Trials@uspto.gov
`571-272-7822
`
`.
`
`Paper No. 23
`Entered: August 10, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`RIMFROSTAS,
`Petitioner,
`
`V.
`
`AKER BIOMARINE ANTARCTIC AS,
`Patent Owner.
`
`Case IPR2017-00748
`Patent 9,028,877 B2
`
`Before ERICA A. FRANKLIN, TINA E. HULSE,and
`JACQUELINE T. HARLOW,Administrative Patent Judges.
`
`HARLOW,Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Determining That Claims 1-19 Have Not Been Shown to Be Unpatentable
`35 U S.C. §318(a) and 37 CER. $42.73
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`I.
`
`INTRODUCTION
`
`Rimfrost AS (“Petitioner”) filed a Petition requesting an interpartes
`
`review of claims 1-19 of U.S. Patent No. 9,028,877 B2 (Ex. 1001, “the
`
`’877 patent”). Paper 2 (“Pet.”). Aker Biomarine Antarctic AS (“Patent
`
`Owner’’) declinedto file a Preliminary Response.
`
`On August 16, 2017, we instituted an interpartes review of all
`
`challenged claims onall grounds asserted. Paper 8. On November8, 2017,
`
`Patent Ownerfiled a Patent Owner Responseto the Petition. Paper 13 (“PO
`
`Resp.”). On January 24, 2018, Petitionerfiled a Reply to the Patent Owner
`
`Response. Paper 16 (“Reply”).
`
`Weissuethis Final Written Decision pursuantto 35 U.S.C. § 318(a)
`
`and 37 C.F.R. § 42.73. Having considered the record before us, we
`
`determine that Petitioner has not shownby a preponderanceofthe evidence
`
`that claims 1-19 of the ’877 patent are unpatentable. See 35 U.S.C.
`
`§ 316(e).
`
`A. Related Matters
`
`The ’877 patent is asserted in Aker Biomarine Antarctic AS v. Olympic
`
`Holding AS, Case No. 1:16-CV-00035-LPS-CJB(D. Del.). Pet.2; Paper 7,
`
`2-3. In addition, Petitioner has challenged, and we haveinstituted inter
`
`partes review ofthe claims of the ’877 patent in IPR2017-00746. Paper 5,
`
`2.
`
`Petitioner also challenges U.S. Patent No. 9,078,905 B2 (“the
`
`°905 patent”) in IPR2017-00745 and IPR2017-00747. Pet. 3. Both the
`
`’877 patent and the ’905 patent are continuations of U.S. Patent Application
`
`2
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`No. 12/057,775, filed March 28, 2008.
`
`Theparties have not identified any further, currently pending, related
`
`proceedings concerning the ’877 patent.!
`
`B. The ’877 Patent
`
`The ’877 patent,titled “Bioeffective Krill Oil Compositions,” issued
`May 12, 2015, with Inge Bruheim,Snorre Tilseth, and Daniele Mancinelli as
`
`the listed co-inventors. Ex. 1001, [54], [45], [72].
`
`The ’877 patent describes extracts from Antarctic krill, small
`
`shrimp-like animals, that include bioactive fatty acids. Ex. 1001, 1:19-20.
`
`In particular, the 877 patentdiscloses krill oil compositions having “high
`
`levels of astaxanthin, phospholipids, includ[ing] enriched quantities of ether
`
`phospholipids, and omega-3 fatty acids.” Jd. at 9:28-31.
`
`The ’877 patent states that myriad health benefits have been attributed
`
`to krill oil in the prior art. For example, the ’877 patentstates that “[k]rill oil
`
`compositions have been described as being effective for decreasing
`
`cholesterol, inhibiting platelet adhesion, inhibiting artery plaque formation,
`
`preventing hypertension, controlling arthritis symptoms, preventing skin
`
`cancer, enhancing transdermaltransport, reducing the symptomsof
`
`premenstrual symptomsorcontrolling blood glucoselevels in a patient.”
`
`Ex. 1001, 1:46—-52. In addition, the ’877 patent recognizesthat krill oil
`
`' The ’877 patent was also asserted in Jn the Matter ofCertain Krill Oil
`Products and Krill Mealfor Production ofKrill Oil Products, Investigation
`No. 337-TA-1019 (USITC)(Pet. 2—3; Paper 3, 1); however, Petitionerstates
`that the investigation has been “effectively terminated.” Paper 21, 3.
`3
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`compositions, including compositions having up to 60% w/w phospholipid
`
`content and as much as 35% w/w EPA/DHAcontent, were knownin theart
`
`prior to the time of invention. Jd. at 1:52-57. The ’877 patent also indicates
`
`that supercritical fluid extraction with solvent modifier was knownto be a
`
`useful method for extracting marine phospholipids from salmon roe. Id. at
`
`1:65-67.
`
`According to the 877 patent, however, the solvent extraction methods
`
`used in thepriorart to isolate krill oil from the krill “rely on the processing
`
`of frozen krill that are transported from the Southern Oceanto the
`
`processingsite,” which transportation is expensive and may result in the
`
`degradation ofthe krill starting material. Jd. at 2:3-6. Such methods have
`
`included stepsofplacing the material into a ketone solvent, such as acetone,
`
`to extract the lipid soluble fraction, and recovering the soluble lipid fraction
`
`from the solid contents using a solvent such as ethanol. Jd. at 1:32—40.
`
`To overcomethe abovelimitations, the ’877 patent discloses
`
`“methodsfor processing freshly caughtkrill at the site of capture and
`
`preferably on boardaship.” /d. at 10:18-20. The ’877 patent explains that
`
`the krill may befirst subject to a protein denaturation step, such as a heating
`
`step, to avoid the formation of enzymatically decomposedoil constituents.
`Id, at 9:43-50; 10:26-31. Subsequently, the “oil can be extracted by an
`
`optional selection of nonpolar and polar solvents including use of
`
`supercritical carbon dioxide.” Jd. at 9:51-54.
`
`In Example 7 of the ’877 patent, “[k]rill lipids were extracted from
`
`krill meal (a food grade powder) using supercritical fluid extraction with
`
`co-solvent.” Jd. at 31:15—16.
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`Initially, 5%_ethanol300 bar pressure, 333°K and
`
`
`
`
`
`(ethanol:CO2, w/w) were utilized for 60 minutes in order to
`removeneutrallipids and astaxanthin from the krill meal. Next,
`the ethanol content was increased to 23% and the extraction was
`maintained for 3 hours and 40 minutes. The extract was then
`evaporated using a falling film evaporator and the resulting krill
`oil wasfinally filtered.
`
`Id. at 31:17-23.
`
`Example 8 of the ’877 patent preparedkrill oil using the same method
`
`described in Example 7, from the samekrill meal usedin that example.
`
`Ex. 1001, 31:46-47. The krill oil was then analyzed using ?}P NMR
`
`analysis to identify and quantify the phospholipids in the oi. Jd. at 31:47—
`
`49. Table 22? showsthe phospholipid profiles for the raw material, the final
`
`product, and a commercially availablekrill oil, Neptune Krill Oil (““NKO”).
`
`Id. at 32:6-9. Table 22 is reproduced below:
`
`2 Weview reference in the ’877 patent to “table 25” (Ex. 1001, 32:6—9) to be
`an inadvertent typographicalerror, as the specification does not include a
`table 25. We understand Example 8 ofthe specification to refer, instead, to
`Table 22, which sets forth the described phospholipid profiles.
`5
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`TABLE22
`
`Phespholipid profiles
`
`Type B krill
`powder
`
`NKO
`
`Krill Oil obtained in Example 7
`
`PC
`AAPC
`Pi
`1LPC
`PS
`2LPC
`LAAPC
`PE
`AAPE
`SM
`Gre
`DHSM
`NAPE
`CL
`LPE
`LCL
`% PL in
`powderor
`lipid sample
`
`66.0
`12.0
`
`1.2
`
`74
`2.2
`6.0
`
`5.3
`
`83
`
`68.6
`1.0
`
`1.3
`
`13.8
`1.2
`3.4
`
`43
`
`3.4
`
`30.0
`
`75.3
`13.0
`
`0.4
`
`29
`0.9
`3.4
`LS
`
`2.1
`0.5
`
`47.9
`
`Id. at 32:15-39.
`
`The ’877 patent teachesthat the “main polar ether lipids of the krill
`
`mealare alkylacylphosphatidylcholine (AAPC) at 7—9% oftotal polarlipids,
`
`lyso-alkylacylphosphatidylcholine (LAAPC)at 1% oftotal polar lipids
`
`(TPL) and alkylacylphosphatidyl-ethanolamine (AAPE)at <1% of TPL.”
`
`Id. at 32:9-14.
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`C. Illustrative Claim
`
`Ofthe challenged claims, claims 1 and 11 are independent. Claim 1,
`
`reproduced below,is illustrative of the claimed subject matter.
`
`1.
`
`A method of production of krill oil comprising:
`
`a) providing krill;
`to denature lipases and
`b) treating said krill
`phospholipases in said krill to provide a denatured krill
`product; and
`c) extracting oil from said denaturedkrill product
`with a polar solvent to provide a krill oil with from about
`3% to about 10% w/w ether phospholipids; from about
`27% to 50% w/w non-ether phospholipids so that the
`amountoftotal phospholipidsin said krill oil is about 30%
`to 60% w/w; and from about 20% to 50% w/w
`triglycerides, wherein said steps a and b are performed on
`a ship.
`Ex. 1001, 34—59-35:2. Claim 11 requiresthat the krill oil produced by the
`
`method recited includes amounts ofphospholipid components and
`
`triglycerides within the same ranges as claim 1. Id. at 35:23-36:7.
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`D. Prior Art Relied Upon
`
`Petitioner relies uponthe following asprior art references (Pet. 8):
`
`Randolph
`
`US 2005/0058728 Al
`
`Mar.17,2005
`
`(Ex. 1011)
`
`Sampalis
`
`WO 03/011873 A2
`
`Feb. 13,1003
`
` (“Sampalis II”)
`(Ex. 1013)
`
`Bottino, The Fatty Acids ofAntarctic Phytoplankton and Euphausiids. Fatty
`Acid Exchange AmongTrophic Levels ofthe Ross Sea, 27 MARINE BIOLOGY,
`197-204 (1974) (Ex. 1007).
`
`Fricke et al., Lipid, Sterol andFatty Acid Composition ofAntarctic Krill
`(Euphausia superba Dana), 19(11) LIPIDS 821-827 (1984) (Fricke 1984)
`(Ex. 1010).
`
`Grantham, The Utilization ofKrill, UNDP/FAO Southern OceanFisheries
`Survey Programme (1977) (Ex. 1032).
`
`Sampalis et al., Evaluation ofthe Effects ofNeptune Krill Oil™on the
`ManagementofPremenstrual Syndrome andDysmenorrhea, 8(2) ALT.
`MED. REV. 171-179 (2003) (“Sampalis I”) (Ex. 1012).
`
`Tanakaet al., Platelet-Activating Factor (PAF)-Like Phospholipids Formed
`During Peroxidation ofPhosphatidylcholinesfrom Different Foodstuffs,
`59(8) BIOSCI. BIOTECH. BIOCHEM. 1389-1393 (1995) (“TanakaT’”)
`(Ex. 1014).
`
`Tanakaet al., Extraction ofPhospholipidsfrom Salmon Roe with
`Supercritical Carbon Dioxide and an Entrainer, 53(9) J. Oleo Science 417—
`424 (2004) (“TanakaIT”) (Ex. 1015).
`
`Petitioneralso relies on the Declaration of Stephen J. Tallon, Ph.D.
`
`(Ex. 10U6), and the Reply Declaration ofDr. Tallon (Ex. 1086).
`
`Patent Ownerrelies on the Declaration of Nils Hoem, Ph.D.
`
`(Ex. 2001).
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`E. Instituted Challenges
`
`Weinstituted trial based on each challenge to the patentability of the
`
`°877 patent presentedin the Petition (Pet. 7):
`
`and 18
`
`Claim(s)
`1-3, 8, 9,11, 12, 17,
`4,5, 13, and 14
`6 and 15
`
`a
`
`§ 103(a)
`§ 103(a)
`§ 103(a)
`
`a
`
`a)
`
`Tanaka I
`
`References
`Grantham, Fricke 1984, and
`Grantham,Fricke 1984, Tanakal,
`Grantham, Fricke 1984, TanakaI,
`and TanakaII
`Grantham,Fricke 1984, TanakaI,
`and Sampalis I
`Grantham,Fricke 1984, Tanakal,
`
`7and 16
`10 and 19
`
`§ 103(a)
`§ 103(a)
`
`II. ANALYSIS
`
`A. Level ofOrdinary Skill in the Art
`
`Thelevel of ordinary skill in the art is a factual determinationthat
`
`provides a primary guarantee of objectivity in an obviousnessanalysis. A/-
`
`Site Corp. v. VSI Int’LInc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing
`
`Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966); Ryko Mfg. Co. v. Nu-
`
`Star, Inc., 950 F.2d 714, 718 (Fed. Cir. 1991)).
`
`.
`
`Petitioner asserts that a person of ordinary skill in theart at the time of
`
`the invention of the ’877 patent would have had “an advanced degree in
`
`marine sciences, biochemistry, organic (especially lipid) chemistry,
`
`chemical or process engineering, or associated sciences,” as well as a
`complementary understanding of “organic chemistry andin particularlipid
`chemistry, chemical or process engineering, marine biology, nutrition, or
`
`9
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`associated sciences; and knowledgeofor experiencein thefield of
`
`extraction,” in addition to “at least five years applied experience.” Pet. 6;
`
`Ex. 1006 § 27.
`
`Patent Ownerdoesnot addressthe level of ordinary skill in its
`
`Response; however, Patent Owner’s declarant, Dr. Hoem opinesthat the
`
`definition proposed by Petitioner“is consistent with the literature,
`
`credentials of individuals working on lipid extractions, and the skill
`necessary to perform these extractions andinterprettheir results” Ex. 2001
`4 15. Based on that assessment, Dr. Hoem adoptsthe definition of the level
`
`of ordinary skill in the art advanced by Petitioner. Jd.
`
`Weagree with Petitioner, Dr. Tallon, and Dr. Hoem,andfind that
`
`Petitioner’s description of the level of ordinary skill in the art at the time of
`
`invention of the ’877 patent is consistent with the type of problems
`
`encounteredin theart, prior art solutions to those problems,rapidity with
`
`which innovations are made, sophistication of the technology, and
`
`educational level of active workersin the field. See In re GPAC Inc. , 57
`
`F.3d 1573, 1579 (Fed. Cir. 1995). For purposes ofthis Decision, therefore,
`
`we adopt Petitioner’s description. Wealso note that the applied prior art
`
`reflects the appropriate level ofskill at the time of the claimed invention.
`
`See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`
`In addition, we recognize each of Petitioner’s and Patent Owner’s
`
`declarants as qualified to provide the proffered opinions onthe level of skill
`
`and the knowledge of a person of ordinary skill in the art at the time of the
`
`invention. Therelative weight that we assign such testimony, however,is
`
`subject to additional factors. See, e.g.,37C.F.R. § 42.65(a) (“Expert
`
`10
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`testimonythat does notdisclose the underlying facts or data on which the
`
`opinion is basedis entitled to little or no weight.”); Office Patent Trial
`
`Practice Guide, 77 Fed. Reg. 48,756, 48,763 (Aug. 14, 2012) (same).
`
`B. Claim Construction
`
`In an interpartes review,the Boardinterprets claim terms in an
`
`unexpired patent according to the broadest reasonable construction in light
`
`of the specification of the patent in which they appear. 37 C.F.R.
`
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 1368. Ct. 2131, 2142 (2016)
`
`(affirming applicability of broadest reasonable construction standard to inter
`
`partes review proceedings). Underthat standard, and absent any special
`
`definitions, we give claim termstheir ordinary and customary meaning, as
`
`would be understoodby oneofordinary skill in the art at the time of the
`
`invention, in the context of the entire disclosure. In re Translogic Tech.,
`
`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Only those termsthat are in
`
`controversy need be construed, and only to the extent necessary to resolve
`
`the controversy. Nidec Motor Corp. v. Zhongshan Broad Ocean MotorCo.
`
`Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (citing Vivid Techs., Inc. v. Am.
`
`Sci. & Eng’g, Inc.,200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`Although both Petitioner (Pet. 19-29) and Patent Owner (PO Resp.
`
`11-14) offer several claim constructions, we determinethat no explicit
`
`construction of any claim term is necessary for purposesof this Decision. In
`
`reaching this conclusion, we observethat the parties’ proposed constructions
`
`are largely coextensive with each other, and to the extent those constructions
`
`differ, they do so in waysthat do not impact our analysis. For example, our
`
`1]
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`analysis below remains the sameirrespective of whether we apply
`
`Petitioner’s construction of “krill oil” as meaning “lipids extracted from
`
`krill’ (Pet. 21) or Patent Owner’s interpretation,“oil produced from krill”
`
`(PO Resp. 11). Similarly, our analysis is unaffected by whether we apply
`
`Petitioner’s definition of “to denaturelipases and phospholipases,” i.e., “to
`
`alter the conformationalstructure of lipases and phospholipases to reduce
`
`lipid and phospholipid decomposition”(Pet. 24), or Patent Owner’s
`
`construction,“to treat the lipases and phospholipases to rupture hydrogen
`
`bondsthereby changing the molecular structure ofthe lipases and
`
`phospholipases” (PO Resp. 12—13).?
`
`C. Overview ofthe Prior Art
`
`Petitioner relies on combinations including Grantham,Fricke 1984,
`
`TanakaI, TanakaII, Bottino, Sampalis I, and/or Sampalis II, to support its
`
`contention that claims 1-19 of the ’877 patent would have been obvious.
`
`Pet. 7. Pertinent to our discussion below, Patent Ownerasserts that Fricke
`
`19864 supportsits argumentthat the cited combinationfails to disclose the
`
`3 Patent Ownerexpressly accepts, for purposesofthis proceeding,
`Petitioner’s proposed constructionsof “polar solvent,” “freshly harvested
`krill,” and “polar entrainer,” the remaining terms for which the parties
`propose constructions. PO Resp. 13-14.
`
`“Frickeet al., /-O-Alkylglycerolipids in Antarctic Krill (Euphasia Superba
`Dana), 85B Comp. BIOCHEM. PHYSIOL. 131-134 (“Fricke 1986”)
`(Ex. 2006).
`
`12
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`claimed ranges of ether phospholipid content. PO Resp. 14-16. Weprovide
`
`an overview of each reference.
`
`1. Grantham
`
`Grantham is a report published by the Food and Agriculture
`
`Organization of the United Nations, United Nations Development
`
`Programme,regardingtheutilization ofkrill. Ex. 1032. Grantham teaches
`
`that most commercialcatchesof krill appear to consist mainly of Euphasia
`superba. Id. at3.
`
`According to Grantham:
`
`its
`Although the fat content of krill varies markedly,
`composition would seem to remain fairly constant.
`It is
`characterized by its high content of complex (phospho)lipids
`(50%, mainly lecithins (phosphatidyl-choline) and cephalins
`(phosphatidyl ethanolamine)), about 30-40% neutral
`fats
`(glycerides), and about 8% unsaponifiable elements.... Unlike
`other Antarctic zooplankters, it contains no waxes. Cholesterol
`is the only majorsterol found, although traces of vitamin D and
`appreciable quantities of the pro-vitamin are also present... .
`Most of the commonfatty acids are present, notably oleic, C205,
`palmitic andmyristic. The three ‘essentials’ are found, totalling
`5%. The erucic acid content is low. Several unusual species are
`also evident. The occasional reports of high free fatty acid
`content (high acid value) are probably due to lipolysis during
`frozen storage of samples.
`Id. at 19 (internal citations omitted).
`
`Grantham notesthat once harvested,krill spoil rapidly, particularly
`
`because the liver and stomach contain highly active enzymes,resulting in
`
`autolysis.
`
`/d. at 18. Thus, Grantham teaches,“krill can be held at ambient
`
`temperaturesfor only very limited periods before being preserved by one
`
`13
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`meansor another, and that (apart from any physical damage that may ensue)
`
`it is not practicable to transfer the catch under these conditions from one ship
`
`to another factory vessel.” Jd. at 19. Grantham discloses the following
`
`methodfor processingkrill on a ship (id. at 33):
`
`FreshCovghtKell
`
`
`
`Cvosn Frozen Kull
`
`
` Comminute Microwave
`
`ook
`
`oeSat!|
`Treatment ai 3640
`23
`
`YoNa Cl
`
`
`
`
`
`
`Press or
`Centrifuge
`
`Press coke
`15% Protein
`
`
`
`Separate
`Press,beatMiba
`(43% RM)
`
`
`
`
`
`29-60% RM (52% AM)
`5-10%Sugar
`Juice
`¢.9. Molasses
`17-25%Solids
`Meo!
`
`
`
`(Ferment)
`
`Csist) Aiconat 8-10%RM
`
`Evaporata
`
`Heat Cocgutate
`$0-97°C for 3-15 Mins.
`
`Optioncl
`Process
`
`& Sterilise
`Freeze, Dry,
`
`Broth
`‘a
`—
`18%RM)
`
`ese |
`
`KPC
`
`Sepercie e.g.
`
`90-60%
`
`Flakes
`
`<>
`
`10% (4% RN)
`COCOSSIN
`54
`
`Pock
`
`—m
`Sreihee
`Max (05%
`Protein|Pack|Concentcate
`
`
`Vest
`
`Poste
`20-354 RM (37 YAM}
`
`Grantham discloses that the processing method depicted in the above flow
`
`chart, which producesa krill paste that may be stored at -18° to -20°C for up
`
`to a year, can be performedona freezertrawler or on land. Jd. at 32-33. As
`
`14
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`illustrated in the flow chart, that process includes a cooking(i.e., heating)
`
`step. Id. at 33.
`
`Grantham teachesfurther that most krill products are unstable during
`
`storage, whetherthat storage be by freezing, drying, or sterilization and,
`
`thus, benefit from some method ofstabilization prior to final preservation.
`
`Id. at 36. According to Grantham,heat treatmentis the most commonsuch
`
`method,and “[b]oiling krill and krill products has been shownto.inactivate
`
`the proteolytic, lipolytic and pigment degrading enzymes.” /d. Grantham
`
`teachesthat solvent extraction has been used to removethe fats from the
`
`boiled krill. Jd. at 39.
`
`Grantham additionally teaches:
`
`Krill fat, while difficult to remove by traditional means,
`has been seen to be of unusual composition in several respects.
`The high content ofpoly-unsaturatedfatty acids, the presence of
`unusual fatty acid species,
`the absence of waxes, and the
`composition of the non-glyceride fractions suggest possible
`applications additional
`to the food and industrial outlets
`presently foundfor fish oils. A full assessmentis recommended
`of the possibilities for krill fat in the areas of pharmaceuticals,
`cosmetics, perfumery, dietetics and other specialised fields.
`Id. at 57.
`
`15
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`2. Fricke 1984
`
`Fricke 1984 discloses the “‘lipid classes, fatty acids of total and
`
`individual lipids andsterols of Antarctic krill (Euphausia superba Dana)
`
`from twoareasof the Antarctic Ocean” as determined bythin layer
`
`chromatography,gasliquid chromatography, andgasliquid
`
`chromatography/massspectrometry analyses. Ex. 1010, Abstract.
`
`Accordingto Fricke 1984, krill were collected and were quick frozen, and
`
`lipids were extracted using the method of Folch.° Jd. at1. Fricke 1984
`
`teaches further that samples were also cooked on board “immediately after
`
`hauling,” and were stored under the same condition. Jd. at 2-3.
`
`> Folch et al., A Simple Methodfor the Isolation andPurification ofTotal
`Lipids From Animal Tissues, 266 J. BIOL. CHEM. 497-509 (1957)
`(Ex. 1017).
`
`16
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`Table 1 of Fricke 1984 is reproduced below.
`TABLE }
`
`Lipid Composition of Antarctic Krill
`(Eupheusla superba Dana)
`
`Sample
`
`12/1977
`
`3/1981
`
`Total lipid content
`(% wet weight)
`
`2.74.2
`
`6.2 £ 0.3
`
`Phospholipids
`Phosphatidylcholine
`Phosphatidylethanolamine
`Lysophosphatidyicholine
`Phosphatidylinosito}
`Cardiolipin
`Phosphatidic acid
`
`Triac ylglycerols
`Freo fatty acids?
`Diacylglycerols
`Stesots
`Monoacylglycerols
`
`Others?
`
`Total
`
`45.620.)
`6.1 + 0.4
`1.526.2
`0.920.1
`1040.4
`0.6204 |
`
`33,34 0.5
`$.2£90.5
`2.8£0.4
`1.14 0.4
`16+02
`
`33.340.5
`i161 t13
`1.34 06.4
`L720]
`0.4 + 0.2
`
`40.440.1
`8.5 21.0
`3.640.1
`1.4+0.1
`0.9 20.1
`
`0.920.1
`
`0.5 20.1
`
`98.9
`
`99.3
`
`Table 1 showsthetotallipid content and the lipid composition data for the
`
`two krill samples analyzed by Fricke 1984. Jd. at 2. As indicated in
`
`Table 1, the krill samples respectively included approximately 33.3%
`
`+/- 0.5% w/w and 40.4% +/- 0.1% w/w triacylglycerols. Id.
`
`3. TanakalI
`
`Tanaka I examines the “PAF-like lipids formed during peroxidation of
`
`[phosphatidylcholines (““PCs”)] from hen egg yolk, salmonroe, sea urchin
`
`eggs, and krill in an FeSO4/EDTA/ascorbate system.” Ex. 1004, Abstract.
`
`Tanaka J discloses the PC subclasses, and their relative amounts, present in
`
`Antarctic krill (Euphausia superba) extract. Ex. 1014, 2,3. Tanakal
`
`explains that PC waspurified from crude krill lipid extract using column
`
`chromatography and thin layer chromatography. Jd. at 2. Successive
`
`17
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`degradations of the purified extract using alkaline and acid hydrolysis were
`
`then performed to measure the percentages of PC subclasses in the extract.
`
`Td.
`
`Table 1 of Tanaka I is reproduced below.
`
`Table I. Subclass Composition of PCs from Food Stuffs
`
` PC
`
`Diacyl
`
`Alkylacyl
`
`Alkenylacy!
`
`Hen egg yolk
`Salmon roe
`Sea urchin egg
`Krill
`
`99.24+0.2
`98.8+0.2
`S7.5#1.1
`77.041.2
`
`%
`0.8+0.1
`1.2+0.2
`41,540.3
`23.041.2
`
`<0.1
`<0.1
`1.0408
`<0.1
`
`Values are means +SE for four experiments.
`
`Ex. 1014, Table 1. Table 1 showsthat the ether phospholipid AAPC
`
`accounted for 23.0% +/- 1.2% ofthe total PC presentin Antarctic krill
`
`extract. Jd. at 3.
`
`Tanaka J concludesthat although the study “demonstrated the
`
`formation of P AF-like phospholipids during peroxidation of PCs from
`
`different foodstuffs[,].. . the occurrence ofPAF-like lipids in somestored
`
`foodsis still speculative and requires further investigation.” Ex. 1014, 5.
`
`4. Tanaka II
`
`TanakaIJ describes the extraction of phospholipids from salmon roe
`
`using supercritical carbon dioxide andthe polar entrainer ethanol. Ex. 1015,
`
`Abstract, 1. TanakaII reports the effect of ethanol concentration, extraction
`
`time, and extraction temperature on phospholipid yield. Jd. at Abstract.
`
`TanakaII discloses:
`
`Many researchers have already reported since a pure
`carbon dioxide does not dissolve [phospholipids
`(“PLs”)]
`
`18
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`effectively, extraction of PLs might be achieved bythe addition
`of a polar entrainer to SC-CO:. An entrainer is a substance of
`medium volatility added to a mixture of compressed gas and a
`low volatility substance. As the solubility in SC-CO>at the same
`extracting conditions (temperature and pressure) is drastically
`enhanced, extraction can be conducted at a lower pressure. The
`logical choice for a co-solvent in the food industry would be
`ethanol. The authors used ethanolasthe entrainer to extract PLs
`in SC-COy2because:
`(i) It is suitable for food use; and (1) the
`phase behavior of CO2/ethanol mixes at high pressure is
`available.
`
`Ex. 1015, 3 (internal citations omitted). Tanaka IJ additionally explains that
`
`“Tb]ecause CO?is stable chemically, it does not react with other materials in
`
`treatment. Easy separation and removal of CO2 from the products eliminates
`
`any problem related to toxic residual solvents.” Jd. at 1.
`
`5. Bottino
`
`Bottino observes that “[t]he study of krill has becomeintensive in
`
`recent times, perhapsas a result of its potential importance as food,” and
`
`explains that “[a] variety of organisms[are] usually included underthat
`
`generic name,but in the Southern Oceans the name Euphausia superba has
`
`been considered almost a synonym for krill.” Ex. 1007,1.
`
`Bottino describesthe fatty acid profiles for E. superba,E.
`
`crystallorophias, and phytoplankton. Ex. 1007, Abstract. Bottino explains
`
`that, in contrast to prior studies, lipids were extracted from E. superba
`
`“immediately after capture.” Jd. at2. Euphausiids lipid extraction was
`performed “with a chloroform:methanol (2:1, v/v) mixture,” as previously
`
`described by Folch, andthe fatty acids were analyzed using
`
`chromatography. /d. at 1.
`
`19
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`Table 1 of Bottino is reproducedbelow.
`
`Table 1. Euphauaia superba. Fatty acids (as weight per cent of total acids)
`
`Fatty acid? Station 8
`Whole krill Hp+sb
`
`Station 9
`Whole krill
`
`Station II
`Whole krill HP+S
`
`12.9
`20.9
`0.9
`10.7
`22.8
`te
`
`7 4 6 8 3
`
`8.
`
`10.7
`21.2
`1.2
`6.7
`17.1
`0.9
`2.5
`1.2
`1.9
`22.2
`9.4
`
`14:0
`16:0
`18:0
`
`16:)a-7)
`18: 1(n-9)
`20: 1(n-9)
`18:2(n-3)
`18:3(n-3)
`18:4(n-3)
`20:5¢{n-3)
`22:6(n-3)
`Minor fatty
`acids®
`
`—mowowed
`any—-—w»Oo
`
`eT2n-RONDUN&eo
`
`4.9
`
`5.0
`
`3.9
`
`3.
`
`1
`
`3.3
`
`‘the number preceding the colon gives the number of carbon atoms in the
`chain,
`the number following the colon the number of double bonds;
`(n-x):
`number of carbons in the chain minus number of carbons between the methyl -
`end and the nearest double bond.
`
`brepatopancreas plus stomach.
`“only those fatty acids present at a level of
`
`1% ot more are included.
`
`Ex. 1007, Table 1. Table 1 discloses the fatty acid content ofE. superba
`
`obtained from threedifferent locations(i.e., stations) as a weight percent of
`
`total fatty acids. Jd. at2. Notably, only those fatty acids present at 1% or
`
`more as a weight percentoftotal fatty acids are included in Table 1. Jd.
`
`Table 1 n.c.
`
`20
`
`Remaining
`carcass
`
`13.5
`23.4
`
`oe8©©©©6rnee—-DO|eWVoO
`
`nN’...~-©RO-NYOMWYww
`
`:.oe:7+:weFwooMWNYOoPFYow
`
`.
`
`] 8 ' 0 2
`
`] 3 1 7
`
`14
`24.
`
`2t.
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`Table 3 of Bottino is reproduced below.
`
`Table 3, fatly achds af Aararctic phycoptamtoa and cupaauelies (ea weight pac cunt ef cotat acids)
`
`Fatry ecié certeganhees at Stations?
`ayreneta
`Aiprauete
`168
`Ha
`ie
`%
`*
`‘ta mo ‘“ a 1%
`(average of
`toaroge of "ea
`J atations} 7 stations)
`
`-
`-
`ab
`+
`120068a
`A
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`or
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`1.9 Of i -
`2.5
`1.4
`@£.2
`8.9
`2.9
`0.20003
`an
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`24
`OFF
`24
`-
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`4.0
`- i? @G
`-
`13
`19:9
`-
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`tevee
`0,3
`-
`-
`1.9
`-
`9.7?
`1.3
`0.2
`-
`-
`I139
`0.2
`2.5
`GA
`68
`@2
`-
`2.2
`1.22.3 3.3
`1.9
`£6
`2.0
`tid
`-
`1M G8
`-
`~
`-
`-
`~
`reo -
`-
`O68
`tha
`14.0
`9.7 29.5 38,5
`15.9
`27.8 95.5 W.7
`17.6
`19.3
`SF
`13.0
`9.5
`18:0
`O.4
`19°
`O83
`£6
`2S
`1.70
`63.6
`-
`324 0?
`it
`O32
`-
`{S10
`an. Met
`18.9
`16.0
`16,8 U7 18.5
`16.7
`87.2
`13.6 FF 88.3
`test
`7 9.9
`432
`2.0
`2.0
`2.6
`2.2
`19
`9.6
`5,2
`1.700
`1.5
`1.0
`18:0
`0.6
`220 Ee ae -
`-
`-
`-
`2 -
`-
`West(n-2)
`-
`-
`-
`OF
`=
`19
`2.0 3 ©. i -
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`Metin?)
`-
`2.8
`4S
`$6
`2.4 OF
`£2
`$6
`O82
`09
`15°
`0.3
`-
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`= 8 «+
`Oo
`0
`0.6
`1.8 ta too -
`-
`sitet
`OS BF OF
`3.3
`6.6
`$2
`1.0
`2.7
`0.6
`0.7 i trace
`USetlar?)
`test{orZ) FBS OS 2 SLY
`SS 9 8B 8 LZ
`LY tS
`a5
`1Pibdaet)
`1.6
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`tBrt(n-9)
`12.8
`16.0
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`9.3 16.3 26.8 FL 20.2
`12,5
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`=
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`
`23 $9 4.30 606 1.04632 06 40 2.8 4.a0066.5) O98 0.8acidad 0.6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prademiaaced ia each station. Stétloa 9: atulonina, Rendo-~
`Mloroscopic exeainsiiien fmdicated tha: the following gemera
`rims: Stacioa 1M; Pactesadseten, Pragtlorie, Kiachta, Ourachron, Silleoflagettacas: Scation tt: Corechron, Puyllaria,
`Chantocaroe, Biileotiaxellatun; Station 14+ Conethiw, Pruptlarta, eachta,. Tlackwaide: Stanton 13: Ceopptea elytuces
`Station 4: Mssewente; Btetion (5: Amesspatts, Cumiscans, Minolta, thalemisetre, Pragtiorte; Stations 17 aad #8:
`Progtiaria, Wteckte, Cngeinadigoys, Maoliagntiaces, Tluchaniog.
`Meaty thase fatty acids prosent ac @ level of IF ar aware are inetuded. See feetoates co fables | and 2 for further cxn
`planrcion.
`
`.
`
`21
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`Ex. 1007, Table 3. Table 3 reports the identity and average amountof each
`
`fatty acid present in the E. superba samples analyzed as a weight percent of
`
`total fatty acids.
`
`6. Sampalis I
`Sampalis I describes a clinical trial “[t]o evaluate the effectiveness of
`
`NeptuneKrill Oil™ (NKO™)for the managementof premenstrual
`
`syndrome and dysmenorrhea.” Ex. 1012, 1. SampalisI explains that
`
`NeptuneKrill Oil is “extracted from Antarctic krill also known as Euphausia
`
`superba. Euphausia superba, a zooplankton crustacean,is rich in
`phospholipids andtriglycerides carrying long-chain omega-3
`
`polyunsaturated fatty acids, mainly EPA and DHA, andin various potent
`
`antioxidants including vitamins A and E, astaxanthin, anda novel
`
`flavonoid.” Jd. at 4.
`
`Sampalis I discloses that each patient in the clinical trial was “asked to
`
`take two 1-gram soft gels of either NKO or omega-3 18:12 fish oil (fish oil
`
`containing 18% EPA and 12% DHA)oncedaily with meals duringthefirst
`
`month ofthe trial.” Zd. Sampalis I reports that “[t]he final results of the
`
`present study suggest within a high level of confidence that Neptune Krill
`
`Oil can significantly reduce the physical and emotional symptomsrelated to
`
`premenstrual syndrome,andis significantly more effective for the
`
`management of dysmenorrhea and emotional premenstrual symptoms than
`
`fish oil.” Jd. at 8.
`
`22
`
`

`

`IPR2017-00748
`Patent 9,028,877 B2
`
`7. Sampalis II
`Sampalis II discloses a “phospholipid extract from a marine or aquatic
`
`biomass[that] possesses therapeutic properties. The phospholipid extract
`
`comprises a variety of phospholipids, fatty acid, metals anda novel
`
`flavonoid.” Ex. 1013, Abstract. Sampalis II explains that the disclosed
`
`phospholipid and its components “are useful in the prevention or treatment
`
`of a variety of disease states and for the aesthetic enhancementof an animal,
`
`including human, body. Pharmaceutical, nutraceutical and cosmetic
`
`compositions containing the extract and usesthereofare also within the
`
`invention.” Jd. at3:6-11.
`
`Sampalis II further discloses that
`
`[t]he phospholipid extract of the present invention may be
`extracted from a variety of marine or aquatic biomass sources.
`Preferred sources of
`the phospholipid
`composition are
`crustaceans, in particular, zooplankton. A particularly preferred
`zooplankton is Krill.
`Krill can be found in any marine
`environment around the world.
`For example,
`the Antarctic
`Ocean (wherethekrill is Euphasia superba), the Pacific Ocean
`(wherethekrill is Euphasiapacifica), the Atlantic Ocean and the
`Indian Oceanall contain krill habitats.
`
`Ex. 1013, 25:2-10.
`
`8. Fricke 1986
`
`Fricke 1986 teachesthat “[s}mall amounts ofalkoxylipids, commonly
`
`referred to a