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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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`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.: IPR2018-00295
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`U.S. Patent 9,320,765
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`Issue Date: April 26, 2016
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`Title: Bioeffective Krill Oil Compositions
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`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`PURSUANT TO 37 C.F.R. § 42.23(b)
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`Inter Partes Review Case No.: IPR2018-00295
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`U.S. Patent No. 9,320,765
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`TABLE OF CONTENTS
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`I.
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`II.
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`INTRODUCTION ........................................................................................... 1
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`CLAIMS 1-48 WOULD HAVE BEEN OBVIOUS ....................................... 3
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`A.
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`2.
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`3.
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`Claims 1-4, 7, 9-11, 14, 18-20, 24-28, 31, 33-35, 38, 42-44 and 47
`Would Have Been Obvious In View of Sampalis I, Catchpole, Fricke
`and Breivik II ......................................................................................... 3
`1.
`A POSITA Would Have Combined The Conventional
`Extraction Processes of The Cited References And Obtained
`The Claimed Krill Oil Compositions .......................................... 3
`Patent Owner’s Argument That PAF Concerns Taught Away
`From Encapsulating Krill Oil Having The Ether Phospholipids
`Content Recited In The Challenged Claims Is Unavailing .......13
`Catchpole Teaches and Discloses Krill Oil Compositions
`Having Greater Than 5% Ether Phospholipids As Recited In
`Claims 18-20, 42-44 and 47 ......................................................23
`Claims 5-6, 12-13, 15-16, 21-23, 29-30, 36-37 39-40 and 45-46 are
`Obvious In View of Sampalis I, Catchpole, Fricke, Breivik II and
`Bottino I ............................................................................................... 28
`Claims 8, 17, 24, 32, 41 and 48 Would Have Been Obvious
`In View of Sampalis I, Catchpole, Fricke, Breivik II, Bottino I
`and Randolph ....................................................................................... 28
`III. CONCLUSION ..............................................................................................29
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`B.
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`C.
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`IV. CERTIFICATE OF COMPLIANCE ............................................................31
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`Inter Partes Review Case No.: IPR2018-00295
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`I.
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`INTRODUCTION
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`U.S. Patent No. 9,320,765
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`Patent Owner’s Response (“POR,” Paper No. 14) does not contest that the
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`references relied upon by Petitioner (i.e., Sampalis I (Exhibit 1012), Catchpole
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`(Exhibit 1009), Fricke (Exhibit 1010), Breivik II (Exhibit 1037) and Bottino I
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`(Exhibit 1007) teach and disclose the elements recited in the claims of the ‘765
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`patent. Instead, urging that the challenged claims would not have been obvious by
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`a preponderance of the evidence, Patent Owner proffers three meritless arguments:
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`1.
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`a POSITA would not have combined the above-identified references,
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`each disclosing components extracted from krill, because Patent Owner has
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`chosen to categorize the well-known and conventional extraction processes
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`described in those references as either “selective” or “non-selective” (POR, pp.
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`14-22);
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`2.
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`a POSITA would have been deterred from encapsulating a krill oil
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`composition having “greater than about” 3% ether phospholipids because of
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`concerns that certain ether phospholipids could be precursors to compounds
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`exhibiting Platelet Activating Factor (“PAF”) activity (POR, pp. 22-26); and
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`3.
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`the phrase “greater than about 5%” ether phospholipids, recited in a
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`number of dependent claims, should be construed so that Catchpole does not teach
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`Inter Partes Review Case No.: IPR2018-00295
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`or disclose a krill oil composition having more than 5% ether phospholipids
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`(POR, pp. 11-13).
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`Contrary to Patent Owner’s arguments, the preponderance of evidence
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`demonstrates that the challenged claims of the ‘765 patent would have been
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`obvious based upon the prior art combinations set forth in the in the Institution
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`Decision. (See generally Paper No. 9, pp. 13-18; see also Paper 2, Petition, pp. 28-
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`60). Specifically, a POSITA: (1) would have known that the phospholipids and its
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`attendant phosphatidylcholine and ether phosphatidylcholine sub-components, as
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`well as triglycerides, were naturally present in krill, and could be readily extracted
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`within predictable and known ranges; (2) would have known that conventional
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`extraction techniques (e.g., process conditions and solvent systems) could be
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`modified to achieve readily predictable changes in the composition of the resulting
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`krill oil; and (3) would have been motivated to encapsulate an effective amount of
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`a krill oil containing “greater than about” 3% ether phospholipids because of the
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`known health benefits linked to phospholipids and associated omega-3 fatty acids.
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`Accordingly, a POSITA would have possessed a reasonable expectation of
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`obtaining krill oil compositions as recited in the challenged claims.
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`II. CLAIMS 1-48 WOULD HAVE BEEN OBVIOUS
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`U.S. Patent No. 9,320,765
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`A. Claims 1-4, 7, 9-11, 14, 18-20, 24-28, 31, 33-35, 38, 42-44 and 47
`Would Have Been Obvious In View of Sampalis I, Catchpole,
`Fricke and Breivik II
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`1.
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`A POSITA Would Have Combined The Conventional
`Extraction Processes of The Cited References And Obtained
`The Claimed Krill Oil Compositions
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`For purposes of this motion, Patent Owner categorized the conventional
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`extraction processes disclosed in Catchpole (Exhibit 1009), Fricke (Exhibit 1010)
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`and Breivik II (Exhibit 1037) as either “selective” or “non-selective.” (POR, pp.
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`17-18). Although there is no basis for this artificial and post-hoc distinction,
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`Patent Owner nevertheless urges, “a POSITA would not combine references using
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`selective extraction techniques such as Catchpole and Breivik II with a reference
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`using a non-selective extraction technique such as Fricke 1984 to arrive at a krill
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`oil with a specific, defined lipid profile as claimed. . . . The components in lipid
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`extracts obtained by such selective and non-selective techniques would be different
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`and are not interchangeable to provide a single identified oil.” (POR, p. 22)
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`(emphasis, italics in original). Patent Owner’s attempt to create an artificial
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`distinction between purported “selective” extraction processes utilizing
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`supercritical CO2 and ethanol, as taught and disclosed by Catchpole and Breivik II,
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`and “non-selective” extraction processes, as described in Fricke, cannot withstand
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`scrutiny, and fails to support the argument that the challenged claims are not
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`obvious.1
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`As an initial matter, the majority of Patent Owner’s argument regarding the
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`combinability of its self-styled “selective” and “non-selective” extraction processes
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`is unsubstantiated attorney argument. (POR, pp. 14-21). While Patent Owner
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`purportedly relies on the “testimony” of Dr. Hoem to support this argument, a
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`review of Dr. Hoem’s Declaration reveals that it is essentially a verbatim recitation
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`of the arguments appearing in Patent Owner’s response. (Compare POR, pp. 14-
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`15, 17-20, 21 with Hoem Declaration (Exhibit 2001), ¶¶48,49-51,54). Thus, Dr.
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`1 Notably, in proceedings involving related U.S. Patent Nos. 9,078,905 and
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`9,028,877 (Exhibit 1103 (IPR 2017-00745), Final Written Decision, Paper 24;
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`Exhibit 1104 (IPR 2017-00746), Final Written Decision, Paper 23), which also
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`relied, in part, upon Catchpole, Fricke and Breivik II, Patent Owner never once
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`argued that a POSITA would not have combined these references because they
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`disclosed so-called “selective” and “non-selective” extraction processes.
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`Hoem fails to provide adequate objective support for the statements in his
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`U.S. Patent No. 9,320,765
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`declaration, and his “testimony” lacks probative value. See 37 C.F.R. § 42.65(a).
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`Turning to the substance of Patent Owner’s argument, Patent Owner posits
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`that “it was far from predictable or easy to extract complex lipids, including
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`phospholipids, from a source material,” pointing to the testimony of Petitioner’s
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`expert, Dr. Tallon. (POR, p. 15). That testimony, however, is tethered to a
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`question about a PCT application entitled “Extraction of Highly Unsaturated
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`Lipids With Liquid Dimethyl Ether,” the application’s broad definition of the
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`phrase “complex lipids,” and the application’s statement that “it is difficult to find
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`a solvent or solvent mixture in which the majority of phospholipids . . . can be
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`extracted.” (Exhibit 2019, pp. 82-85) (emphasis added). Citation to this question
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`and answer from Dr. Tallon’s deposition fails to advance Patent Owner’s tenuous
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`position regarding the obviousness of the challenged patent claims. (Tallon
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`Reply/Opposition (Exhibit 1086), ¶¶176-179).
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`In an baseless attempt to lend credence to the fabricated distinction between
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`so-called “selective” and “non-selective” extraction processes, Patent Owner tries
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`to create the false premise that a “POSITA would understand that the polar
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`extraction method used in Catchpole will selectively extract components that are
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`different than the combination of polar and non-polar solvents used in Fricke is
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`intended for non-selective extraction of all classes of lipids.” (POR, p. 17).
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`However, this is not the foundation upon which the unpatentability of the
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`challenged claims is grounded.
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`Instead, the issue, which Patent Owner strenuously avoids, is whether the
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`broad ranges of phospholipids and triglycerides recited in the challenged claims
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`would have been obvious to a POSITA in view of references disclosing well-
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`known, conventional extraction processes. The answer to this inquiry is a
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`resounding yes. Based on the teachings of Catchpole in view of Fricke, it clearly
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`would have been well within the ability of a POSITA to obtain a krill oil
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`composition having “greater than about” 3% ether phospholipids, from about 30%
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`to 60% phospholipids and from about 20% to 50% triglycerides and greater than
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`100 mg/kg astaxanthin esters as recited in the claims. (Tallon Reply/Opposition
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`(Exhibit 1086), ¶¶49&25-50). (See Tallon Decl. (Exhibit 1006), ¶¶282-283,287).
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`In an inept effort to bolster the argument that so-called “selective” and “non-
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`selective” processes would not have been combined, Patent Owner attempts to blur
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`the line between patent claims that recite a specific process and those directed to a
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`particular composition. Specifically, Patent Owner asserts that “selective” and
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`“non-selective” processes would not be combined “to arrive at a krill oil with a
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`specific, defined lipid profile as claimed [and] to provide a single defined oil.”
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`(POR, p. 22).
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`Contrary to the inference Patent Owner seeks to draw, the ‘765 patent:
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`• does not claim a unique krill oil extraction process;
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`• does not claim a product-by-process claim to obtain a specific krill oil
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`composition; and
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`• does not claim a single novel krill oil composition.
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`Instead, the challenged claims recite an almost limitless number of
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`compositions having broad ranges of components naturally present in krill (e.g.,
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`“greater than about 3%” ether phospholipids, 27-50% non-ether phospholipids, 20-
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`50% triglycerides and greater than about 100 mg/kg of astaxanthin esters) that,
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`based upon the teachings in the art, would be well within the purview of a
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`POSITA. (Tallon Reply/Opposition (Exhibit 1086), ¶¶14-24,49).
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`Patent Owner’s gratuitous statement that “[d]ifferent solvents and different
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`extraction schemes applied to krill will produce krill lipid extracts with different
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`lipid profiles” is both unremarkable and inapplicable. (POR, p. 18). All extraction
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`processes and corresponding solvent systems are selective in certain respects. As
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`such, it was known in the art that conventional extraction processes employing
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`different process conditions and solvent systems could be predictably modified to
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`produce krill oil compositions having different percentages of, inter alia, ether
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`phospholipids, non-ether phospholipids, triglycerides and astaxanthin esters.
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`(Tallon Reply/Opposition (Exhibit 1086), ¶¶17-24,50,176-179,221).
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`Patent Owner tries salvage its obviousness position by erroneously asserting
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`that “the extraction technique described in [Catchpole] results in selective
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`extraction of phospholipids after first removing neutral lipids (which include
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`triglycerides) in the first step [and] [t]here is no disclosure in the [sic] Catchpole of
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`the composition of the ‘other compounds’ in Extract 2 of Catchpole and certainly
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`no disclosure of the triglyceride content of the that Extract 2.” (POR, p. 20).
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`However, Patent Owner’s suggestion that the initial extraction in the Example 18
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`process would have removed all triglycerides lacks foundation and is wrong.
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`(Tallon Reply/Opposition (Exhibit 1086), ¶¶37,25-46).
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`Example 18 of Catchpole uses an initial CO2 extraction process (e.g., 300
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`bar at 40ºC) to remove a neutral lipid fraction. However, a POSITA would have
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`known that triglycerides would not have been completely removed under these
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`process conditions. (Tallon Reply/Opposition (Exhibit 1086), ¶¶25-46; see also
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`Hoem Dep. (Exhibit 1110), 73:18-24; 69:12-71:5; and Exhibit 1080, pp.0009-
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`U.S. Patent No. 9,320,765
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`0011). After the initial extraction, a subsequent CO2-ethanol extraction was
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`performed and the resulting Extract 2 had 53.7% “other compounds.”
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`Based upon the teachings of, inter alia, Tanaka, a POSITA would have
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`recognized that a subsequent extraction using CO2 and ethanol would produce an
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`extract that included triglycerides not removed during the initial extraction.2 A
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`POSITA would have also understood that in addition to astaxanthin esters, the
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`“other compounds” in Extract 2 included a significant triglyceride fraction (e.g.,
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`approximately 30%).3 (See Tallon Decl. (Exhibit 1006), ¶46 (extract 2 “32-37%
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`2 Tanaka is cited in the Background of the Invention of the ‘765 patent (Exhibit
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`1001, 1:65-2:2), and discloses that treating krill with CO2-ethanol results in a
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`fraction rich in triglycerides (i.e., more than 75%). (Exhibit 1015, p. 0004).
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`3 Breivik II, which Patent Owner seeks to pigeonhole as “selective,” expressly
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`discloses that a CO2 and ethanol extraction process, similar to the one described in
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`Catchpole’s Example 18, resulted in a krill extract having “phospholipids,
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`triglycerides and astaxanthin.” (See e.g., Exhibit 1037, p. 0007, line 31 - p. 0008,
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`line 3; p. 0008, lines 11-21; p. 0008, lines 21-33; p. 0009, lines 5-11).
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`triglycerides”)). As a result, a POSITA would have known that Extract 2
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`U.S. Patent No. 9,320,765
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`contained greater than 20% triglycerides. (Tallon Reply/Opposition (Exhibit
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`1086), ¶¶25-50).
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`Contrary to Patent Owner’s arguments, phospholipids and triglycerides are
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`not difficult to extract from krill, and the methods to do so were well known at the
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`time of the earliest effective filing date of the ‘765 patent. (Tallon
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`Reply/Opposition, ¶¶178-179). At bottom, a POSITA would have appreciated that
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`a lipid composition, including phospholipids and triglycerides, could be readily
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`extracted in ratios that approximate the concentrations in the starting krill material.
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`(Tallon Reply/Opposition, ¶¶221,14-17). (See Tallon Decl. (Exhibit 1006), ¶286).
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`Petitioner has not only demonstrated by a preponderance of evidence there
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`would have been a reasonable expectation that a POSITA would arrive at a krill oil
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`composition having the claimed ranges of phospholipids, ether phospholipids,
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`triglycerides and astaxanthin esters; Petitioner has also shown why those claimed
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`ranges would have been desirable and, therefore, why a POSITA would have been
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`motivated to combine the elements disclosed in the prior art references set forth in
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`Ground 1. (See, e.g., Petition, pp. 42-46, 55, 59-60; Tallon Decl. (Exhibit 1006),
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`¶¶50-54, 280-287,302). See Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355, 1361
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`(Fed. Cir. 2016) (affirming courts should “consider common sense, common
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`wisdom, and common knowledge in analyzing obviousness”).
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`Catchpole describes a host of health benefits associated with the
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`administration of phospholipids, including ether phospholipid compositions
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`extracted from krill. In particular, Catchpole discloses a process to produce krill
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`oil that contains desirable levels of particular phospholipids, and explains that
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`phospholipids are associated with a number of health benefits. (Petition, p. 30).
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`(Tallon Decl. (Exhibit 1006), ¶¶137-140).
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`Similarly, Breivik II discloses processing freshly captured krill and
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`extracting the krill using CO2 and ethanol. (Petition, pp. 34-35). (Tallon Decl.,
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`¶¶119-122,124-128). Breivik II also discloses the health benefits of marine
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`phospholipids and that the omega-3 fatty acid bound to the marine phospholipids
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`have particularly useful properties. (See Exhibit 1037, p. 0005, lines 20-30).
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`(Tallon Decl. (Exhibit 1006), ¶¶116,135).
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`It is not disputed that Fricke (Exhibit 1010) disclosed that an extract with 20-
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`50% triglycerides could be obtained from krill using a conventional extraction
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`process. (Petition, pp. 32-33). (Tallon Decl., ¶¶167-168,281,283). Additionally,
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`Sampalis I discloses that krill oil phospholipids have a superior lipid profile, the
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`highest quantities of DHA, and are the only phospholipids that contain a
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`combination of EPA and DHA on the same molecule. (Exhibit 1012, p. 0008).
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`(Tallon Decl., ¶¶201-202). It was also well known in the art that this unique
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`association between the phospholipids and long chain omega-3 fatty acids increase
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`bioavailability and are beneficial, particularly in connection with cardiovascular
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`disease. (Petition pp. 42-46). (Tallon Decl., ¶¶246-247). Moreover, astaxanthin
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`was recognized as a well-known antioxidant, and it was known that Neptune’s
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`NKO krill oil product was “rich in phospholipids and triglycerides.” (Sampalis I
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`(Exhibit 1012), p. 0004). It was also well known that an encapsulated dosage form
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`of krill oil could be safely administered as evidenced by the commercial Neptune
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`krill oil product. (See Exhibit 1012, 1070). (Tallon Decl. (Exhibit 1006), ¶205).
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`In sum, the ranges recited in the claims of the ‘765 patent would have been
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`easily obtainable by known conventional extraction processes available to a
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`POSITA, and that a POSITA would have been motivated to do so. (Tallon
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`Reply/Opposition (Exhibit 1086), ¶¶14-50,221-222). (Tallon Decl., ¶¶50-54,286-
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`287,302). See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 418 (2007) (an
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`obviousness analysis “need not seek out precise teachings directed to the specific
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`subject matter of the challenged claim, for a court can take account of the
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`inferences and creative steps that a person of ordinary skill in the art would
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`employ”).
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`2.
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`Patent Owner’s Argument That PAF Concerns
`Taught Away From Encapsulating Krill Oil
`Having The Ether Phospholipids Content Recited
`In The Challenged Claims Is Unavailing
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`In an attempt to fend-off the obviousness of the challenged claims, Patent
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`Owner urges that a POSITA “would have been directed away from using krill oil
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`with the claimed levels of ether phospholipids” because “the prior art taught that
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`dietary ether lipids such as those found in krill could . . . be converted . . . to
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`potent inflammatory Platelet Activating Factor (PAF).” (POR, p. 23).
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`Notwithstanding the fact that the Board previously rejected this identical
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`argument, this argument is still not supported by any of the references relied on by
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`Patent Owner. Additionally, Patent Owner’s PAF argument is refuted by “real
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`world” evidence demonstrating that there were no “PAF concerns” associated
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`with commercial krill oil products. Finally, Patent Owner’s contrived PAF
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`argument is contrary to representations made by Patent Owner to the U.S. Food
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`and Drug Administration (“FDA”). Patent Owner’s PAF argument should be
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`given short shrift. (Tallon Reply/Opposition (Exhibit 1086), ¶¶124-175).
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`First, in proffering its PAF argument, Patent Owner again purports to rely
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`upon the “testimony” Dr. Hoem. However, a review of Dr. Hoem’s Declaration
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`shows that the majority, if not all, of the statements in Dr. Hoem’s Declaration
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`substantially mirrors Patent Owner’s PAF argument. (Compare POR, pp. 22-29
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`with Exhibit 2001, ¶¶55-63). As Dr. Hoem’s “testimony” is nothing more than his
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`haec verba affirmation of the PAF argument appearing in Patent Owner’s
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`Response, Dr. Hoem’s Declaration lacks probative value. See 37 C.F.R. §
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`42.65(a).
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`Additionally, Patent Owner’s PAF argument is identical to the argument
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`rejected by the Board in proceedings involving related U.S. Patent Nos. 9,078,905
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`and 9,028,877. Exhibit 1103 (IPR 2017-00745), Final Written Decision, Paper 24,
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`pp. 30-37; Exhibit 1104 (IPR 2017-00746), Final Written Decision Paper 23, pp.
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`54-61. Patent Owner’s repackaged PAF argument, relying, in part, upon the same
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`four references previously considered by the Board (Prescott (Exhibit 2003),
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`Zimmerman (Exhibit 2004), Calder (Exhibit 2005) and Tanaka I (Exhibit 1014))
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`has not improved over time and still lacks merit.
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`Turning to the substance of Patent Owner’s argument, it cannot legitimately
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`be disputed that krill ether phospholipids are chemically distinct from PAF
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`analogs, or that the prior art demonstrates that the krill ether phospholipids are not
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`the same compounds as PAF or PAF-like lipids. (Tallon Reply/Opposition
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`(Exhibit 1086), ¶¶51-92). For example, PAF is a phospholipid having an acyl
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`component that is an acyl group (an ethyl group having a single carbon atom
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`bonded through a carbonyl). In contrast, ether phospholipids in krill and krill oil,
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`and as recited in the ‘765 patent, possess acyl chains ranging from 14-25 carbon
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`atoms, and as result do not exhibit PAF signaling activity. (Tallon
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`Reply/Opposition, ¶¶62,55-61). Specifically, Table 23 of the ‘765 patent reports
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`that acyl groups in krill oil AAPC range in length from 14 to 24 carbon atoms.
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`(Tallon Reply/Opposition (Exhibit 1086), ¶60). Yet, PAF activity only exists if the
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`acyl group is significantly shorter, in the range 1-4 carbon atoms. See Prescott
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`(Exhibit 2003), p. 13). Tallon Reply/Opposition, ¶¶76,72,78,80,82, Exhibit 1086).
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`In fact, Prescott teaches that ether phospholipids having longer acyl groups, such
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`as those present in krill and krill oil, would not exhibit PAF activity. (Exhibit
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`2008, p. 13).
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`In addition, it was known that PAF-like lipids have lower activity than PAF
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`itself because they are only mimicking the functionality of PAF, and every
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`deviation from the true PAF molecule rapidly decreases the activity. Beyond a
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`Inter Partes Review Case No.: IPR2018-00295
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`small deviation, PAF-like activity ceases completely. (Tallon Reply/Opposition,
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`U.S. Patent No. 9,320,765
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`¶80). As a result, the Board concluded:
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`[T]he ether phospholipids of Catchpole are not
`the same compounds as PAF or PAF-like lipids. . . .
`***
`PAF and the PAF-like compounds . . .
`are structurally and functionally distinct from the
`ether phospholipids present in Catchpole’s krill
`extract which do not exhibit PAF-like behavior. . . .
`PAF-like activity typically exists only where the acyl
`group of the phospholipid is in the range of 1-4
`carbon atoms.
`(Exhibit 1103, pp. 33-34) (emphasis added).
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`Further, the references cited by Patent Owner fail to draw any nexus
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`between the dietary intake of krill ether phospholipids and the production of PAF
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`or PAF-like lipids. (Tallon Reply/Opposition (Exhibit 1086), ¶67). For example,
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`Tanaka I simply “investigated the PAF-like lipids formed during peroxidation of
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`PCs from hen egg yolk, salmon roe, sea urchin eggs, and krill in an [in vitro]
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`FeS04/EDTA/ascorbate system” and concludes, “the occurrence of PAF-like lipids
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`in some stored foods is still speculative and requires further investigation.”
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`(Exhibit 1014, p. 0001, 0005). (Tallon Reply/Opposition, ¶65). Revealingly,
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`U.S. Patent No. 9,320,765
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`Patent Owner’s declarant, Dr. Hoem could not recall having seen any indication in
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`the prior art that ether phospholipids can be degraded into PAF-like molecules
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`once ingested. (See Exhibit 1090, 35:4-9). In fact, if there were actual concerns
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`about PAF, it is indeed curious that the ‘765 patent proclaims that the recited krill
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`oil compositions reduced inflammation (e.g., Exhibit 1001, 16:24-28), but fails to
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`suggest that this was unexpected in view of those alleged concerns. Based upon
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`the evidence presented, the Board found:
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`At best, Prescott, Tanaka, and Zimmerman, three
`“teaching away” references relied upon by Patent Owner,
`simply suggest the possible formation of peroxidation
`products from dietary ether phospholipids under artificial
`conditions, and disclose that certain of those artificially
`generated products are similar enough to PAF to trigger
`the same inflammatory effects. Critically, however,
`none of these references draws a link between the
`artificial oxidation of natural ether phospholipids
`present in krill, and the in vivo signaling behavior of
`krill ether phospholipids.
`(Exhibit 1103, pp. 34-35) (emphasis added).
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`Finally, “real world” evidence demonstrates that there were no concerns
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`relating to the level of phospholipids and, in particular, ether phospholipids present
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`in krill oil products sold prior to the earliest effective filing date of the ‘765 patent.
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`(Tallon Reply/Opposition (Exhibit 1086), ¶¶8,98,93-116,130-136). For example,
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`Dr. Hoem testified that the ether phospholipid levels in Neptune’s commercial krill
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`oil product (“NKO”) were “high” and “substantial,” and would have raised PAF
`
`concerns. (Exhibit 1090, 58:10-20; 54:16-55:10). Yet, there were no reported
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`PAF concerns associated with Neptune’s NKO.4 As the Board observed:
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`[T]he commercial realities at the time of
`invention of the [‘765] patent do not support Patent
`Owner’s contention that an ordinarily skilled artisan
`would have sought to avoid using krill oil extracts
`having “high” ether phospholipid levels as a dietary
`supplement. . . . Notably, Dr. Hoem also testified that
`commercially available NKO, which was on sale prior
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`4 There is no statement or suggestion in Neptune’s GRAS (Generally Recognized
`
`As Safe) Notice to the FDA (Exhibit 1075) that there were any PAF concerns
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`associated with Neptune’s krill oil product. (See McQuate Decl. (Exhibit 1044),
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`¶¶13,64-72).
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`to the invention of the [‘765] patent (Ex. 1090, 61:9-
`12). . . . had a “substantial or high” level of ether
`phospholipids. . . . Nevertheless, the record is devoid
`of evidence suggesting any concern relating to
`potential harm from the ether phospholipids present
`in NKO, or any other commercially available prior
`art krill oil extract. To the contrary, the evidence of
`record demonstrates that NKO was generally
`recognized as safe.
`(Exhibit 1103, pp. 36-37) (emphasis added).
`
`In addition to the same four references relied upon previously, Patent Owner
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`now also points to four new publications in an attempt to revive its failed PAF
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`“teaching away” argument. However, these new publications, in combination with
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`its prior unavailing arguments and references, are insufficient to disturb the
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`Board’s prior conclusions regarding krill ether phospholipids and the absence of
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`PAF concerns. For example, the study referenced in Blank (Exhibit 2009) relates
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`to dietary diacylphospholipids, not krill ether phospholipids. Further, Blank was
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`unable to draw any conclusion regarding the formation of PAF:
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`Whether and to what extent these levels of dietary
`ether lipids would affect the production of, and
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`subsequent biological responses induced by PAF, in
`humans are presently unknown.
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`(Exhibit 2009, pp. 5-6). (Tallon Reply/Opposition (Exhibit 1086), ¶¶84-87).
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`Additionally, Zierenberg (Exhibit 2008) relates to diacylphosphatidylacholine
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`which is not even an ether phospholipid. (Tallon Reply/Opposition, ¶83). Further,
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`Hartvigsen (Exhibit 2010) describes only the peroxidation of diacylglycerol ethers
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`(“DAGE”) which is also not an ether phospholipid. (Tallon Reply/Opposition
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`(Exhibit 1086), ¶¶88-92). Finally, Marathe is focused on short-chained alkyl
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`phosphatidylcholines in oxidized low density lipoproteins (LDP) and in particular
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`short-chained C4 analogs and homologs. (Exhibit 1094, pp. 0001, 0007). Instead
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`of supporting Patent Owner’s argument, Marathe shows why the ether
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`phospholipids in krill oil extracts would not act like PAF molecules: “The PAF
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`receptor shows a several hundredfold selectively for the sn-1 ether bond of PAF,
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`and complete specificity for the sn-2 acetyl residue compared with the long
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`chain fatty acyl residue of most alkyl phosphatidylcholines.” (Exhibit 1094, p.
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`0001) (emphasis added). (Tallon Reply/Opposition, ¶¶56,55-70).5
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`5 Blank, Zierenberg and Marathe are each dated well before two references (i.e.,
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`Underscoring the specious nature of Patent Owner’s PAF argument is its
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`representations to the FDA. In particular, Patent Owner (“Aker”) submitted a
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`GRAS Notice for a “high phospholipid krill oil,” yet never informed the FDA that
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`there were any concerns or issues regarding the ingestion of krill oil products and
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`PAF. (See Exhibit 1089). (McQuate Decl. (Exhibit 1044), ¶¶14-15,81-83,87-95).
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`In fact, Aker’s GRAS Notice expressly relied on Sampalis I’s administration of
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`Neptune’s NKO product to argue that its high phospholipid krill oil product was
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`safe, and even pointed out that Sampalis I “suggest[s] that krill oil soft gels were
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`well tolerated.” (Exhibit 1089, p. 0019). (See Exhibit 1090, 52:10-16).6 Aker’s
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`Sampalis I (Exhibit 1012) and Bunea (Exhibit 1020)) that Patent Owner relies
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`upon as evidence of the safety of “high phospholipid krill oil” in its GRAS Notice.
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`(Exhibit 1089, pp. 0019-0020).
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`6 Had either Patent Owner or Neptune been aware of any PAF concerns associated
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`with krill oil extracts, those concerns needed to raised and addressed in their
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`respective GRAS Notices. (See McQuate Decl. (Exhibit 1044), ¶¶13-14,71-72, 81,
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`83,87-91).
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`GRAS also relied upon another NKO study, Bunea (Exhibit 1020), and concluded
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`U.S. Patent No. 9,320,765
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`“[n]o adverse effects were noted.” (Exhibit 1089, p. 0020).
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`As part of its Notice, Aker also represented to the FDA:
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`A comprehensive search of the scientific
`databases for safety and toxicity i
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