Trials@uspto.gov
`571-272-7822
`
`PaperNo.24
`Entered: August 10, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`RIMFROSTAS,
`Petitioner,
`
`V.
`
`AKER BIOMARINE ANTARCTICAS,
`Patent Owner.
`
`Case IPR2017-00745
`Patent 9,078,905 B2
`
`Before ERICA A. FRANKLIN, TINAE. HULSE,and
`JACQUELINE T. HARLOW,AdministrativePatent Judges.
`
`HARLOW,Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Determining That Claims 1-20 Have Been Shownto Be Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`I.
`
`INTRODUCTION
`
`Rimfrost AS (“Petitioner’’) filed a Petition requesting an interpartes
`
`review of claims 1—20 of U.S. Patent No. 9,078,905 B2 (Ex. 1001, “the
`
`’905 patent”). Paper 2 (“Pet.”). Aker Biomarine Antarctic AS (“Patent
`
`Owner”) declinedto file a Preliminary Response.
`
`On August 16, 2017, we instituted an interpartes review ofall
`
`challenged claims onall grounds asserted. Paper 9. On November8, 2017,
`
`Patent Ownerfiled a Patent Owner Responseto the Petition. Paper 14 (“PO
`
`Resp.”). On January 24, 2018,Petitionerfiled a Reply to the Patent Owner
`
`Response. Paper 17 (“Reply”).
`
`Weissuethis Final Written Decision pursuant to 35 U.S.C. § 318(a)
`
`and 37 C.F.R. § 42.73. Having considered the record before us, we
`
`determinethat Petitioner has shownby a preponderanceofthe evidencethat
`
`claims 1—20 ofthe ’905 patent are unpatentable. See 35 U.S.C. §316(e).
`
`A. Related Matters
`
`The ’905 patent is asserted in Aker Biomarine Antarctic AS v. Olympic
`
`HoldingAS, Case No. 1:16-CV-00035-LPS-CJB (D.Del.). Pet.2; Paper 3,
`
`1. In addition, Petitioner has challenged, and we have instituted interpartes
`
`review of, the claims of the ’905 patent in IPR2017-00747. Paper5, 2.
`
`Petitioner also challenges U.S. Patent No. 9,028,877 B2 (“the
`
`’877 patent) in IPR2017-00746 and IPR2017-00748. Paper 5,2. Both the
`
`*905 patent and the 877 patent are continuations of Application
`
`No.12/057,775, filed March 28, 2008.
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Theparties have not identified any further, currently pending, related
`proceedings concerning the ’905patent. '
`
`B. The ’905 Patent
`
`The ’905patent,titled “Bioeffective Krill Oil Compositions,” issued
`July 14, 2015, with Inge Bruheim, Snorre Tilseth, and Daniele Mancinelli as
`the listed co-inventors. Ex. 1001, [54], [45], [72].
`
`The ’905 patent describes extracts from Antarctic krill, small
`shrimp-like animals, that include bioactive fatty acids. Ex. 1001, 1:19-20.
`In particular, the 905 patent discloseskrill oil compositions having “high
`levels of astaxanthin, phospholipids, includ[ing] enriched quantities of
`
`ether phospholipids, and omega-3fatty acids.” Jd. at 9:28—31.
`The ’905 patent states that myriad health benefits have been attributed
`to krill oil in the prior art. For example, the ’905 patent states 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 glucose levels in a patient.”
`Ex. 1001, 1:46-52. In addition, the ’905 patent recognizesthat krill oil
`compositions, including compositions having up to 60% w/w phospholipid
`
`' The ’905 patent wasalso asserted in Jn the MatterofCertain Krill Oil
`Products andKrill Mealfor Production ofKrill Oil Products, Investigation
`No. 337-TA-1019 (USITC)(Pet. 2-3; Paper3, 1); however,Petitioner states
`that the investigation has been “effectively terminated.” Paper 22,3.
`3
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`content and as much as 35% w/w EP A/DHA content, were knownin the art
`
`prior to the time of invention. Jd. at 1:52-57. The ’905 patentalso indicates
`that supercritical fluid extraction with solvent modifier was knownto be a
`useful method for extracting marine phospholipids from salmonroe. Jd.at
`
`1:65-67.
`
`Accordingto the ’905 patent, however, the solvent extraction methods
`usedin theprior art to isolate krill oil from the krill “rely on the processing
`of frozen krill that are transported from the Southern Oceanto the
`processing site,” which transportation is expensive and mayresult in the
`degradationofthe krill starting material. Jd. at 2:3-6. Such methods have
`includedsteps of placing 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 suchas ethanol.
`/d. at 1:32—40.
`
`To overcomethe abovelimitations, the 905 patent discloses
`
`“methods for processing freshly caught krill at the site of capture and
`preferably on boardaship.” Jd. at 10:18-20. The ’905 patent explains that
`the krill may be first subject to a protein denaturationstep, 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 nonpolarandpolar solvents including use of
`supercritical carbon dioxide.” Jd. at 9:51—54.
`In Example 7 ofthe ’905 patent, “[k]rill lipids were extracted from
`krill meal (a food grade powder)using supercritical fluid extraction with
`
`co-solvent.” Jd. at32:15—16.
`
`

`

`IPR2017-00745
`Patent 9,078,905 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 wasincreased to 23% and the extraction was
`maintained for 3 hours and 40 minutes. The extract was then
`evaporatedusing a falling film evaporatorandtheresulting krill
`oil wasfinally filtered.
`
`Id. at 32:17-23.
`
`Example 8 of the 905 patent prepared krill oil using the same method
`
`described in Example 7, from the samekrill meal used in that example.
`
`Ex. 1001, 32:45—46. The krill oil was then analyzed using *'P NMR
`
`/d. at 32:46—
`analysis to identify and quantify the phospholipidsin the oil.
`48. Table 22? showsthe phospholipid profiles for the raw material, the final
`product, and a commercially available krill oil, Neptune Krill Oil (““NKO”).
`Id. at 33:6-9. Table 22 is reproduced below:
`
`2 Weview referencein the 905 patent to “table 25” (Ex. 1001, 33:6—9) to be
`an inadvertent typographicalerror,as the specification doesnotinclude a
`table 25. We understand Example 8 ofthe specification to refer, instead, to ~
`Table 22, which sets forth the described phospholipid profiles.
`5
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`TABLE 22
`
`Phospholipid profiles
`
`Type B krill
`powder NKO_Krill Oil obtained in Example 7
`
`
`PC
`AAPC
`Pl
`ILPC
`PS
`2LPC
`LAAPC
`PE
`AAPE
`SM
`Gre
`DHSM
`NAPE
`CL
`LPE
`1,Cl.
`% PL in
`powderor
`lipid sample
`
`66.0
`12.0
`
`1.2
`
`74
`2.2
`64
`
`5.3
`
`8.3
`
`68.6
`7.0
`
`1.3
`
`13.8
`1.2
`3.4
`
`L3
`
`3.4
`
`30.0
`
`75.3
`13.0
`
`0.4
`
`2.9
`0.9
`3.4
`L8
`
`2.1
`0.5
`
`47.9
`
`Id. at 33:15-39.
`
`The ’905 patent teachesthat the “main polar etherlipids ofthe krill
`meal are alkylacylphosphatidylcholine (AAPC) at 7—-9% oftotal polar lipids,
`lyso-alkylacylphosphatidylcholine (LAAPC)at 1% oftotal polarlipids
`(TPL) and alkylacylphosphatidyl-ethanolamine (AAPE)at <1% of TPL.”
`
`Id. at 33:9-14.
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`C. Illustrative Claim
`
`Independent claim 1, reproducedbelow,is illustrative of the claimed
`
`subject matter.
`
`1.
`
`Encapsulated krill oil comprising:
`a capsule containing an effective amountofkrill oil,
`said krill oil comprising from about 3% to about 15% w/w
`ether phospholipids.
`Ex. 1001, 35:47—50. Independent claims 12 and 18 further specify the lipid
`composition ofthe krill oil, the type ofkrill used, and the material in which
`the krill oil is encapsulated. Id. at 36:29—36, 36:48—56.
`
`' D. Prior Art Relied Upon
`
`Petitioner relies upon the following asprior art references (Pet. 8-9):
`
`
`Randolph US 2005/0058728 Al=Mar. 17, 2005 (Ex. 1011)
`Catchpole
`WO 2007/123,424
`Nov. 1, 2007
`(Ex. 1009)
`Bottino, The Fatty Acids ofAntarctic Phytoplankton andEuphausiids. Fatty
`AcidExchange Among Trophic Levels ofthe Ross Sea, 27 MARINE BIOLOGY
`197~204 (1974) (Ex. 1007).
`
`Frickeet al., Lipid, Sterol andFatty Acid Composition ofAntarctic Krill
`(Euphausia superbaDana), 19(11) LIPIDS 821-827 (1984) (“Fricke 1984”)
`(Ex. 1010).
`
`Sampalis et al., Evaluation ofthe Effects ofNeptune Krill Oil™onthe
`ManagementofPremenstrual Syndrome andDysmenorrhea, 8(2) ALT.
`MED.REV. 171-179 (2003) (Ex. 1012).
`
`Petitioner also relies on the Declaration of Stephen J. Tallon, Ph.D.
`
`(Ex. 1006), and the Reply Declaration of Dr. Tallon (Ex. 1086).
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Patent Ownerrelies on the Declaration of Nils Hoem, Ph.D.
`
`(Ex. 2001).
`
`E. Instituted Challenges
`
`Weinstituted trial based on each challenge to the patentability of the
`
`’905 patent presentedin the Petition (Pet. 7):
`
`References
`Claim(s)
`
`
`1-4, 9, and 10 § 103(a)|Catchpole and Sampalis
`)
`§ 103(a)|Catchpole, Sampalis, and Randolph
`
`6, 12, 15,16, and 18|§ 103(a) atchpole, Sampalis, and Fricke 1984
`7, 8, 13, 14, 17, 19,
`Catchpole, Sampalis, Fricke 1984,
`and 20
`and Bottino
`§ 103(a)
`
`Catchpole, Sampalis, and Bottino
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Il. ANALYSIS
`
`A. Level ofOrdinary Skill in the Art
`
`Thelevel of ordinary skill in the art is a factual determinationthat
`providesa primary guarantee ofobjectivity in an obviousness analysis. Al-
`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 personof ordinary skill in the art at the time of
`
`the invention of the ’905 patent would have had “an advanced degree in
`
`marine sciences, biochemistry, organic (especially lipid) chemistry,
`
`chemicalor process engineering, or associated sciences,” as well as a
`complementary understandingof “organic chemistry andin particularlipid
`chemistry, chemicalor process engineering, marine biology, nutrition, or
`8
`
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`

`IPR2017-00745
`Patent 9,078,905 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 theliterature,
`
`credentials of individuals working onlipid extractions, andthe skill
`
`necessary to perform these extractions andinterpret their results.” Ex. 2001
`q 15. Based onthat assessment, Dr. Hoem adoptsthe definition of the level
`
`of ordinary skill in the art advanced by Petitioner. Id.
`Weagree with Petitioner, Dr. Tallon, and Dr. Hoem,andfindthat
`
`Petitioner’s description of the level of ordinary skill in the art at the time of
`
`invention of the ’905 patentis consistent with the type of problems
`
`encounteredin theart, priorart 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 purposesofthis Decision, therefore,
`
`we adoptPetitioner’s description. Wealso note that the applied prior art
`
`reflects a level of skill at the time of the claimed invention consistent with
`
`our determination. 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 opinionsonthe levelof skill
`and the knowledge ofa person ofordinary skill in the art at the time ofthe
`invention. Therelative weight that we assign such testimony, however,is
`
`9
`
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`

`IPR2017-00745
`Patent 9,078,905 B2
`
`subject to additional factors. See, e.g.,37C.F.R. § 42.65(a) (“Expert
`testimony that does notdisclose the underlying facts or data on which the
`opinionis 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 Board interprets claim terms in an
`
`unexpired patent according to the broadest reasonable constructionin light
`of the specification of the patent in which they appear. 37C.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 absentany special
`definitions, we give claim termstheir ordinary and customary meaning, as
`would be understood by oneof ordinary skill in the art at the time ofthe
`
`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. 19-25) and Patent Owner (PO Resp.
`11-13) offer several claim constructions, we determinethat no explicit
`construction of any claim lerm is necessary for purposesofthis Decision. In
`
`reaching this conclusion, we observethat the parties’ proposed constructions
`are largely coextensive with eachother, and to the extent those constructions
`
`10
`
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`

`IPR2017-00745
`Patent 9,078,905 B2
`
`differ, they do so in waysthat do not impact our analysis. For example, our
`
`analysis below remains the sameirrespective of whether we apply
`Petitioner’s construction of “krill oil” as meaning“lipids extracted from
`krill” (Pet. 20) or Patent Owner’s interpretation,“oil produced from krill”
`(POResp. 11). Similarly, our analysis is unaffected by whether we apply
`
`Petitioner’s definition of “effective amountofkrill oil,” i.e., “at least the
`
`range of between 0.2 and 10 gramsofkrill oil” (Pet. 21), or Patent Owner’s
`construction,“0.2 grams to 10 gramsofkrill oil” (PO Resp. 12).3
`
`? Pulenl Owner expressly accepts, tor purposesofthis proceeding,
`Petitioner’s proposed constructionsof“polar solvent extract” and “plant
`phytonutrient,” the remaining terms for which the parties propose
`constructions. PO Resp. 12-13.
`
`1]
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`C. Overview ofthe Prior Art
`
`Petitioner relies on combinations including Catchpole, Sampalis,
`
`Fricke 1984, Randolph, and/or Bottino to support its contention that claims
`
`1—20 of the ’905 patent would have been obvious. Pet. 6. Patent Owner
`asserts that Fricke 1986,* Tanaka,° Prescott,° and Zimmerman’ support its
`
`argumentthat an ordinarily skilled artisan would not have madePetitioner’s
`
`proposed combinations, andfurther, that the prior art teaches away from the
`encapsulation of krill oil with high levels of ether phospholipids. See, e.g.,
`PO Resp. 13-18. Weprovide an overview of each reference below.
`
`1. Catchpole
`Catchpole discloses “a process for separating lipid materials
`
`containing phospholipids” (Ex. 1009, 1:5—6) in order to produce a product
`
`containing “desirable levels of particular phospholipids”(id. at 3:27—28).
`Catchpole states that phospholipids “have been implicated in conferring a
`
`4 Frickeet al., /-O-Alkylglycerolipids in Antarctic Krill (Euphausia Superba
`Dana), 85B COMP. BIOCHEM. PHYSIOL. 131—134 (1986)(“Fricke 1986”)
`(Ex. 2006).
`
`> Tanakaet al., Platelet-Activating Factor (PAF)-Like Phospholipids
`FormedDuring Peroxidation ofPhosphatidylcholinesfrom Different
`Foodstuffs, 59(8) BIOSCI. BIOTECH. BIOCHEM. 1389-1393 (1995) (Ex. 1014).
`
`6 Prescott et al., Platelet-Activating Factor andRelatedLipidMediators, 69
`ANNU. REV. BIOCHEM. 419-45 (2000) (Ex. 2003).
`
`7 Zimmermanetal., The Platelet-Activating Factor SignalingSystem andIts
`Regulators in SyndromesofInflammation and Thrombosis, 30 CRIT. CARE
`MED. S284—S301 (2002) (Ex. 2004).
`
`12
`
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`

`IPR2017-00745
`Patent 9,078,905 B2
`
`numberofhealth benefits including brain health, skin health, eczema
`
`treatment, anti-infection, wound healing, gut microbiota modifications, anti-
`
`canceractivity, alleviation of arthritis, improvementofcardiovascular
`health, and treatment of metabolic syndromes. They can also be used in
`
`sports nutrition.” Jd. at 1:29-2:2. Catchpole further discloses that products
`havinghigh levels of particular phospholipids “may be employedin a
`numberofapplications, including infant formulas, brain health, sports
`
`nutrition and dermatological compositions.” Jd. at 25:9-13.
`
`Catchpole describes, in Example 18, the fractionation ofkrill lipids
`from krill powder using a process that employssupercritical CO2inafirst
`extraction, and a CO? and absolute ethanol mixture in a second. Jd. at 24:1-
`
`16. Table 16, reproduced below,reports the phospholipid concentrations
`presentin the krill oil extract obtained by Catchpole. Jd. at Table 16.
`
`Table 16 Composition, %
`Ls Othercompounds
`
`AAPC} AAPE
`
`As shownin Table 16, the composition of Extract 2 includes 39.8%
`
`phosphatidylcholine (“PC”). Jd. The ether phospholipids
`alkylacylphosphatidylcholine (““AAPC”) and
`alkylacylphosphatidylethanolamine (“AAPE”) werealso present in
`Extract 2, representing 4.6% and 0.2%,respectively, ofthe extracted
`composition. Jd. In addition, summing each ofthe reported phospholipid
`
`13
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`

`IPR2017-00745
`Patent 9,078,905 B2
`
`amountsreported for Extract 2 yields a total phospholipid concentration
`
`of 45.1%. Id.
`
`2. Sampalis
`Sampalis describesa clinicaltrial “[t]o evaluate the effectiveness of
`
`NeptuneKrill Oil™ (NKO™)for the managementof premenstrual
`syndrome and dysmenorrhea.” Ex. 1012, 1. Sampalis explains that Neptune
`
`Krill Oil is “extracted from Antarctic krill also known as Euphausia
`
`superba. Euphausia superba, a zooplankton crustacean,is rich in
`phospholipids and triglycerides carrying long-chain omega-3
`polyunsaturatedfatty acids, mainly EPA and DHA, andin various potent
`antioxidants including vitamins A and E, astaxanthin, and a novel
`
`flavonoid.” Jd. at 4.
`
`Sampalis discloses that eachpatient 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)once daily with meals duringthefirst
`
`monthofthetrial.” Jd. Sampalis reports that “[t]he final results of the
`
`present study suggest within a high level of confidence that NeptuneKrill
`Oil can significantly reduce the physical and emotional symptomsrelated to
`premenstrual syndrome,andis significantly moreeffective for the
`managementof dysmenorrhea and emotional premenstrual symptomsthan
`
`fish oil.” Jd. at 8.
`
`3. Fricke 1984
`
`Fricke 1984 discloses the“lipid classes, fatty acids of total and
`
`individual lipids andsterols of Antarctic krill (Euphausia superba Dana)
`
`14
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`from twoareasof the Antarctic Ocean”as determinedby thin layer
`
`chromatography,gas liquid chromatography,andgasliquid
`
`chromatography/mass spectrometry analyses. Ex. 1010, Abstract.
`According to Fricke 1984, krill were collected and were quick frozen, and
`lipids were extracted using the method of Folch.® /d. at1. Fricke 1984
`teachesfurther that samples were also cooked on board “immediately after
`
`hauling,” and were stored under the same condition. Jd. at 2-3.
`
`Table 1 of Fricke 1984 is reproduced below.
`TABLE 1
`
`Lipid Composition of Antarctic Krill
`(Euphausta superba Dans)
`
`Sample
`
`12/1977,
`
`31981
`
`Total lipid content
`
`2.7 40.2(% wet weight) 6.2 + 0.3
`
`
`
`.
`
`Phospholipids
`Phosphatidytchotine
`Phosphatidylethanolamine
`Lysophosphatidytchotine
`Phosphatidylinosito}
`Cardiolipin
`Phosphatidic acid
`
`3§.6420.1
`6.1 + 0.4
`1.5 0.2
`0.90.1
`1.0 + 0.4
`0.6 + 0.4
`
`33.340.5
`$.2 £0.5
`2.6 + 0.4
`1.12 0.4
`1.60.2
`
`Neutral lipids
`Triacytgiycerols
`Free fatty acids?
`Diacylglycerols
`Sterols
`Monoacylglycerols
`
`Others
`
`33.340.5
`16.8 £ 1.3
`1.3+0.1
`1.740.1
`0.4 40.2
`
`40420.1
`8.521.060
`36 £01
`1420.1
`0.9 20.1
`
`0.920.1
`
`0520.1
`
`99.3
`98.9
`Total
`
`
`Table 1 showsthetotallipid content and the lipid composition data for the
`
`two krill samples analyzed by Fricke 1984. Jd. at 2. As indicated in
`
`8 Folch et al., A Simple Methodforthe Isolation andPurification ofTotal
`Lipidesfrom AnimalTissues, 266 J. BIOL. CHEM. 497-509 (1957)
`(Ex. 1017).
`
`15
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`IPR2017-00745
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`
`Table 1, the krill samples respectively included approximately 33.3%
`
`+/- 0.5% w/w and 40.4% +/- 0.1% w/w triacylglycerols. Jd.
`
`4. Randolph
`Randolphdiscloses compositions for modulating cytokines to regulate
`
`an inflammatory or immunomodulatory responseincluding, interalia,
`
`rosehips and krill oil. Ex. 101198. With regard to rosehips, Randolph
`
`discloses that the composition may include one or morerosehip ingredients,
`
`such as “dried rosehips, rosehip oil, and rosehip extracts.” Id. | 24.
`
`Concerning krill oil, Randolphdiscloses that
`
`[a] composition of the invention can include krill oil. Krill oil
`can be obtained from any memberof the Euphausia family, for
`example Euphausia superba.
`Conventional oil producing
`techniques can be used to obtain the krill oil.
`In addition, krill
`oil can be obtained commercially from Neptune Technologies
`and Bioresources ofQuebec, Canada.
`Id. J 39. Randolph further explains that “[a] composition can contain any
`
`amountofkrill oil,” but will typically contain “between about 300 mg and
`
`about 3000 mgof a krill oil ingredient.” Jd. J 40.
`
`Randolphalso disclosesthat, “‘[t]he ingredients of the composition can
`be processed into forms having varying delivery systems. For example, the
`ingredients can be processed andincluded in capsules, tablets, gel tabs,
`
`lozenges,strips, granules, powders, concentrates, solutions,lotions, creams
`or suspensions.” Ex. 1011946. Randolph furtherdisclosesthat “[a] soft
`gel capsule of the composition can be manufacturedto include krill oil. This
`capsule can be manufactured using conventional capsule manufacturing
`
`16
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`techniques. The amountofkrill oil in each capsule is about 300 mg.” Jd.
`
`q 52.
`
`5. Bottino
`
`Bottino observesthat “[t]he study ofkrill has becomeintensive in
`
`recent times, perhaps asa result ofits 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 forkrill.” Ex. 1007, 1.
`
`Bottino describesthe fatty acid profiles for E. superba, E.
`
`crystallorophias, and phytoplankton. Ex. 1007, Abstract. Bottino explains
`
`that, in contrastto 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, and the fatty acids were analyzed using
`
`chromatography. /d. at 1.
`
`17
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Table 1 of Bottino is reproduced below.
`
`Table 1. Euphaueta superba. Fatty acids (as weight per cent of total acids)
`
`
`Station lI
`Station 9
`Patty acid? Station 8
`Whole krill HP+S> Whole krill Whole krill HP+S Remaining
`carcass
`
`
`14:0
`
`16:0
`
`18:0
`
`16:3} (n-7)
`18:1 (n-9)
`
`20: 1(n-9)
`18:2(n-3)
`
`18:3(n-3)
`
`14.9
`
`21.2
`
`0.7
`
`9.0
`18,2
`
`0.6
`2.6
`
`1.t
`
`10.7
`
`21.2
`
`1.2
`
`6.7
`17.1
`
`6.9
`2.5
`
`1.2
`
`12.9
`
`20.9
`
`0.9
`
`10.7
`22.8
`
`tl
`2.7
`
`1.4
`
`14.3
`
`24.7
`
`1.4
`
`8.9
`21.7
`
`0.9
`2.0
`
`1.0
`
`12.9
`
`13.5
`
`22.3 23.4
`
`{.3
`
`1.4
`
`8.2
`25.8
`
`8.0
`21.5
`
`1.2 |
`2.1
`1.9
`
`1.0
`
`1.1
`
`1824 (n-3)
`20:5(n=3)
`22:6(n-3)
`Minor fatty
`
`4.9 5.0 3.9 3.1 3.6acids® 3.3er
`
`3.3
`11.4
`7.3
`
`
`
`3.8
`11.6
`9.4
`
`3.6
`13.9
`8.1
`
`
`
`2.2
`16.0
`8.6
`
`
`
`1.9
`22.2
`9.4
`
`2.6
`11.8
`8.3
`
`
`
`
`
`"vhe 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.
`
`bHepatopancreas plus stomach.
`“only those fatty acids present at a level of 1% or 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. Id. at2. Notably, only those fatty acids presentat 1% or
`moreas a weight percentoftotal fatty acids are included in Table 1. Jd.
`
`Table 1 n.c.
`
`18
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Table 3 of Bottino is reproduced below.
`
`Table 2, Patiy acids of Antarctic phytoptantton and cuphaustide (ea weight per cent of cotal seids)
`
`
`fpraussa
`tiphauetd
`Fatty acid Phytoplankcoa at Stations
`Teeategs of eryetaliowghvas
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`
`
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`
`Nicroscople exsmination indicated thar the folicwing gemera predominated ia each station. Station 9: Badorina, Wrado—
`ring: Station (%: Shalesstoatro, Prsgilaria, Mftachta, fonitowe, Silieostagettaces; Scation Ili corwthron, fragilaria,
`Chaetocaros, Rillegttuxellates; Station 12: Conethnm, Prugilaria, Mechta, Tincinnids; Statiow 131 Comples alature:
`Staton 14: Phasccvette; Station 1S: Phorocystic, Cmetovencs, Miterria, Terlessioutre, Freefiarmit; Statinns |7 and 18:
`Prgtinete, Mitzehio, Cevetnecdiaumy, Ofpullagellares, Tlitionide.
`Monty those fatty acids presence ac a level of IZ or more are inctuded. Sec footnates co Tables | and 2 for further ex-
`planation.
`
`19
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Ex. 1007, Table3. 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. Fricke 1986
`
`Fricke 1986 teachesthat “[s]mall amounts of alkoxylipids, commonly
`
`referred to as glyceryl ethers or etherlipids, are present in the lipids of many
`
`marine animals.” Ex. 2006, 1. Fricke notes that “[w]hile investigating the
`
`complete lipid composition of Antarctic Krill” in the study reported in
`Fricke 1984, “there was someevidencefor the presence of 1-O-
`
`alkylglycerolipids in trace amounts,” which suggested “that some
`
`degradation processes had taken place during storage.” Jd. Fricke 1986
`
`explains that the samples analyzed in Fricke 1984 “were frozen on board a
`research vessel in 1977 and 1981 and could only be investigated after some
`
`monthsof frozen storage.” Jd. Accordingly, Fricke 1986 set out to verify
`
`the findings of Fricke 1984,using lipid extracts from freshly caught krill that
`
`were prepared on-board during an expedition in 1985. Jd.
`
`According to Fricke 1986, 1-O-alkylglycerolipids “were found as
`minorlipid components,”and “ranged from 0.3 to 0.6% oftotal lipid content
`
`of Antarctic Krill’ (Ex. 2006, 2) as shownin Table 1, reproduced below.
`
`20
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Table 1. Lipid content and t-O-alkyiglycero! content in total lipids of Antarctic Krill (Euphausia superba Dana). Data are
`expressed as wt % and represent means and standard deviation of at least three separate experiments
`Ae
`Bt
`3
`Dt
`E3
`2.74+0.2
`6.2403
`9.2403
`8.3407
`10.3404
`Lipid content 5}
`(0.43 + 0.04
`0.50 + 0.02
`0.53 + 0.01
`0.65 + 0.03
`0.58 + 0.03
`1-O-Alkylglycerol-content
`*Krill caught in Decembes 1977.
`tKrill caught in March 1981.
`{Krill} caught in March/April 1985. Krill samples extracted immediately after catching.
`§Krill muscle analyzed.
`{On a wet weight basis.
`*tKrill samples stored at — 30°C.
`
`F3§
`5.7 490.3
`0.58 + 0.01
`
`Id. at Table 1.
`
`With regard to the preparation ofthe 1977 and 1981 samples,
`
`Fricke 1986 teachesthat alkylglycerolipids wereisolated after stepwise
`
`hydrolysis oftotal lipids. Ex. 2006, 1. Phospholipids and neutral lipids
`
`were separated using thin layer chromatography, and phospholipids were
`
`incubated with phospholipase C. Jd. Fricke 1986 teachesthat the
`alkylglycerols were prepared from the phospholipids andneutrallipids by
`concentrated methanolic hydrochloric acid, and the alkylglycerols were
`isolated using thin layer chromatography. Jd. at 1-2. Concerning the 1985
`samples, Fricke 1986 explains that those samples weretreated “according to
`Snyderet al. (1971) with Vitride (sodium-di-hydro-bis-(2-methoxyethoxy)-
`
`aluminate) to form thefree alkylglycerols.” Jd.
`
`7. Tanaka
`
`Tanaka examinesthe “PAF-like lipids formed during peroxidation of
`
`PCsfrom hen egg yolk, salmonroe, sea urchin eggs, and krill in an
`FeSO./EDTA/ascorbate system.” Ex. 1014, Abstract. Tanaka discloses the
`
`phosphatidylcholine subclasses, andtheir relative amounts,presentin,
`Antarctic krill (Euphausia superba) extract. Ex. 1014, 2,3. Tanaka
`
`explains that phosphatidylcholine was purified from crudekrill lipid extract
`using column chromatography andnmlayer chromatography. Jd. at2.
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`Successive degradationsofthe purified extract using alkaline and acid
`
`hydrolysis were then performed to measure the percentages of
`
`phosphatidylcholine subclasses in the extract. Id.
`
`Table 1 of Tanakais reproduced below.
`
`Table I. Subclass Composition of PCs from Food Stuffs
`
` PC
`
`Diacyl
`
`Alkylacyl
`
`Alkenylacyl
`
`%
`<0.1
`0.8+0.1
`99.2+0.2
`Hen egg yolk
`<0.1
`1.240.2
`98.8+0.2
`Salmon roe
`1.0+0.8
`41.540.3
`57.5+1.1
`Sea urchin egg
`
`
`
`77.041.2 23.0+1.2Krill <0.1
`
`Values are means + SE for four experiments.
`
`Ex. 1014, Table 1. Table 1 showsthat the ether phospholipid AAPC
`
`accountedfor 23.0% +/- 1.2% ofthe total phosphatidylcholine presentin
`
`Antarctic krill extract. Id. at 3.
`
`Tanaka concludesthatalthough the study “demonstrated the
`
`formation of P AF-like phospholipids during peroxidation of PCs from
`
`different foodstuffs[,] .. . the occurrence ofPAF-like lipids in some stored
`
`foodsis still speculative and requires furtherinvestigation.” Ex. 1014, 5.
`
`8. Prescott
`
`Prescott discloses that PAF “is a phospholipid with potent, diverse
`
`physiologicalactions,particularly as a mediator of inflammation.”
`
`Ex. 2003, Abstract. Prescott explains that
`
`[t]he PAF receptor recognizes the sn-1 ether bond of PAF,its
`short sn-2 acetyl] residue, and the choline head group; alteration
`of any ofthesestructures greatly decreasessignaling through the
`PAF receptor. Extension of the sn-2 acetyl residue by one
`methylene is without consequence, but extension by two
`22
`
`

`

`IPR2017-00745
`Patent 9,078,905 B2
`
`methylenes decreases activity by a factor of 10- to 100-fold,
`depending on the assay. Extension beyondthis results in the loss
`of signaling through the PAF receptor.
`Ex. 2003, 13 (internal citations omitted).
`
`Prescott further discloses that “[o]xidation of complexlipids in
`
`reduced systemshasdefined potential oxidation pathwaysand products, but
`whether such oxidizing conditionsexist in vivo is problematic, given the
`
`unstable nature ofthe reactive intermediates and the potential of metabo