`
`The Japanese consume a higher amount of EPA and DHA in their diets than Western
`
`populations. In fact, Defendants’ own reference states that the results from studies where the
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`patient population is exclusively Japanese cannot be generalized to other populations.2053 The
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`Japanese diet comprises between 8 and 15 times more EPA and DHA than typical the typical
`
`Western diet. The Western diet typically consists of higher amounts of polyunsaturated omega-6
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`fatty acids and saturated fatty acids. Therefore, a person of ordinary skill would understand that
`
`the Japanese respond differently to lipid lowering agents than Westerners.
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`Further, Defendants have failed to offer a purported combination of references as part of
`
`their obviousness contentions that include Nozaki and Hayashi. Similarly, they fail to offer any
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`motivation to combine Nozaki and Hayashi with the other references of their purported
`
`obviousness combinations. Therefore, Defendants should be precluded from relying on these
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`references.
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`(iii) Grimsgaard, Mori 2000
`and/or Maki Do Not Disclose
`Purported Knowledge that
`DHA was Responsible for the
`Increase in LDL-C
`
`Defendants assert, incorrectly, that “it was known in the art as of February 2009 that
`
`administration of DHA (alone or in a mixture) resulted in the negative effect of increasing LDL-
`
`C levels.”2054 Defendants’ caveat of DHA being “alone or in a mixture” is telling that it was not
`
`known that DHA alone resulted in an increase in LDL-C levels. Further, the prior art Defendants
`
`rely on to support this statement does not categorize the increase in LDL-C as a “negative effect”
`
`in light of the overall impact of the disclosed composition on all lipid parameters. Further, the
`
`
`2053 Yokoyama 2007 at 1097 (“Because our population was exclusively Japanese, we cannot generalise our results to
`other populations.”).
`2054 Defendants’ Joint Invalidity Contentions at 532.
`
`CONFIDENTIAL
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`Ex. 1019, p. 736 of 2444
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`patients in Grimsgaard, Mori 2000 and Maki had normal to borderline-high baseline TG levels.
`
`As discussed above in Section III, a person of ordinary skill would not expect the same LDL-C
`
`effect in patients with lower baseline TG levels—the subjects of Grimsgaard, Mori 2000 and/or
`
`Maki —as in very-high TG patients because patients with higher TG levels had different lipid
`
`responses compared to patients with lower TG levels. Patients with very-high TG levels were
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`considered fundamentally different from patients with borderline-high or high triglycerides from
`
`a lipid chemistry, medical, clinical guideline, regulatory, and therapeutic standpoint. A person of
`
`ordinary skill in the art would have expected that fish oils (and other TG lowering agents) would
`
`not increase LDL-C substantially in patients with normal to borderline high TG levels, but would
`
`substantially increase LDL-C in patients with very high TG levels.
`
`Defendants rely on Grimsgaard, Mori 2000 and/or Maki to demonstrate that it was known
`
`that “DHA was responsible for the increase in LDL-C levels.”2055 The discussion related to
`
`Grimsgaard in Section V.D.3.c.1.a.ii.a.i and Mori 2000 in Section V.D.3.c.1.a.i.a.iii is
`
`incorporated herein by reference.
`
`Defendants argue that Maki discloses the administration of purified DHA resulted in the
`
`desired reduction of TGs, but also significantly increased LDL-C levels.2056 Maki was designed
`
`to assess the impact of 1.52g/day DHA supplements on the serum lipid profile of patients with
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`below-average levels of HDL-C levels.2057 The DHA supplemented group was administered
`
`capsules containing 1.52 g/day DHA and 0.84 g/day palmitic acid, in addition to other saturated,
`
`
`2055 Defendants’ Joint Invalidity Contentions at 529.
`2056 Defendants’ Joint Invalidity Contentions at 532.
`2057 Maki at 190.
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`CONFIDENTIAL
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`IPR2022-00215
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`Ex. 1019, p. 737 of 2444
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`monounsaturated and polyunsaturated fatty acids. 2058 Therefore, Maki demonstrated that when
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`1.52 g/day DHA and 0.84 g/day palmitic acid is administered to patients with below-average
`
`levels of HDL-C levels and borderline-high TG levels, a significant increase in LDL-C is
`
`observed.2059 However, one cannot attribute the rise in LDL-C solely to DHA, because the
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`authors admit that “changes in fatty acid intake other than DHA, particularly palmitate, may have
`
`also contributed to the elevation in LDL cholesterol.”2060 Further, Maki admits that the
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`“mechanism(s) responsible for the changes in the lipid profile associated with DHA
`
`supplementation are not fully understood.”2061 Therefore, the results of Maki are inconclusive as
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`to DHA’s effect alone on LDL-C levels.
`
`Defendants mischaracterize the rise in LDL-C associated with the administration of
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`omega-3 fatty acids as being a “negative effect” because they incorrectly focus on only the LDL-
`
`C effect and fail to look at the lipid effects as a whole. In fact, Maki does not find the increase in
`
`LDL-C to be troublesome; Maki states that “the lack of increase in the total/HDL cholesterol
`
`ratio, the decline in the triglyceride/HDL cholesterol ratio and the reduction in the proportion of
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`cholesterol carried by small, dense LDL particles render the changes in LDL cholesterol level
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`less worrisome.”2062 Therefore, when one of ordinary skill in the art reviewed all the lipid effects
`
`of the DHA-rich algal triglycerides, they would have understood that the increase is LDL-C was
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`“less worrisome” because of the “potentially favorable effects on triglycerides, the
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`2058 Maki at 191.
`2059 Maki at 195.
`2060 Maki at 197; Yu et al., Plasma Cholesterol-Predictive Equations Demonstrate that Stearic Acid is Neutral and
`Monounsaturated Fatty Acids are Hypocholesterlemic, 61 AM J CLIN NUTR 1129, 1136 (1995).
`2061 Maki at 197.
`2062 Maki at 197.
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`CONFIDENTIAL
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`738
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`IPR2022-00215
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`Ex. 1019, p. 738 of 2444
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`triglyceride/HDL cholesterol ratio and the fraction of LDL cholesterol carried by small, dense
`
`particles.”2063
`
`Therefore, Grimsgaard, Mori 2000 and/or Maki fail to substantiate Defendants’ assertion
`
`that it was known that DHA was responsible for the increase in LDL-C levels. Further,
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`Defendants ignore, without explanation, other studies that demonstrate that DHA decreases or
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`has little effect on LDL-C levels.2064 Defendants identify no other basis upon which a person of
`
`ordinary skill would have sought to combine the Omacor PDR/Lovaza PDR with Katayama,
`
`Matsuzawa, Takaku, Grimsgaard, Mori 2000 and/or Maki.
`
`(iii)
`
`The ‘399 Patent is not Obvious Over the
`Omacor PDR/Lovaza PDR, in Combination
`with Katayama in View of Satoh and/or in
`View of Satoh or Shinozaki in Further View
`of Contacos
`
`With respect to the ‘399 Patent, Defendants present a combination of five references: “the
`
`Omacor PDR/Lovaza PDR, in combination with the known clinical benefits of administering
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`pure EPA as evidenced by Katayama in view of Satoh and/or in view of Satoh or Shinozaki in
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`further view of Contacos.”2065 Defendants also present charts purporting to assert that an
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`additional 60 references may be combined in order to render the Claims obvious. Not only do
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`Defendants ignore the improbability that a person of ordinary skill would combine 60 separate
`
`references, they additionally do not suggest any identify for combining these references.
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`Although Defendants need not point to an explicit statement in the prior art motivating the
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`combination of these references, any assertion of an “apparent reason” to combine must find a
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`2063 Maki at 197.
`2064 See e.g., Grimsgaard; Agren; Conquer 1996; Nelson; Hamazaki; Woodman; Nestel; Childs.
`2065 Defendants’ Joint Invalidity Contentions at 529.
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`CONFIDENTIAL
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`IPR2022-00215
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`Ex. 1019, p. 739 of 2444
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`basis in the factual record.2066 Defendants’ unsupported cobbling of selective disclosures
`
`represents hindsight reconstruction.2067 Defendants’ contentions are no more than an assertion
`
`that certain claim elements were known in the prior art. Throughout their contentions,
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`Defendants’ selectively cite to data points in a reference without considering other disclosures or
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`even the reference as a whole. Each reference, however, must be evaluated for all that it
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`teaches.2068 Accordingly, Defendants fail to meet their burden to establish prima facie
`
`obviousness.
`
`The Lovaza PDR fails to disclose or even suggest the claimed method of reducing
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`triglycerides in a subject with the claimed pharmaceutical composition with the specified fatty
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`acid compositions or administration period. The Lovaza PDR further does not disclose a method
`
`to effect the specified TG reduction without substantially increasing LDL-C. Indeed, the Lovaza
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`PDR discloses the exact opposite, that the EPA/DHA composition contained within the reference
`
`would cause a significant increase in LDL-C levels in the very high TG patient population, for
`
`whom the product is indicated. At most, the Lovaza PDR discloses administration of a
`
`
`2066 See, e.g., In re Vaidyanathan, 381 F. App’x 985, 993–94 (Fed. Cir. 2010) (“[W]hile KSR relaxed some of the
`formalism of earlier decisions requiring a ‘teaching, suggestion, or motivation’ to combine prior art references, it did
`not remove the need to anchor the analysis in explanation of how a person of ordinary skill would select and apply
`the teachings of the references. . . . Obviousness is determined as a matter of foresight, not hindsight.”); Daiichi
`Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) (The assertion of a starting point “must
`avoid hindsight bias; it must look at the state of the art at the time the invention was made to find a motivation to
`select and then modify a lead compound to arrive at the claimed invention.” This turns on the known “properties and
`elements of the prior art compounds.”) (emphasis in original); Forest Labs., Inc. v. Ivax Pharm., Inc., 438 F. Supp.
`2d 479, 492-93 (D. Del. 2006) (rejecting defendants’ contention that claims to (+)-citalopram were “prima facie
`obvious in light of . . . claims [to] racemic citalopram” despite its use to “treat the same condition,” and concluding
`that defendants “have not demonstrated by clear and convincing evidence that one skilled in the art would have been
`motivated to resolve citalopram in June 1988.”), aff’d, 501 F.3d 1263 (Fed. Cir. 2007).
`2067 See, e.g., Innogenetics N.V. v. Abbott Laboratories, 512 F.3d 1363 (Fed. Cir. 2008) (noting that, even under
`KSR, “[w]e must still be careful not to allow hindsight reconstruction of references to reach the claimed invention
`without any explanation as to how or why the references would be combined to produce the claimed invention”).
`2068 Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1305 (Fed. Cir. 2011)
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`CONFIDENTIAL
`
`740
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 740 of 2444
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`prescription fish oil, a combination of approximately 465 mg EPA and 375 mg DHA, as an
`
`adjunct to diet to reduce TG levels in adult patients with very-high (at least 500 mg/dL) TG
`
`levels.
`
`Defendants formulate an obviousness argument that relies on Contacos. 2069 However,
`
`Defendants fail to provide any factual or legal basis as to why Contacos discloses a claim
`
`element, an “apparent reason” or motivation to combine the elements in the manner claimed,2070
`
`or “a reasonable expectation of success”2071 of achieving the claimed invention.
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`Contacos disclosed administration of fish oil, pravastatin, and combination of fish oil and
`
`pravastatin, but it does not disclose administration of EPA of the recited composition. Therefore,
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`Contacos fails to provide motivation to administer purified EPA to a very high TG patient
`
`population and does not provide any reasonable expectation of success in lowering TG levels in
`
`the very high TG patient population without increasing LDL-C. Contacos also fails to provide
`
`motivation to administer purified EPA to a very high TG patient population and does not provide
`
`any reasonable expectation of success in lowering TG levels in the very high TG patient
`
`population without increasing LDL-C.
`
`The proposed combinations do not render the independent claim of the ’399 Patent
`
`obvious and Defendants’ burden to prove otherwise is especially difficult because the PTO
`
`
`2069 Id.
`2070 KSR, 550 U.S. at 417–19; TriMed, Inc. v. Stryker Corp., 608 F.3d 1333, 1341 (Fed. Cir. 2010). Hindsight may
`not be employed to identify relevant prior art and relevant teachings therein: Heidelberger Druckmaschinen AG v.
`Hantscho Comm. Prods., Inc., 21 F.3d 1068, 1071–72 (Fed. Cir. 1994); Monarch Knitting Mach. Corp. v. Sulzer
`Morat GmbH, 139 F.3d 877, 881 (Fed. Cir. 1998).
`2071 Proctor & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009) (henceforth, “P&G”);
`Takeda Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1361 (Fed. Cir. 2007); KSR, 550 U.S. at 416 (a
`combination of elements “must do more than yield a predictable result;” combining elements that work together “in
`an unexpected and fruitful manner” would not have been obvious).
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`CONFIDENTIAL
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`741
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`IPR2022-00215
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`Ex. 1019, p. 741 of 2444
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`considered Katayama, Satoh, Shinozaki, Contacos, Geppert, Kelley and Lovaza (both generally
`
`and the Lovaza package insert specifically) during prosecution.2072
`
`The analysis of the independent claim of the ’399 Patent is incorporated into all asserted
`
`claims that depend from this Claim.
`
`(a)
`
`A Person of Ordinary Skill Would
`Not Have Been Motivated to
`Replace the Mixed Fish Oil Active
`Ingredient in Lovaza with EPA of
`the Recited Composition
`
`For an invention to be obvious, there must have been an “apparent reason” to make it.
`
`The subject matter of the ‘399 patent claims would not have been obvious in light of these
`
`references because a person of ordinary skill would not have been motivated to purify EPA or
`
`been able to reasonably expect that the claimed pharmaceutical composition would reduce TG
`
`levels without an increase in LDL-C levels.
`
`(i)
`
`Katayama, Satoh and/or
`Shinozaki Do Not Disclose
`Purported Known Clinical
`Benefits of Administering
`Pure EPA
`
`Defendants rely on Katayama, Satoh and/or Shinozaki to demonstrate the “known clinical
`
`benefits of administering pure EPA - lowering triglycerides without raising LDL-C.” As
`
`discussed in Section V.D.3.c.1.a.i.a.i, incorporated herein by reference, Katayama merely
`
`confirms the safety of long term treatment of Epadel and its ability to lower both serum total
`
`cholesterol and triglyceride levels. Katayama does not mention LDL-C levels at all, let alone
`
`discuss any purported “benefits” observed related to LDL-C. Katayama does not disclose or
`
`
`2072 See, e.g., Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012)(taking into account that “the
`examiner considered during prosecution all the prior art cited by [the defendants] against the claimed invention.
`Thus, the examiner found that the prior art applied in this case had not precluded patentability even before the clear
`and convincing standard came into play”).
`
`CONFIDENTIAL
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`742
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`IPR2022-00215
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`Ex. 1019, p. 742 of 2444
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`suggest that the LDL-C results obtained were a clinical benefit, nor would a person of ordinary
`
`skill view these references as teaching such a benefit for very-high TG patients.
`
` Satoh administered 1.8g/day of >98% EPA to patients in order to measure the effects of
`
`EPA on C-reactive protein and examine how alteration of lipoprotein profile by EPA affects
`
`systemic inflammation. Satoh reported a statistically significant reduction in LDL-C only when
`
`compared to baseline, there was no significant effect when compared to placebo.2073
`
`Defendants’ characterization of Satoh as disclosing the lowering of TG levels without increasing
`
`LDL-C to be a “clinical benefit” is incorrect.2074 Satoh does not disclose or suggest that the
`
`LDL-C results obtained were a clinical benefit, nor would a person of ordinary skill view these
`
`references as teaching such a benefit for very-high TG patients. As discussed above, one of
`
`ordinary skill in the art would not expect LDL-C to increase in a patient with TG below 500
`
`mg/dL and Satoh provides no evidence to the contrary. A person of ordinary skill in the art,
`
`however, would have expected that fish oils (and other TG lowering agents) would substantially
`
`increase LDL-C in patients with very high TG levels. Satoh fails to provide motivation to
`
`administer purified EPA to a very high TG patient population and does not provide any
`
`reasonable expectation of success in lowering TG levels in the very high TG patient population
`
`without increasing LDL-C.
`
`Further, Satoh was a small study conducted in only Japanese patients. This study would
`
`not have been extrapolated to Western populations because the Japanese diet contains much
`
`more fish and has a number of other different attributes. The Japanese consume a higher amount
`
`of EPA and DHA in their diets than Western populations. In fact, Defendants’ own reference
`
`
`2073 Satoh at 145.
`2074 Defendants’ Joint Invalidity Contentions at 528-29.
`
`CONFIDENTIAL
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`743
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`IPR2022-00215
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`Ex. 1019, p. 743 of 2444
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`

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`states that the results from studies where the patient population is exclusively Japanese cannot be
`
`generalized to other populations.2075 The Japanese diet comprises between 8 and 15 times more
`
`EPA and DHA than typical the typical Western diet. The Western diet typically consists of
`
`higher amounts of polyunsaturated omega-6 fatty acids and saturated fatty acids. Therefore, a
`
`person of ordinary skill would understand that the Japanese respond differently to lipid lowering
`
`agents than Westerners.
`
`Shinozaki studied the long-term effect of EPA on serum levels of Lipoprotein (a) (Lp(a))
`
`and lipids such as triglycerides, total cholesterol, and low density lipoprotein particles.
`
`Defendants’ characterization of Shinozaki as disclosing the lowering of TG levels without
`
`increasing LDL-C to be a “clinical benefit” is incorrect.2076 Shinozaki says nothing about an
`
`LDL-C effect because it measured LDL particle number, not LDL-C. The finding disclosed by
`
`Shinozaki was that “long term administration of EPA may lower Lp(a) and serum lipids.”2077 In
`
`addition to Shinozaki’s lack of disclosure regarding LDL-C, Defendants identify no other basis
`
`upon which a person of ordinary skill would have sought to combine the composition disclosed
`
`in Shinozaki.
`
`Therefore, Katayama, Satoh and/or Shinozaki fail to substantiate Defendants’ assertion
`
`that pure EPA lowers triglycerides without raising LDL-C. Further, other studies cited by
`
`Defendants suggest that EPA increases LDL-C.2078 Defendants identify no other basis upon
`
`
`2075 Yokoyama 2007 at 1097 (“Because our population was exclusively Japanese, we cannot generalise our results to
`other populations.”).
`2076 Defendants’ Joint Invalidity Contentions at 529-29.
`2077 Shinozaki at 107-109.
`2078 See, e.g., Rambjor.
`
`CONFIDENTIAL
`
`744
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`IPR2022-00215
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`Ex. 1019, p. 744 of 2444
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`

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`
`which a person of ordinary skill would have sought to combine the Lovaza PDR with Katayama,
`
`Satoh, Shinozaki and/or Contacos.
`
`(ii)
`
`Geppert and/or Kelley Do
`Not Disclose Purported
`Knowledge that DHA was
`Responsible for the Increase
`in LDL-C
`
`Defendants assert, incorrectly, that “it was known in the art as of February 2009 that
`
`administration of DHA (alone or in a mixture) resulted in the negative effect of increasing LDL-
`
`C levels.”2079 Defendants’ caveat of DHA being “alone or in a mixture” is telling that it was not
`
`known that DHA alone resulted in an increase in LDL-C levels. Further, the prior art Defendants
`
`rely on to support this statement do not categorize the increase in LDL-C as a “negative effect”
`
`in light of the overall impact of the disclosed composition on all lipid parameters. Further, the
`
`patients in Geppert and Kelley had normal and borderline-high/high baseline TG levels,
`
`respectively. As discussed above in Section III, a person of ordinary skill would not expect the
`
`same LDL-C effect in patients with lower baseline TG levels—the subjects of Geppert and/or
`
`Kelley —as in very-high TG patients because patients with higher TG levels had different lipid
`
`responses compared to patients with lower TG levels. Patients with very-high TG levels were
`
`considered fundamentally different from patients with borderline-high or high triglycerides from
`
`a lipid chemistry, medical, clinical guideline, regulatory, and therapeutic standpoint. Although a
`
`person of ordinary skill in the art would have expected that fish oils (and other TG lowering
`
`agents) would not increase LDL-C substantially in patients with normal to borderline high TG
`
`
`2079 Defendants’ Joint Invalidity Contentions at 532.
`
`CONFIDENTIAL
`
`745
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 745 of 2444
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`

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`levels, a person of ordinary skill in the art would expect a substantial increase in LDL-C in
`
`patients with very high TG levels.
`
`Defendants rely on Geppert and/or Kelley to demonstrate that it was known that “DHA
`
`was responsible for the increase in LDL-C levels.”2080 Both Geppert and Kelley administer
`
`DHA-rich oil that is contaminated with other saturated and polyunsaturated fatty acids.
`
`Therefore, a person of ordinary skill would have known it is unsuitable for evaluating the
`
`independent effects of DHA because it is not clear how much of the supplement’s effects can be
`
`attributed to DHA.2081 For example, Defendants’ own prior art teaches that changes in fatty acid
`
`intake other than DHA, particularly palmitate, may contribute to elevations in LDL-C.2082
`
`In Geppert, 0.94 g/day of DHA derived from microalgae oil was administered to
`
`normolipidaemic vegetarians for 8 weeks. A person of ordinary skill would not have been
`
`convinced that DHA increases LDL-C based on Geppert. As Geppert acknowledges, prior
`
`studies have shown “[i]nconsistent effects of DHA on LDL cholesterol.”2083 Rather than reading
`
`Geppert in isolation, a person of ordinary skill would have read Geppert together with the prior
`
`studies cited in Geppert. As such, a person of ordinary skill would have concluded that there
`
`was confusion in the art and it was unclear whether DHA increased LDL-C.
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`A person of ordinary skill would have expected that Geppert’s results would be
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`applicable to other components of fish oil such as EPA. Nothing in Geppert suggests that DHA
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`was the only component of fish oil to increase LDL-C. For example, there is no data comparing
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`2080 Defendants’ Joint Invalidity Contentions at 530.
`2081 See Mori 2006 at 96.
`2082 Maki at 197.
`2083 Geppert at 784.
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`DHA to fish oil or EPA. In fact, Geppert discusses DHA and fish oil together when trying
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`explain the mechanism of LDL-C increase.2084 A person of ordinary skill would have not
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`expected that EPA and DHA would have different effects on LDL-C based on Geppert.
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`Defendants contend that Kelley shows that DHA was responsible for the increase in
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`LDL-C.2085 In Kelley, patients fasting serum TG levels of 150 to 400 mg/dL received 7.5 g/day
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`of DHA oil containing 3 g of DHA for 90 days. Kelley does not show that DHA is responsible
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`for the increase in LDL-C. Kelley suggests that increase in LDL-C is a general phenomenon
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`associated with triglyceride-lowering drugs, stating that a similar increase was induced by fibrate
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`therapy.2086 Further, Kelley teaches that the increase in LDL-C is not harmful when viewed in
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`context with the other lipid effects reported in the study. Kelley states that:
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`DHA supplementation may lower the risk of CVD by reducing
`plasma triacylglycerols; triaclyglycerol:HDL; the number of
`small, dense LDL particles; and mean diameter of VLDL particles.
`An increase was observed in fasting LDL cholesterol, but it
`is unlikely this increase is detrimental because no increase was
`observed in the overall number of LDL particles; actually, there
`was an 11% reduction that was statistically not significant. The
`reason LDL cholesterol increased despite no change in LDL
`particle number was that the LDL particles were made larger and
`hence more cholesterol rich by DHA treatment.2087
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`Kelley specifically teaches that the increase in LDL-C caused by DHA supplementation
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`is unlikely to be “detrimental” because there was not a parallel increase in overall LDL particle
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`number. Kelley’s ultimate conclusion is that “[o]verall, DHA supplementation reduced the
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`concentrations of atherogenic lipids and lipoproteins and increased concentrations of
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`2084 Id.
`2085 Defendants’ Joint Invalidity Contentions at 530.
`2086 Kelley at 329.
`2087 Kelley at 329
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`cardioprotective lipoproteins” and that “DHA supplementation may improve cardiovascular
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`health.”2088 Rather than concluding that DHA was uniquely responsible for a rise in LDL-C
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`levels, a person of ordinary skill would understand Kelley to disclose that DHA had uniquely
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`beneficial cardioprotective effects. Indeed, instead of identifying DHA as composition with
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`negative attributes, a person of ordinary skill would understand that the reference taught towards
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`the use of DHA. In addition, none of the study subjects in Kelley had a TG level above 400
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`mg/dL and, for the reasons previously discussed, a person of ordinary skill would understand the
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`very high TG patient population to be different in terms of their response to lipid therapy,
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`including administration of DHA. A person of ordinary skill in the art would have expected that
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`fish oils (and other TG lowering agents) would not increase LDL-C substantially in patients with
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`normal to borderline high TG levels, but a person of ordinary skill in the art would expect a
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`substantial increase in LDL-C in patients with very high TG levels.
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`Therefore, Geppert and/or Kelley fail to substantiate Defendants’ assertion that it was
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`known that DHA was responsible for the increase in LDL-C levels.
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`Throughout their contentions, Defendants’ selectively cite to data points in a reference
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`without considering other disclosures or even the reference as a whole. Each reference,
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`however, must be evaluated for all that it teaches.2089 As is the case with Kelley, Defendants use
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`hindsight to characterize a reference based on LDL-C levels alone without considering the other
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`lipid effects studied, considered and reported.2090 The isolated manner in which Defendants
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`2088 Kelley at 324, 332.
`2089 Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1305 (Fed. Cir. 2011)
`2090 Kelley at 324 (providing that the objectives of the study were to determine “the effects of DHA supplementation
`on the concentrations of apoproteins; large, medium, and small VLDL, LDL, and HDL particles; and the mean
`diameters of these particles in fasting and postprandial plasma.”).
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`select such data points is not the approach that a person of ordinary skill would have taken at the
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`time of the invention. Defendants’ approach represents the use of impermissible hindsight bias.
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`A person of ordinary skill would take into consideration the entire disclosure of a reference,
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`including lipid effects other than LDL-C. In pointing only to LDL-C, Defendants ignore,
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`without explanation, the other effects of DHA that a person of ordinary skill would consider.
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`With respect to Kelley, These effects would teach a person of ordinary skill that DHA has a
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`favorable effect in hypertriglyceridemic patients.
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`Therefore, Geppert and/or Kelley fail to substantiate Defendants’ assertion that it was
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`known that DHA was responsible for the increase in LDL-C levels. Further, Defendants ignore,
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`without explanation, other studies that demonstrate that DHA decreases or has little effect on
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`LDL-C levels.2091 Defendants identify no other basis upon which a person of ordinary skill
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`would have sought to combine the Lovaza PDR with Katayama, Satoh, Shinozaki, Contacos,
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`Geppert and/or Kelley.
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`(iv) A Person of Ordinary Skill Would Not Have
`been Motivated to Find an Omega-3 Fatty
`Acid “Therapy that Would Reduce TG
`Levels in Patients with TG Levels ≥500
`mg/dL Without Negatively Impacting LDL-
`C Levels.”
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`Plaintiffs agree that although there was a need to find a therapy that would reduce TG
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`levels in patients with very-high TG levels, without negatively impacting LDL-C levels, there
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`was no motivation (or reasonable expectation of success) to find an omega-3 fatty acid therapy,
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`or to modify Lovaza/Omacor, to effect a reduction in TG levels without increasing LDL-C levels
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`for very-high TG patients at the time of the invention. A person of ordinary skill in the art
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`2091 See e.g., Grimsgaard; Agren; Conquer 1996; Nelson; Hamazaki; Woodman; Nestel; Childs.
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`understood that the rise in LDL-C caused by omega-3 fatty acids (or fibrates) and
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`Lovaza/Omacor was a consequence of the TG-lowering mechanism. The therapies that were
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`available at the time of the invention to treat very-high TGs were niacin, fibrates and prescription
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`omega-3 fatty acids (Lovaza/Omacor). However, niacin was associated with a highly
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`undesirable side effects—including “flushing” (or reddening of the face and other areas with a
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`burning sensation) and dyspepsia—that limited their usefulness.2092 Fibrates were effective at
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`reducing TGs, but they also caused an increase in LDL-C levels in patients with very-high TG
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`levels. To combat the rise of LDL-C, doctors often prescribed fibrates in combination with an
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`LDL-C lowering medication such as a statin.2093 However, the risk of rhabdomyolysis increased
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`five-fold if fibrates were administered with a statin.2094 Therefore, physicians were reluctant to
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`recommend, and patients were hesitant embrace, a combination fibrate/statin course of
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`treatment.2095 Finally, Lovaza/Omacor were also effective at reducing TG levels, but, similar to
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`fibrates, could cause a substantial increase in LDL-C levels for very-high TG patients. However,
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`Lovaza/Omacor could be safely administered with statins in order to mitigate increased LDL-C.