner’s burden to demonstrate obviousness from a preponderance to one of
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`absolute certainty predicted upon “scientific evidence.” (Paper 14, p. 21).
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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 would have known
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`that the values Patent Owner pulls from Fricke II are clearly anomalies that could
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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
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`changes 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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`10-18) 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
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`and its attendant phosphatidylcholine and ether phosphatidylcholine sub-
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`components, as well as triglycerides, were present within predictable and known
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`ranges; and (c) would have known that conventional extraction techniques could
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`be modified to take into account any seasonal or geographic fluctuations in the
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`starting krill material resulting in predictable changes in the composition of the
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`resulting krill oil. As a result, a POSITA in would have possessed a reasonable
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`expectation of obtaining krill oil compositions as recited in the challenged claims.1
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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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`II.
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`CLAIMS 1-20 WOULD HAVE BEEN OBVIOUS
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`A. The Teachings Of Catchpole And Sampalis Render
`Claims 1-4 And 9-10 Obvious
`The combined teachings Catchpole (Exhibit 1009) (krill oil having an ether
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`phospholipid content of 4.6%) and Sampalis (Exhibit 1012) (Neptune’s
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`encapsulated NKO krill oil product) disclose the krill oil compositions recited in
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`claims 1-4 and 9-10. In an effort to avoid these teachings, Patent Owner
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`erroneously maintains that a POSITA would not encapsulate krill oil having
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`“high” levels of ether phospholipids because of concerns that certain ether
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`phospholipids could be precursors to Platelet Activation Factor (“PAF”) activity
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`associated with inflammation. (Paper 14, pp. 8-9, 14-17). Patent Owner’s “PAF
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`teaching away” argument is meritless.
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`1.
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`Possible PAF Activity Does Not Teach Away
`From The Challenged Claims
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`Patent Owner asserts that it was known that ether phospholipids “are
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`precursors for compounds with high Platelet Activating Factor (“PAF”) activity,”
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`and that “PAF is involved in triggering acute inflammatory and thrombotic
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`cascades. . . . .” (Paper 14, pp. 8, 15). Predicated entirely on the “opinion” offered
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`by Dr. Hoem, Patent Owner asserts that a POSITA would not be motivated to
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`encapsulate an effective amount of krill oil containing “high” ether phospholipid
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`levels because of concerns regarding the possible formation of PAF. (Paper 14,
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`pp. 14-16, 18-20, 27-28).2 In advancing this “teaching away” argument, Patent
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`Owner blindly points to three publications that reference PAF and PAF-like
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`compounds: Prescott (Exhibit 2003); Zimmerman (Exhibit 2002); and Tanaka I
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`(Exhibit 1014). (Paper 14, pp. 9-10; Exhibit 2001), ¶ 31).3 Patent Owner’s
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`“teaching away” argument fails in several crucial respects.
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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
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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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`3 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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`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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`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).
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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, 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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`4 Dr. Hoem testified that “any measurable level” of ether phospholipids would
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`have purportedly raised concerns about PAF. (Exhibit 1090, 57:5-58:5).
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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 not relate to oral
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`administration of natural ether phospholipids and the activity of the potential
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`degradation products that is being described. (Tallon Reply (Exhibit 1086), ¶ 30).
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`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
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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 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), ¶ 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).
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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-
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`vivo signaling behavior. (Tallon Reply (Exhibit 1086), ¶¶ 26-27, 30). This,
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`combined with the low activity of the degradation products compared with true
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`PAF, their low concentration, the proliferation of different degradation products of
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`which the majority have no PAF-like activity, and the body’s natural
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`metabolization to remove them from the body, would not have discouraged a
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`POSITA from encapsulating an effective amount of a krill oil composition
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`containing from about 3% to 15% ether phospholipids. (Tallon Reply (Exhibit
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`1086), ¶ 32).
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`2.
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`“High” Levels Of Ether Phospholipids Were
`Recognized As Providing 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 “high” ether phospholipid levels.5 (Paper
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`14, pp. 14-15, 18, 20, 27-28). Contrary to Patent Owner’s assertion, a POSITA
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`would have been aware that krill oil compositions with “high” ether phospholipid
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`5 Dr. Hoem testified that “any measurable level” of ether phospholipids would
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`have purportedly raised concerns about PAF. (Exhibit 1090, 57:5-58:5).
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`levels, including then-existing commercial krill oil products, exhibited a variety of
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`health benefits.
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`For example, it was known that ether phospholipids exhibited health
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`benefits through their enhanced delivery of DHA to the brain: “DHA-containing
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`ether 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
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`free 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,
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`193, 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
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`(Exhibit 1036), 1:9-14). (Tallon Reply (Exhibit 1086), ¶¶ 45-49). In fact, Dr.
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`Tallon made recommendations regarding the beneficial properties of
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`phospholipids, including ether phospholipids, in a report predating the priority
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`date of the ‘905 patent, notwithstanding his awareness of the possible role PAF
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`plays in inflammation. (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
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`phospholipid content of 30% ([7.0% AAPC + 1.2% LAAPC] x 0.30). (Tallon
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`Reply (Exhibit 1086), ¶ 52). In fact, during the prosecution of the ‘905 patent,
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`Patent Owner used this same rationale to argue that the NKO product has 2.46%
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`ether phospholipids. (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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`phospholipids was 42.96%, not 30% as disclosed in Table 22.6
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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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`6 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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`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 acids facilitates the passage of fatty
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`acid molecules through the intestinal wall, increasing bioavailability and
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`ultimately improving the omega-3:omega-6 fatty acid ratio”. (Exhibit 1020), p.
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`0002; Tallon Dec (Exhibit 1006), ¶ 23). (Tallon Reply (Exhibit 1086), ¶ 36).
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`Bunea expressly reported that patients who took Neptune’s NKO Krill Oil
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`experienced no adverse effects. (Exhibit 1020, pp. 0001-0002, 0007-0008; Tallon
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`Dec. (Exhibit 1006), ¶¶ 171-172, 176-177). (Tallon Reply (Exhibit 1086), ¶ 37).
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`Similarly, Sampalis I teaches that the administration of 2000 mg/day of
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`Neptune’s NKO Krill Oil for several months was safe and effective. (Exhibit
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`1012, pp. 0001, 0003-0004, 0008; Tallon Dec. (Exhibit 1006), ¶¶ 67-71). In fact,
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`Patent Owner relied upon Sampalis I in the section of its GRAS Notification
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`entitled “Data Pertaining to Safety” submitted to the FDA. (Exhibit 1089, p.
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`0018). (Tallon Reply (Exhibit 1086), ¶ 38).
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`Neptune Krill Oil (NKO) and Krill Bill NKO products, marketed and sold
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`as of the earliest effective filing date, promoted the benefits associated with high
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`phospholipid content. At least as early as 2006, Krill Bill was advertised as “Krill
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`Bill 100% Neptune Krill Oil - the purest combination of phospholipids,
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`antioxidants, omega-3, omega-6, and omega-9 fatty acids.” (Exhibit 1070, p.
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`0001). (Tallon Reply (Exhibit 1086), ¶¶ 52-55). Krill Bill was described as
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`containing many of the krill oil components disclosed and claimed by the ‘905
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`patent, for example: (i) >40% by weight phospholipids; (ii) >30% by weight
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`phosphatidylcholine; (iii) >30% by weight omega-3 fatty acids; and (iv) >150
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`mg/100 gm esterified astaxanthin (>1500 mg/kg astaxanthin esters). (Exhibit
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`1070, p. 0003 (reproduced below)):
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`While Dr. Hoem testified that any “measurable amount” of ether
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`phospholipids would have raised PAF concerns, he could not explain why
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`Neptune’s NKO product could be marketed and sold without concerns about
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`alleged PAF activity, or why Patent Owner relied upon the safety of that product
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`in submissions to the FDA. (Exhibit 1090), 50:20-52:16).
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`A POSITA would have readily known that “high levels” of ether
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`phospholipids were actually present in commercial krill oil products and not
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`harmful. (Tallon Reply (Exhibit 1086), ¶¶ 36-44, 50-59).
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`Patent Owner also contends that, despite the well-documented benefits of
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`krill oil having a “high” phospholipid content (including ether phospholipids), a
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`POSITA would have instead utilized “low” ether phospholipid levels, such as
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`purportedly reported in Fricke II (Exhibit 2006). (Paper 14, pp. 16-17, 20). This
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`argument is unpersuasive. As detailed infra pp. 19-24, a POSITA would have
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`recognized that the ether phospholipid level disclosed in Fricke II was both
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`internally inconsistent and artificially low because Fricke II utilized an obsolete
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`and imprecise analytical technique that indirectly tries to quantify the ether
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`phospholipid content by measuring a hydrolyzed fraction of an oil sample. (Tallon
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`Reply (Exhibit 1086), ¶¶ 63-69). Even Dr. Hoem admitted that he has never seen
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`ether phospholipids as low as reported in Fricke II for a krill oil having a 40%
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`phospholipid content. (Exhibit 1090, 108:12-23).
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`Claims 1-4 and 9-10 would have been obvious to a POSITA given the
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`teachings of Catchpole and Sampalis. (Tallon Dec. (Exhibit 1006), ¶¶ 193-201).
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`(Tallon Reply (Exhibit 1086), ¶¶ 110-28).
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`B. Claims 5 And 11 Are Obvious
`Patent Owner’s defense of claims 5 and 11 is predicated on the
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`erroneousness proposition that the “prior art teaches away from encapsulation of
`
`krill oil with high levels of ether phospholipids.” (Paper 14, pp. 18-19, 28). As
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`detailed previously, Patent Owner’s “teaching away” argument is baseless. (See
`
`supra, pp. 4-16). A POSITA would not have been deterred from encapsulating
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`krill oil having greater than about 3% ether phospholipids because of alleged
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`Inter Partes Review Case No.: IPR2017-00745
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`concerns about PAF, as evidenced by the encapsulated krill oil products having
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`U.S. Patent No. 9,078,905
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`“high” levels of ether phospholipids that were marketed and sold. (See supra, pp.
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`10-16).
`
`Claim 5 would have been obvious to a POSITA given the teachings of
`
`Catchpole, Sampalis and Randolph, while claim 11 would have been obvious in
`
`view of the teachings of Catchpole, Sampalis and Bottino. (Tallon Dec. (Exhibit
`
`1006), ¶¶ 202-11, 231-32). (Tallon Reply (Exhibit 1086), ¶¶ 129-30, 146-47).
`
`C. The Teachings Of Catchpole, Sampalis And Fricke Render
`Claims 6, 12, 15-16 And 18 Obvious
`Patent Owner maintains that a POSITA would not have combined the
`
`teachings of Catchpole (Exhibit 1009) (krill oil having 4.8% ether phospholipids),
`
`Sampalis (Exhibit 1012) (Neptune’s encapsulated NKO krill oil product) and
`
`Fricke (Exhibit 1010) (krill oil containing 7.8% ether phospholipids and 20-50%
`
`triglycerides) because Dr. Tallon “provided no scientific evidence that backs up”
`
`his conclusion regarding the combination of references. (Paper 14, p. 21). Patent
`
`Owner then erroneously asserts that Frick II (Exhibit 2006) purportedly shows that
`
`the ether phospholipid content disclosed in Fricke was not 7.8%, as detailed by Dr.
`
`Tallon (Tallon Dec. (Exhibit 1006), ¶ 98), but was at most only 0.6%. (Paper 14,
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`Inter Partes Review Case No.: IPR2017-00745
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`pp. 16, 23-25). Thus, Patent Owner argues that a POSITA would not have
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`U.S. Patent No. 9,078,905
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`combined the teaching of Catchpole, Sampalis and Fricke. Patent Owner’s
`
`arguments based upon Fricke II are misplaced.
`
`1.
`
`Reasonable Expectation Of Success Does Not Have To
`Be Demonstrates To An Absolute, Scientific Certainty
`Patent Owner’s attempt to elevate Petitioner’s burden to require that a
`
`“reasonable expectation of success” be supported by “scientific evidence” can be
`
`quickly dismissed. (Paper 14, p. 21). It is well-settled that “[o]bviouness does not
`
`require absolute predictability of success. . . . For obviousness under § 103, all
`
`that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d
`
`1351, 1360 (Fed. Cir. 2009). Petitioner and Dr. Tallon have clearly demonstrated
`
`that a POSITA, combining the teachings of Catchpole, Sampalis and Fricke would
`
`have possessed a reasonable expectation of obtaining the krill oil recited in the
`
`challenged claims based upon the teachings of Catchpole, Sampalis and Fricke.
`
`Fricke II Did Not Directly Measure Ether Phospholipids
`2.
`Fricke II analyzed 1-O-alkylglycerolipids present in two samples of
`
`Antarctic krill by first separating the total lipid extract into phospholipids and
`
`neutral lipids using thin layer chromatography. The phospholipid fraction was
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`Inter Partes Review Case No.: IPR2017-00745
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`then hydrolyzed enzymatically. The resulting phospholipid and neutral lipid
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`U.S. Patent No. 9,078,905
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`fractions were first converted to free alkylglycerols and then to isopropylidene
`
`derivatives of the alkylglycerols, which were finally quantified. (Exhibit 2006, pp.
`
`1-2). (Tallon Reply (Exhibit 1086), ¶ 63).
`
`Importantly, the ether lipid values reported by Fricke II are not direct
`
`measurements of the ether phospholipids present in the krill. Rather, the
`
`compound quantified, 1-O-alkyleglycerol, is a degraded or deacylated version of
`
`the original ether lipids that has no phospholipid head group and no acyl group on
`
`the sn-2 position. Consequently, 1-O-alkyleglycerol has a significantly smaller
`
`molecular mass than the ether phospholipids present in krill and krill oil. (Tallon
`
`Reply (Exhibit 1086), ¶ 67).
`
`Fricke II’s method requires successive degradation of the natural ether
`
`phospholipid into a glycerolipid with only the ether linked fatty acid remaining,
`
`and then further to an isopropylidene derivative. There are numerous steps during
`
`this successive degradation in which losses of the final quantifiable compound
`
`could occur including, but not limited to, limited selectivity of the phospholipase
`
`conversion. Thus, the content of ether phospholipids in the original sampled krill
`
`oil will necessarily be greater than the mass of 1-O-alkylglycerol measured by
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`Inter Partes Review Case No.: IPR2017-00745
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`Fricke II. (Tallon Reply (Exhibit 1086), ¶ 67). This explains why Fricke II’s
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`U.S. Patent No. 9,078,905
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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
`
`by others, and demonstrates that Fricke II’s values are anomalies that a POSITA
`
`would not rely upon. (Tallon Reply (Exhibit 1086), ¶ 69). Even Patent Owner’s
`
`expert Dr. Hoem admits that he has not observed krill oils with such low levels of
`
`ether phospholipid. (Exhibit 1090, 108:12-23).
`
`Further, Patent Owner and Dr. Hoem refer only to the 1-O-alkylglycerolipid
`
`values reported in Fricke II, and incorrectly propose those values represent the
`
`ether phospholipid content of the analyzed sample. (Paper 14, p. 25; Exhibit 2001,
`
`¶ 35). As described above, the values reported by Fricke II only quantify the
`
`deacylated glycerolipid content, not the original acylated ether phospholipids from
`
`which they were derived. (Tallon Reply (Exhibit 1086), ¶ 67).
`
`Contrary to Patent Owner’s arguments, a POSITA would have understood
`
`that the ether phospholipid levels reported in Fricke II are anomalies that are
`
`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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`U.S. Patent No. 9,078,905
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`3.
`
`A POSITA Would Have Known That Frick II’s
`Method Was Inaccurate And Non-Representative
`Fricke II’s results were reported more than 10 years before the priority date
`
`of the ‘905 patent. By 2006, additional results were available to a POSITA using
`
`modern, more accurate analytical techniques, including the direct quantification of
`
`the ether phospholipids using 31P-NMR spectroscopy (Catchpole (Exhibit 1009),
`
`p. 0014; Tallon Dec. (Exhibit 1006), ¶ 90) or analysis of the main ether lipid
`
`AAPC by directly quantifying partially hydrolyzed 1-O-alkyl-2-lyso glycerol
`
`phosphatidylcholine levels. (Tanaka I (Exhibit 1014), p. 0002; Tallon Dec.
`
`(Exhibit 1006), ¶¶ 130-31). (Tallon Reply (Exhibit 1086), ¶¶ 71-74, 79).
`
`A POSITA would have a compelling reason to rely upon the results
`
`obtained using a more precise analytical technique, such as NMR, and disregard
`
`Fricke II’s outdated and inaccurate method that failed to directly measure ether
`
`phospholipid content or differentiate between ether phospholipids and other
`
`possible sources of ether lipids in the samples analyzed. (Tallon Reply (Exhibit
`
`1086), ¶ 71).
`
`In contrast to Fricke II’s indirect method, the enhanced accuracy of NMR
`
`results is highlighted by an article co-authored by Dr. Hoem which acknowledges
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`Inter Partes Review Case No.: IPR2017-00745
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`that NMR is the preferred method for analyzing the components of krill oil.
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`U.S. Patent No. 9,078,905
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`((Exhibit 1079), pp. 0001, 0003-0004, 0011). (Tallon Reply (Exhibit 1086), ¶¶
`
`72-73). In particular, the article studied “the usefulness of the combination of 31P,
`
`1H and 13C nuclear magnetic resonance (NMR) spectroscopies to characterize
`
`krill oil profile. . . . The method was characterized by high sensitivity, accuracy,
`
`and reproducibility.” (Exhibit 1079, Abstract, p. 0001) (emphasis added). The
`
`authors concede that 31P-NMR provides a direct, sensitive, and selective method
`
`of analysis, allowing phospholipids to be analyzed in their natural intact state,
`
`without the additional uncertainty of chemical modification steps that convert
`
`them into another form for analysis. This analytical technique also directly
`
`responds to the presence of the characteristic
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