`571-272-7822
`
`
`
`
`
`
`
`
`
`
`
`
`
` Paper No. 23
`
`
` Entered: August 10, 2018
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`RIMFROST AS,
`Petitioner,
`
`v.
`
`AKER BIOMARINE ANTARCTIC AS,
`Patent Owner.
`____________
`
`Case IPR2017-00746
`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 Been Shown to Be Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`RIMFROST EXHIBIT 1104 Page 0001
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`I.
`
`INTRODUCTION
`
`Rimfrost AS (“Petitioner”) filed a Petition requesting an inter partes
`
`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”) declined to file a Preliminary Response.
`
`On August 16, 2017, we instituted an inter partes review of all
`
`challenged claims on all grounds asserted. Paper 8. On November 8, 2017,
`
`Patent Owner filed a Patent Owner Response to the Petition. Paper 13 (“PO
`
`Resp.”). On January 24, 2018, Petitioner filed a Reply to the Patent Owner
`
`Response. Paper 16 (“Reply”).
`
`We issue this 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
`
`determine that Petitioner has shown by a preponderance of the 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 have instituted inter
`
`partes review of, the claims of the ’877 patent in IPR2017-00748. 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
`
`No. 12/057,775, filed March 28, 2008.
`
`2
`
`RIMFROST EXHIBIT 1104 Page 0002
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`The parties have not identified any further, currently pending, related
`
`proceedings concerning the ’877 patent.1
`
`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 patent discloses krill oil compositions having “high
`
`levels of astaxanthin, phospholipids, includ[ing] enriched quantities of ether
`
`phospholipids, and omega-3 fatty acids.” Id. 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 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 transdermal transport, reducing the symptoms of
`
`premenstrual symptoms or controlling blood glucose levels in a patient.”
`
`Ex. 1001, 1:46–52. In addition, the ’877 patent recognizes that krill oil
`
`compositions, including compositions having up to 60% w/w phospholipid
`
`
`
`1 The ’877 patent was also asserted in In the Matter of Certain Krill Oil
`Products and Krill Meal for Production of Krill Oil Products, Investigation
`No. 337-TA-1019 (USITC) (Pet. 2–3; Paper 3, 1); however, Petitioner states
`that the investigation has been “effectively terminated.” Paper 21, 3.
`3
`
`RIMFROST EXHIBIT 1104 Page 0003
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`content and as much as 35% w/w EPA/DHA content, were known in the art
`
`prior to the time of invention. Id. at 1:52–57. The ’877 patent also indicates
`
`that supercritical fluid extraction with solvent modifier was known to 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 the prior art to isolate krill oil from the krill “rely on the processing
`
`of frozen krill that are transported from the Southern Ocean to the
`
`processing site,” which transportation is expensive and may result in the
`
`degradation of the krill starting material. Id. at 2:3‒6. Such methods have
`
`included steps 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 such as ethanol. Id. at 1:32‒40.
`
`To overcome the above limitations, the ’877 patent discloses
`
`“methods for processing freshly caught krill at the site of capture and
`
`preferably on board a ship.” Id. at 10:18‒20. The ’877 patent explains that
`
`the krill may be first subject to a protein denaturation step, such as a heating
`
`step, to avoid the formation of enzymatically decomposed oil 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.” Id. 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.” Id. at 31:15‒16.
`
`4
`
`RIMFROST EXHIBIT 1104 Page 0004
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`Initially, 300 bar pressure, 333°K and 5% ethanol
`(ethanol:CO2, w/w) were utilized for 60 minutes in order to
`remove neutral lipids 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 was finally filtered.
`
`Id. at 31:17‒23.
`
`Example 8 of the ’877 patent prepared krill oil using the same method
`
`described in Example 7, from the same krill meal used in that example.
`
`Ex. 1001, 31:46‒47. The krill oil was then analyzed using 31P NMR
`
`analysis to identify and quantify the phospholipids in the oil. Id. at 31:47‒
`
`49. Table 222 shows the phospholipid profiles for the raw material, the final
`
`product, and a commercially available krill oil, Neptune Krill Oil (“NKO”).
`
`Id. at 32:6‒9. Table 22 is reproduced below:
`
`
`
`2 We view reference in the ’877 patent to “table 25” (Ex. 1001, 32:6‒9) to be
`an inadvertent typographical error, as the specification does not include a
`table 25. We understand Example 8 of the specification to refer, instead, to
`Table 22, which sets forth the described phospholipid profiles.
`5
`
`RIMFROST EXHIBIT 1104 Page 0005
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`
`
`Id. at 32:15‒39.
`
`The ’877 patent teaches that the “main polar ether lipids of the krill
`
`meal are alkylacylphosphatidylcholine (AAPC) at 7–9% of total polar lipids,
`
`lyso-alkylacylphosphatidylcholine (LAAPC) at 1% of total polar lipids
`
`(TPL) and alkylacylphosphatidyl-ethanolamine (AAPE) at <1% of TPL.”
`
`Id. at 32:9‒14.
`
`
`
`6
`
`RIMFROST EXHIBIT 1104 Page 0006
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`C. Illustrative Claim
`
`Of the 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 denatured krill 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
`amount of total phospholipids in 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 requires that the krill oil produced by the
`
`method recited includes amounts of phospholipid components and
`
`triglycerides within the same ranges as claim 1. Id. at 35:23–36:7.
`
`
`
`
`
`7
`
`RIMFROST EXHIBIT 1104 Page 0007
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`D. Prior Art Relied Upon
`
`Petitioner relies upon the following as prior art references (Pet. 8–9):
`
`Breivik
`
`US 2010/0143571 A1
`
`June 10, 2010
`
`(Ex. 1035)
`
`Catchpole WO 2007/123,424
`
`Nov. 1, 2007
`
`(Ex. 1009)
`
`Sampalis
`
`WO 03/011873 A2
`
`Feb. 13, 1003
`
`(“Sampalis II”)
`(Ex. 1013)
`
`Bottino, The Fatty Acids of Antarctic Phytoplankton and Euphausiids. Fatty
`Acid Exchange Among Trophic Levels of the Ross Sea, 27 MARINE BIOLOGY
`197–204 (1974) (Ex. 1007).
`
`Fricke et al., Lipid, Sterol and Fatty Acid Composition of Antarctic Krill
`(Euphausia superba Dana), 19(11) LIPIDS 821–827 (1984) (“Fricke 1984”)
`(Ex. 1010).
`
`Sampalis et al., Evaluation of the Effects of Neptune Krill Oil™ on the
`Management of Premenstrual Syndrome and Dysmenorrhea, 8(2) ALT.
`MED. REV. 171–179 (2003) (“Sampalis I”) (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).
`
`Patent Owner relies on the Declaration of Nils Hoem, Ph.D.
`
`(Ex. 2001).
`
`
`
`
`
`8
`
`RIMFROST EXHIBIT 1104 Page 0008
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`E. Instituted Challenges
`
`We instituted trial based on each challenge to the patentability of the
`
`’877 patent presented in the Petition (Pet. 6–7):
`
`Claims
`
`Basis
`
`References
`
`1‒3, 6, 8, 9, 11, 12,
`15, 17, and 18
`
`§ 103(a) Breivik, Catchpole, and Fricke 1984
`
`4, 5, 13, and 14
`
`§ 103(a)
`
`7 and 16
`
`§ 103(a)
`
`10 and 19
`
`§ 103(a)
`
`Breivik, Catchpole, Fricke 1984,
`and Bottino
`Breivik, Catchpole, Fricke 1984,
`and Sampalis I
`Breivik, Catchpole, Fricke 1984,
`and Sampalis II
`
`II. ANALYSIS
`
`A. Level of Ordinary Skill in the Art
`
`The level of ordinary skill in the art is a factual determination that
`
`provides a primary guarantee of objectivity in an obviousness analysis. Al-
`
`Site Corp. v. VSI Int’l Inc., 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 the art 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 and in particular lipid
`
`chemistry, chemical or process engineering, marine biology, nutrition, or
`
`associated sciences; and knowledge of or experience in the field of
`
`9
`
`RIMFROST EXHIBIT 1104 Page 0009
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`extraction,” in addition to “at least five years applied experience.” Pet. 5–6;
`
`Ex. 1006 ¶ 27.
`
`Patent Owner does not address the level of ordinary skill in its
`
`Response; however, Patent Owner’s declarant, Dr. Hoem opines that 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 and interpret their results” Ex. 2001
`
`¶ 15. Based on that assessment, Dr. Hoem adopts the definition of the level
`
`of ordinary skill in the art advanced by Petitioner. Id.
`
`We agree with Petitioner, Dr. Tallon, and Dr. Hoem, and find 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
`
`encountered in the art, prior art solutions to those problems, rapidity with
`
`which innovations are made, sophistication of the technology, and
`
`educational level of active workers in the field. See In re GPAC Inc., 57
`
`F.3d 1573, 1579 (Fed. Cir. 1995). For purposes of this Decision, therefore,
`
`we adopt Petitioner’s description. We also 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 opinions on the level of skill
`
`and the knowledge of a person of ordinary skill in the art at the time of the
`
`invention. The relative weight that we assign such testimony, however, is
`
`subject to additional factors. See, e.g., 37 C.F.R. § 42.65(a) (“Expert
`
`10
`
`RIMFROST EXHIBIT 1104 Page 0010
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`testimony that does not disclose the underlying facts or data on which the
`
`opinion is based is 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 inter partes review, the Board interprets 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, 136 S. Ct. 2131, 2142 (2016)
`
`(affirming applicability of broadest reasonable construction standard to inter
`
`partes review proceedings). Under that standard, and absent any special
`
`definitions, we give claim terms their ordinary and customary meaning, as
`
`would be understood by one of ordinary 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 terms that are in
`
`controversy need be construed, and only to the extent necessary to resolve
`
`the controversy. Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.
`
`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. 19‒30) and Patent Owner (PO Resp.
`
`11‒13) offer several claim constructions, we determine that no explicit
`
`construction of any claim term is necessary for purposes of this Decision. In
`
`reaching this conclusion, we observe that the parties’ proposed constructions
`
`are largely coextensive with each other, and to the extent those constructions
`
`differ, they do so in ways that do not impact our analysis. For example, our
`
`11
`
`RIMFROST EXHIBIT 1104 Page 0011
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`analysis below remains the same irrespective 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. 12). Similarly, our analysis is unaffected by whether we apply
`
`Petitioner’s definition of “to denature lipases and phospholipases,” i.e., “to
`
`alter the conformational structure 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
`
`bonds thereby changing the molecular structure of the lipases and
`
`phospholipases” (PO Resp. 12).3
`
`
`
`
`
`3 Patent Owner expressly accepts, for purposes of this proceeding,
`Petitioner’s proposed constructions of “polar solvent,” “freshly harvested
`krill,” and “polar entrainer,” the remaining terms for which the parties
`propose constructions. PO Resp. 13.
`
`12
`
`RIMFROST EXHIBIT 1104 Page 0012
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`C. Overview of the Prior Art
`
`Petitioner relies on combinations including Breivik, Catchpole,
`
`Fricke 1984, Bottino, Sampalis I, and/or Sampalis II to support its
`
`contention that claims 1–19 of the ’877 patent would have been obvious.
`
`Pet. 6–7. Patent Owner asserts that Fricke 1986,4 Tanaka,5 Prescott,6 and
`
`Zimmerman7 support its argument that an ordinarily skilled artisan would
`
`not have made Petitioner’s proposed combinations, and further, that the prior
`
`art teaches away from the encapsulation of krill oil with high levels of ether
`
`phospholipids. See, e.g., PO Resp. 14–20, 23–26. We provide an overview
`
`of each reference below.
`
`1. Breivik
`
`Breivik “relates to a process for preparing a substantially total lipid
`
`fraction from fresh [kr]ill, and a process for separating phospholipids from
`
`the other lipids.” Ex. 1035 ¶ 1. According to Breivik, approximately 50%
`
`
`
`4 Fricke et al., 1-O-Alkylglycerolipids in Antarctic Krill (Euphausia Superba
`Dana), 85B COMP. BIOCHEM. PHYSIOL. 131–134 (1986) (“Fricke 1986”)
`(Ex. 2006).
`
`5 Tanaka et al., Platelet-Activating Factor (PAF)-Like Phospholipids
`Formed During Peroxidation of Phosphatidylcholines from Different
`Foodstuffs, 59(8) BIOSCI. BIOTECH. BIOCHEM. 1389–1393 (1995) (Ex. 1014).
`
`6 Prescott et al., Platelet-Activating Factor and Related Lipid Mediators, 69
`ANNU. REV. BIOCHEM. 419–45 (2000) (Ex. 2003).
`
`7 Zimmerman et al., The Platelet-Activating Factor Signaling System and Its
`Regulators in Syndromes of Inflammation and Thrombosis, 30 CRIT. CARE
`MED. S284–S301 (2002) (Ex. 2004).
`13
`
`RIMFROST EXHIBIT 1104 Page 0013
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`of the lipids in E. superba are phospholipids, and oil extracted from
`
`E. superba contains lower amounts of environmental pollutants than
`
`traditional fish oils. Id. ¶¶ 6‒7. Breivik notes that krill lipases remain active
`
`after the krill is dead, and, thus, krill oil may contain an undesired amount of
`
`free fatty acids, making it desirable to use a process that will provide for a
`
`low degree of hydrolysis of the krill lipids. Id. ¶ 8.
`
`Breivik teaches that its lipid extraction process “requires a minimum
`
`of handling of the raw materials, and is well suited to be used on fresh
`
`[kr]ill, for example onboard the fishing vessel.” Ex. 1035 ¶ 15. According
`
`to Breivik, the process includes an optional heat pre-treatment of the krill to
`
`inactivate enzymatic decomposition of the lipids, ensuring a product with a
`
`low level of free fatty acids. Id.
`
`Breivik describes an extraction process in which fresh krill is washed
`
`with ethanol, and the ethanol washed krill is then extracted with supercritical
`
`CO2 containing 10% ethanol. Ex. 1035 ¶¶ 39‒40. Breivik also discloses a
`
`process in which the raw material is heated at 80ºC for 5 minutes before the
`
`first wash with ethanol. Id. ¶ 47. According to Breivik, “heat-treatment
`
`gives an increased yield of lipids compared to the same treatment with no
`
`heating.” Id. ¶ 51.
`
`2. 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
`
`14
`
`RIMFROST EXHIBIT 1104 Page 0014
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`number of health benefits including brain health, skin health, eczema
`
`treatment, anti-infection, wound healing, gut microbiota modifications, anti-
`
`cancer activity, alleviation of arthritis, improvement of cardiovascular
`
`health, and treatment of metabolic syndromes. They can also be used in
`
`sports nutrition.” Id. at 1:29–2:2. Catchpole further discloses that products
`
`having high levels of particular phospholipids “may be employed in a
`
`number of applications, including infant formulas, brain health, sports
`
`nutrition and dermatological compositions.” Id. at 25:9–13.
`
`Catchpole describes, in Example 18, the fractionation of krill lipids
`
`from krill powder using a process that employs supercritical CO2 in a first
`
`extraction, and a CO2 and absolute ethanol mixture in a second. Id. at 24:1–
`
`16. Table 16, reproduced below, reports the phospholipid concentrations
`
`present in the krill oil extract obtained by Catchpole. Id. at Table 16.
`
`
`
`As shown in Table 16, the composition of Extract 2 includes 39.8%
`
`phosphatidylcholine (“PC”). Id. The ether phospholipids
`
`alkylacylphosphatidylcholine (“AAPC”) and
`
`alkylacylphosphatidylethanolamine (“AAPE”) were also present in
`
`Extract 2, representing 4.6% and 0.2%, respectively, of the extracted
`
`composition. Id. In addition, summing each of the reported phospholipid
`
`15
`
`RIMFROST EXHIBIT 1104 Page 0015
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`amounts reported for Extract 2 yields a total phospholipid concentration
`
`of 45.1%. Id.
`
`3. Fricke 1984
`
`Fricke 1984 discloses the “lipid classes, fatty acids of total and
`
`individual lipids and sterols of Antarctic krill (Euphausia superba Dana)
`
`from two areas of the Antarctic Ocean” as determined by thin layer
`
`chromatography, gas liquid chromatography, and gas liquid
`
`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.8 Id. at 1. Fricke 1984
`
`teaches further that samples were also cooked on board “immediately after
`
`hauling,” and were stored under the same condition. Id. at 2‒3.
`
`
`
`8 Folch et al., A Simple Method for the Isolation and Purification of Total
`Lipides from Animal Tissues, 266 J. BIOL. CHEM. 497–509 (1957)
`(Ex. 1017).
`
`16
`
`RIMFROST EXHIBIT 1104 Page 0016
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`Table 1 of Fricke 1984 is reproduced below.
`
`Table 1 shows the total lipid content and the lipid composition data for the
`
`two krill samples analyzed by Fricke 1984. Id. 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.
`
`4. Bottino
`
`Bottino observes that “[t]he study of krill has become intensive in
`
`recent times, perhaps as a result of its potential importance as food,” and
`
`explains that “[a] variety of organisms [are] usually included under that
`
`generic name, but in the Southern Oceans the name Euphausia superba has
`
`been considered almost a synonym for krill.” Ex. 1007, 1.
`
`Bottino describes the fatty acid profiles for E. superba, E.
`
`crystallorophias, and phytoplankton. Ex. 1007, Abstract. Bottino explains
`
`17
`
`RIMFROST EXHIBIT 1104 Page 0017
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`that, in contrast to prior studies, lipids were extracted from E. superba
`
`“immediately after capture.” Id. at 2. 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. Id. at 1.
`
`Table 1 of Bottino is reproduced below.
`
`Ex. 1007, Table 1. Table 1 discloses the fatty acid content of E. superba
`
`obtained from three different locations (i.e., stations) as a weight percent of
`
`total fatty acids. Id. at 2. Notably, only those fatty acids present at 1% or
`
`
`
`18
`
`RIMFROST EXHIBIT 1104 Page 0018
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`more as a weight percent of total fatty acids are included in Table 1. Id.
`
`Table 1 n.c.
`
`Table 3 of Bottino is reproduced below.
`
`
`
`19
`
`RIMFROST EXHIBIT 1104 Page 0019
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`Ex. 1007, Table 3. Table 3 reports the identity and average amount of each
`
`fatty acid present in the E. superba samples analyzed as a weight percent of
`
`total fatty acids.
`
`5. Sampalis I
`
`Sampalis describes a clinical trial “[t]o evaluate the effectiveness of
`
`Neptune Krill OilT M (NKOT M) for the management of premenstrual
`
`syndrome and dysmenorrhea.” Ex. 1012, 1. Sampalis explains that NKO 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 polyunsaturated fatty acids,
`
`mainly EPA and DHA, and in various potent antioxidants including vitamins
`
`A and E, astaxanthin, and a novel flavonoid.” Id. at 4.
`
`Sampalis 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) once daily with meals during the first
`
`month of the trial.” Id. Sampalis 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 symptoms related to
`
`premenstrual syndrome, and is significantly more effective for the
`
`management of dysmenorrhea and emotional premenstrual symptoms than
`
`fish oil.” Id. at 8.
`
`
`
`
`
`20
`
`RIMFROST EXHIBIT 1104 Page 0020
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`6. 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 and a 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 enhancement of an animal,
`
`including human, body. Pharmaceutical, nutraceutical and cosmetic
`
`compositions containing the extract and uses thereof are also within the
`
`invention.” Id. at 3:6–11.
`
`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 (where the krill is Euphasia superba), the Pacific Ocean
`(where the krill is Euphasia pacifica), the Atlantic Ocean and the
`Indian Ocean all contain krill habitats.
`
`Ex. 1013, 25:2–10.
`
`7. Fricke 1986
`
`Fricke 1986 teaches that “[s]mall amounts of alkoxylipids, commonly
`
`referred to as glyceryl ethers or ether lipids, 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 some evidence for the presence of 1-O-
`
`21
`
`RIMFROST EXHIBIT 1104 Page 0021
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`alkylglycerolipids in trace amounts,” which suggested “that some
`
`degradation processes had taken place during storage.” Id. 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
`
`months of frozen storage.” Id. 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. Id.
`
`According to Fricke 1986, 1-O-alkylglycerolipids “were found as
`
`minor lipid components,” and “ranged from 0.3 to 0.6% of total lipid content
`
`of Antarctic Krill” (Ex. 2006, 2) as shown in Table 1, reproduced below.
`
`Id. at Table 1.
`
`With regard to the preparation of the 1977 and 1981 samples,
`
`Fricke 1986 teaches that alkylglycerolipids were isolated after stepwise
`
`hydrolysis of total lipids. Ex. 2006, 1. Phospholipids and neutral lipids
`
`were separated using thin layer chromatography, and phospholipids were
`
`incubated with phospholipase C. Id. Fricke 1986 teaches that the
`
`alkylglycerols were prepared from the phospholipids and neutral lipids by
`
`concentrated methanolic hydrochloric acid, and the alkylglycerols were
`
`isolated using thin layer chromatography. Id. at 1–2. Concerning the 1985
`
`samples, Fricke 1986 explains that those samples were treated “according to
`
`22
`
`RIMFROST EXHIBIT 1104 Page 0022
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`Snyder et al. (1971) with Vitride (sodium-di-hydro-bis-(2-methoxyethoxy)-
`
`aluminate) to form the free alkylglycerols.” Id.
`
`8. Tanaka
`
`Tanaka examines the “PAF-like lipids formed during peroxidation of
`
`PCs from hen egg yolk, salmon roe, sea urchin eggs, and krill in an
`
`FeSO4/EDTA/ascorbate system.” Ex. 1014, Abstract. Tanaka discloses the
`
`phosphatidylcholine subclasses, and their relative amounts, present in
`
`Antarctic krill (Euphausia superba) extract. Ex. 1014, 2, 3. Tanaka
`
`explains that phosphatidylcholine was purified from crude krill lipid extract
`
`using column chromatography and thin layer chromatography. Id. at 2.
`
`Successive degradations of the purified extract using alkaline and acid
`
`hydrolysis were then performed to measure the percentages of
`
`phosphatidylcholine subclasses in the extract. Id.
`
`Table 1 of Tanaka is reproduced below.
`
`Ex. 1014, Table 1. Table 1 shows that the ether phospholipid AAPC
`
`accounted for 23.0% +/- 1.2% of the total phosphatidylcholine present in
`
`Antarctic krill extract. Id. at 3.
`
`
`
`23
`
`RIMFROST EXHIBIT 1104 Page 0023
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`
`Tanaka concludes that although the study “demonstrated the
`
`formation of PAF-like phospholipids during peroxidation of PCs from
`
`different foodstuffs[,] . . . the occurrence of PAF-like lipids in some stored
`
`foods is still speculative and requires further investigation.” Ex. 1014, 5.
`
`9. Prescott
`
`Prescott discloses that PAF “is a phospholipid with potent, diverse
`
`physiological actions, 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 of these structures greatly decreases signaling through the
`PAF receptor. Extension of the sn-2 acetyl residue by one
`methylene is without consequence, but extension by two
`methylenes decreases activity by a factor of 10- to 100-fold,
`depending on the assay. Extension beyond this results in the loss
`of signaling through the PAF receptor.
`
`Ex. 2003, 13 (internal citations omitted).
`
`Prescott further discloses that “[o]xidation of complex lipids in
`
`reduced systems has defined potential oxidation pathways and products, but
`
`whether such oxidizing conditions exist in vivo is problematic, given the
`
`unstable nature of the reactive intermediates and the potential of metabolism
`
`of the oxidation products.” Ex. 2003, 14.
`
`10. Zimmerman
`
`Zimmerman is a review article that teaches that “[t]he PAF signaling
`
`system can trigger inflammatory and thrombotic cascades, amplify these
`
`cascades when acting with other mediators, and mediate molecular and
`
`cellular interactions (cross talk) between inflammation and thrombosis.”
`24
`
`RIMFROST EXHIBIT 1104 Page 0024
`
`
`
`IPR2017-00746
`Patent 9,028,877 B2
`
`Ex. 2004, Abstract. Zimmerman explains that artificial oxidation of
`
`phosphatidylcholines “generates a large series of phospholipids in which the
`
`polyunsaturated fatty acid at the sn-2 position . . . is fragmented to shorter
`
`chain lengths. Some of these oxidized phospholipids have sufficiently short
`
`sn-2 residues and other structural features that allow them to be recognized
`
`by the PAF receptor.” Id. at 4–5.
`
`D. Obviousness Based on
`Breivik, Catchpole, and Fricke 1984
`
`Petitioner asserts that claims 1‒3, 6, 8, 9, 11, 12, 15, 17 and 18 are
`
`unpatentable under § 103(a) as obvious in view of Breivik, Catchpole and
`
`Fricke 1984. Pet. 31–51. Patent Owner disagrees. PO Resp. 14–21.
`
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`
`differences between the claimed subject matter and the prior art are such that
`
`the subject matter, as a whole, would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art to which said
`
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousness is resolved on the basis of underlying
`
`factual determinations including: (1) the scope and content of the