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`C was often offset by concurrent treatment with statins.6337 The safety and efficacy of using
`
`prescription omega-3 in combination with a statin has been well-established.6338
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`Although an increase in LDL-C was generally observed when omega-3 fatty acids were
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`administered to patients with very-high TG levels, the increase in LDL-C was not necessarily a
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`cause for concern because LDL-C is often low in patients with severe hypertriglyceridemia.
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`Therefore, the final LDL-C concentration may still be in the normal range.6339 Furthermore, it
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`was understood that the overall lipid effect of Lovaza/Omacor was beneficial.6340
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`In two pivotal studies in very-high TG patients, both of which used prospective,
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`randomized, double-blind, placebo-controlled study designs, Lovaza/Omacor increased HDL
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`levels from baseline 13% (p=0.014) and 5.9% (p=0.057).6341 Correspondingly, prescription
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`omega-3 fatty acids were known to have favorable effects on non-HDL-C levels.6342 Therefore,
`
`“[i]n patients with very-high triglyceride levels, prescription omega-3 fatty acids 4 g/day can
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`substantially reduce triglycerides and VLDL levels and may increase LDL levels, but the net
`
`
`6337 See Harris 2008 at 14, McKenney at 722.
`6338 McKenney at 722-23.
`6339 See Westphal at 918, Harris 1997 at 389.
`6340 See Pownall at 295 (stating that “[t]reatment with ω-3 fatty acids appear to change the lipid profile of individuals
`with elevated TG to one that may be less atherogenic by chancing LDL structure; lowering serum [cholesteryl ester
`transfer activity], serum TG and VLDL-C; and increasing serum HDL-C”); Harris 1997 at 389 (stating that “[t]he
`increase in LDL, which was substantial on a percentage basis, has been a common finding in past studies in [very-
`high TG] patients. It may not be as problematic as it appears, however,” and “the use of omega-3 fatty acids for the
`treatment of severe hypertriglyceridemia may be beneficial not only for the short-term prevention of acute
`pancreatitis, but also for the long-term prevention of CHD”); Bays III at 248 (“No clinical trial data exist that this
`rise in LDL-C represents harm or potential “toxicity” to patients. In fact, most evidence supports that omega-3 fatty
`acids reduce cardiovascular risk as do fibrates. Importantly, clinical trials mostly support that even with increases in
`LDL-C, omega-3 fatty acids decrease the total cholesterol (TC) carried by atherogenic lipoproteins, as reflected by
`decreased non-HDL-C levels (TC minus HDL-C)”).
`6341 McKenney 2007 at 721 (citing Harris 1997 and Pownall).
`6342 McKenney 2007 at 722 (see Fig. 1).
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`CONFIDENTIAL
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`2332
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 2332 of 2444
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`effect is a reduction in non-HDL levels. Modest increases in HDL level are also common in
`
`patients treated with prescription omega-3 fatty acids.” Prescription omega-3 therapy was also
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`known to alter lipoprotein particle size and composition in a favorable manner by decreasing the
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`number of small, dense LDL particles to larger LDL particles.6343 Lovaza/Omacor “adversely
`
`raise[d] LDL cholesterol concentration but the increase in LDL cholesterol concentration
`
`reflect[ed] a less atherogenic light LDL subfraction profile that may be favorable.”6344
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`Therefore, one of ordinary skill in the art believed that the use of Lovaza/Omacor, and omega-3
`
`fatty acids generally, “for the treatment of severe hypertriglyceridemia may be beneficial not
`
`only for the short-term prevention of acute pancreatitis, but also for the longer-term prevention
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`of [coronary heart disease].”6345
`
`Therefore, contrary to Defendants’ assertion that “a person of ordinary skill in the art at
`
`the time of the claimed inventions would have been motivated to find a therapy that would
`
`reduce TG levels in patients with TG levels of at least 500 mg/dL without negatively impacting
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`LDL-C levels,”6346 one of ordinary skill in the art at the time of the invention understood that the
`
`rise in LDL-C caused by omega-3 fatty acids was a by-product of reducing TGs in patients with
`
`very-high TG levels. A person of ordinary skill in the art would have expected LDL-C to
`
`increase in very-high TG patients, and in some instances the rise was not concerning because
`
`LDL-C is often low in patients with severe hypertriglyceridemia and therefore final
`
`concentration would still be in the normal range. When LDL-C levels increased beyond what
`
`was recommended by the ATP-III, prescribers often relied on statins to safely and effectively
`
`
`6343 McKenney 2007 at 722 (citing Calabresi and Stalenhoef).
`6344 Stalenhoef at 134.
`6345 Harris 1997 at 389.
`6346 Defendants’ Joint Invalidity Contentions at 795.
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`CONFIDENTIAL
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`2333
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`Ex. 1019, p. 2333 of 2444
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`reduce LDL-C levels. Furthermore, it was well known that the overall lipid effect of
`
`Lovaza/Omacor was beneficial because non-HDL-C levels often increased. Defendants fail to
`
`identify any other basis upon which a person of ordinary skill would have been motivated to find
`
`a therapy that would reduce TG levels in patients with very-high TG levels without negatively
`
`impacting LDL-C levels. Further, a person of ordinary skill in the art would have understood
`
`that EPA therapy would not reduce Apo-B6347 (which is a reflection of total atherogenic
`
`lipoproteins) 6348 in very high TG patients, and accordingly would not have been motivated to
`
`administer the claimed EPA composition to the very high TG patient population.
`
`Defendants make the conclusory allegation that “routine optimization” by a person of
`
`ordinary skill would yield the claimed invention.6349 Defendants, however, have offered no
`
`explanation to support that allegation and they further fail to establish any of the required criteria
`
`of “routine optimization” or the prerequisites to this argument. They also fail to provide any
`
`factual detail to support their allegation and they fail to link the allegation to any particular claim
`
`or claim element. Defendants mere allegation constitute an improper placeholder to later
`
`advance arguments not disclosed in their contentions as required by the Local Rules. In addition,
`
`for the reasons discussed herein, a person of ordinary skill would not be motivated to make the
`
`combinations alleged by Defendants and, for the same reasons, it would not be routine to
`
`combine such references. Where, for example, defendants argue that it would be routine to go
`
`from the high TG patient population to the very high TG patient population,6350 they provide no
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`basis for that conclusory assertion and are incorrect. As discussed, a person of ordinary skill
`
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`6347 see Section V.O.
`6348 see Section III.
`6349 See, e.g., Defendants’ Joint Invalidity Contentions at 822, 790, 804, .
`6350Defendants’ Joint Invalidity Contentions at 816-17
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`CONFIDENTIAL
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`2334
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`Ex. 1019, p. 2334 of 2444
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`would have understood these patient populations to be distinct with different impacts of lipid
`
`therapy on blood-lipid chemistry for each group. Accordingly, a person of ordinary skill would
`
`not have considered the dosage modification suggested by defendants to be routine; Defendants’
`
`argument to the contrary represents hindsight bias.
`
`In addition, a person of ordinary skill would have no motivation to combine these
`
`references because EPA would have been expected to have same result as the mixture of EPA
`
`and DHA used in Lovaza/Omacor.
`
`(v)
`
`A Person of Ordinary Skill Would Not Have
`Had a Reasonable Expectation of Success
`with the Combinations Defendants
`Hypothesize
`
`Defendants provide no evidence that a person or ordinary skill would have had a
`
`reasonable expectation of successfully obtaining the claimed invention—a method of reducing
`
`triglycerides in a subject having very-high triglyceride levels by administering EPA of the
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`recited purity to effect a reduction in triglycerides without substantially increasing LDL-C—by
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`combining the references cited by defendants. For a particular combination of references, there
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`must be a reasonable expectation that the combination will produce the claimed invention. In
`
`this case, the art taught that DHA and EPA have similar effects on LDL-C levels in patients with
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`very-high TG levels.6351 A person of ordinary skill would have expected EPA, like
`
`Lovaza/Omacor, to raise LDL-C levels when administered to patients in the very-high TG
`
`patient population. As discussed in Section III and above, it was well known that TG-lowering
`
`
`6351 As discussed above, see supra section III, a person of ordinary skill would have understood EPA and DHA to
`have the same TG lowering mechanism and would have further understood that the increase in LDL-C
`accompanying the TG-lowering effects of Lovaza was a product of that same mechanism. Accordingly, a person of
`ordinary skill would have expected EPA to increase LDL-C levels in patients with very-high TG levels in similar
`fashion to Lovaza or DHA alone.
`
`CONFIDENTIAL
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`2335
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`Ex. 1019, p. 2335 of 2444
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`agents, specifically fibrates and Lovaza/Omacor, and little or no effect on LDL-C levels for
`
`normal to high TG patients, but caused significant increases in LDL-C levels for patients with
`
`very-high triglycerides. The art cited by Defendants provides no basis for a person of ordinary
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`skill to expect anything to the contrary. A person of ordinary skill would have understood that
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`omega 3-fatty acids, including DHA and EPA, and fibrates cause an increase in LDL-C among
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`very high TG patients, as reflected in the prior art:
`
`
`
`Fibrate6352
`Lovaza/Omacor6353
`
`
`
`LDL-C Effect
`Borderline-High or High
`Very-High TG Patients
`TG Patients
`
`-20%
`-6%
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`+45%
`+45%
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`Accordingly, a person of ordinary skill would not have a reasonable expectation of
`
`success in achieving a reduction in TG levels without substantially increasing LDL-C in patients
`
`with very-high TG levels.6354
`
`Defendants’ position that a person of ordinary skill would have had a reasonable
`
`expectation of success in administrating purified EPA to patients with very high triglyceride
`
`levels to achieve TG lowering without substantially increasing LDL-C is belied by the fact that
`
`Defendants’ provide no evidence that anyone thought to administer Epadel.6355 Epadel was
`
`available for many years prior to the invention of the ’594 patent, to patients with very-high TGs
`
`as a treatment. A person of ordinary skill did not expect Epadel, which consisted of mostly EPA,
`
`
`6352 Tricor®, Physicians’ Desk Reference 502-505 (62d ed. 2008).
`6353 Chan 2002 I at 2381 (Table 3).
`6354 Indeed, as discussed above, a person of ordinary skill would have understood that DHA had a better overall
`effect on lipid parameters, teaching away from this combination.
`6355 Although Epadel was available at different levels of purity, the fact that Epadel—at any level of purity—was not
`examined in any study directed to the very-high TG patient population supports Amarin’s position.
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`CONFIDENTIAL
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`Ex. 1019, p. 2336 of 2444
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`to have superior qualities over a drug such as Lovaza/Omacor, which comprised a mixture of
`
`EPA and DHA, in patients with very-high triglycerides. Indeed, none of clinical studies cited by
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`Defendants are directed to the use of purified EPA in the very-high TG population.
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`Research into the pharmaceutical uses of EPA started as early as the 1970s. In 1990,
`
`Mochida Pharmaceutical, began to market Epadel, a high purity EPA drug. There have been
`
`countless studies conducted which administer Epadel and report the effects observed. Although
`
`a few studies administer Epadel to a patient population which included a few patients with TG
`
`levels > 500 mg/dL, Defendants fail to identify a single reference directed to the administration
`
`of Epadel to patients with very-high TG levels. The fact is, a person of ordinary skill did not
`
`expect Epadel, which consisted of mostly EPA, to have superior qualities over a drug such as
`
`Lovaza/Omacor, which comprised a mixture of EPA and DHA, in patients with very-high
`
`triglycerides.
`
`Defendants argue that because Grimsgaard administered purified ethyl EPA to patients
`
`with borderline-high/high TG, it would have been obvious to try administering purified ethyl
`
`EPA to patients with very-high TG levels with a reasonable expectation of success. Defendants
`
`base this unsupported conclusion on Grimsgaard, Lovaza/Omacor, the known administration of
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`2.7 grams of purified EPA to patients with greater than 500 mg/dL TG by Matsuzawa.6356
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`Defendants’ contentions are no more than a demonstration that certain claim elements was
`
`known in the prior art and demonstrates impermissible hindsight reconstruction.6357 As is
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`reflected in Table 4 of Grimsgaard, the study authors found no difference between the DHA,
`
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`6356 Defendants’ Joint Invalidity Contentions at 797-98.
`6357 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.”).
`
`CONFIDENTIAL
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`IPR2022-00215
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`Ex. 1019, p. 2337 of 2444
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`EPA, and control in terms of LDL-C levels. Defendants use hindsight to argue that, despite EPA
`
`and DHA showing the same effect on LDL-C, one would have chosen EPA and expected that
`
`administration to very-high TG would have resulted in little or no impact on LDL-C. Notably,
`
`none of these references would provide a person of ordinary skill in the art with a reasonable
`
`expectation of successfully obtaining the claimed invention even if there were reasons to
`
`combine disparate, independent elements found in the prior art, which there were not.
`
`
`
`In addition, Grimsgaard was conducted in patients with normal TG levels, so a person of
`
`ordinary skill would have expected no difference between EPA and DHA in terms of LDL-C
`
`level change and would have expected no significant increase (or decrease) in LDL-C, as
`
`reported by that publication. A person of ordinary skill would further have understood that the
`
`data reported by Grimsgaard to be consistent with the understanding that while LDL-C levels are
`
`not significantly impacted in normal to high TG patient populations, LDL-C levels would
`
`increase significantly in very-high TG patients.
`
`Matsuzawa similarly provides no basis for a reasonable expectation of success in
`
`achieving the claimed invention. The subjects of Matsuzawa had a wide range of baseline TG
`
`levels and the study was not directed to the very-high TG patient population. Accordingly, just
`
`as with Grimsgaard, Matsuzawa would not provide a reasonable expectation of success as a
`
`person of ordinary skill would understand patients with very-high TG levels to be different in
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`terms of LDL-C effect than patients with lower TG levels.
`
`CONFIDENTIAL
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`2338
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`IPR2022-00215
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`Ex. 1019, p. 2338 of 2444
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`To the extent that Defendants’ arguments are based on results that are not statistically
`
`significant and not reported by Grimsgaard as significant, a person of ordinary skill would not
`
`draw conclusions from these statistically insignificant differences. Indeed, the standard
`
`deviation for the changes reported is greater than the value of the change itself.
`
`Defendants argue that it would have been obvious to try administering purified ethyl EPA
`
`to patients with very-high TG levels with a reasonable expectation of success. However, the
`
`Federal Circuit has often rejected the notion that showing something may have been “obvious-to-
`
`try” proves that the claimed invention was obvious where the prior art did not suggest what to
`
`try.6358 Rather than there being a limited number of options, the state of the art provided a
`
`plethora of compositions and administration protocols associated with multiple kinds of TG-
`
`lowering therapies.6359 There were not a finite number of options for a person of ordinary skill
`
`seeking to reduce TG levels without increasing LDL-C among the very-high TG patient
`
`population.
`
`Defendants argue that a person of ordinary skill at the time of the invention, based on
`
`studies in normal, borderline-high and high TG patients, knew that administration of DHA alone
`
`resulted in undesirable increased LDL-C levels while administration of EPA alone had little to
`
`no impact on LDL-C levels.6360 However, that statement does not conform with what was
`
`known regarding the effect of Epadel and Lovaza/Omacor in normal, borderline-high and high
`
`TG patients. Instead as Defendants’ own prior art demonstrates, Epadel and Lovaza/Omacor
`
`
`6358 See Sanofi, 748 F.3d at 1360−61.
`6359 See supra Section III.
`6360 Defendants’ Joint Invalidity Contentions at 796-97.
`
`CONFIDENTIAL
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`2339
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`IPR2022-00215
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`Ex. 1019, p. 2339 of 2444
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`were both known to have little or no effect on LDL-C in patients with borderline-high/high TG
`
`levels.
`
`With the lack of any reasonable expectation of success, Defendants argue that their
`
`proposed combination amounts to a simple substitution of one known element for another, and
`
`that that these changes yield predictable results.6361 Such an argument, however, represents pure
`
`and impermissible hindsight bias and further does not consider that reasons for which a person of
`
`ordinary skill would not be motivated to combine these references and affirmatives ways in
`
`which the art taught away from these combinations.
`
`(b)
`
`Defendants Have Not Shown It Would Have Been
`Obvious to Administer Purified EPA in the Dosing
`Regimen Recited in the Claims
`
`(i)
`
`The ‘594 Patent is not Obvious Over WO
`‘118 or WO ‘900, in Combination with the
`Lovaza PDR, and Further in View of Leigh-
`Firbank and/or Mori 2000
`
`With respect to the ‘594 Patent, Defendants present a combination of five references:
`
`“WO ‘118 or WO ‘900, in combination with treatment regimen of Lovaza as evidenced by the
`
`Lovaza PDR, and further in view of Leigh-Firbank and/or Mori 2000.”6362 Defendants also
`
`present charts arguing that an additional 61 references may be combined in order to render the
`
`Claims obvious. Not only do Defendants ignore the improbability that a person of ordinary skill
`
`would combine 61 separate references, they additionally do not identify any motivation for
`
`
`6361 Defendants’ Joint Invalidity Contentions at 798.
`6362 Defendants’ Joint Invalidity Contentions at 800.
`
`CONFIDENTIAL
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`2340
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`IPR2022-00215
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`Ex. 1019, p. 2340 of 2444
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`combining these references. 6363, 6364 Although Defendants need not point to an explicit statement
`
`in the prior art motivating the combination of these references, any assertion of an “apparent
`
`reason” to combine must find a basis in the factual record.6365 Defendants’ unsupported cobbling
`
`of selective disclosures represents hindsight reconstruction.6366 Defendants’ contentions are no
`
`more than an assertion that certain claim elements were known in the prior art. Throughout their
`
`contentions, Defendants’ selectively cite to data points in a reference without considering other
`
`disclosures or even the reference as a whole. Each reference, however, must be evaluated for all
`
`
`6363 Defendants’ bare assertion that the asserted claims are obvious “in view of one or more the references cited in
`V.B.3 and 4, including, the ’954 publication, WO ‘900 , WO ’118, Ando, Grimsgaard, Hayashi, Katayama,
`Matsuzawa, Mataki, Mori 2000, Nakamura, Nozaki, Okumura, Park, Saito 1998, Saito 2008 Satoh, Shinozaki,
`Takaku, Yokoyama 2003, Yokoyama 2007, Calabresi, Chan 2002, Chan 2003, Contacos, Geppert, Kelley, Leigh-
`Firbank, Maki, Mori 2006, Rambjør, Sanders or Theobold in combination with the knowledge of a person of
`ordinary skill in the art in light of the dosing regimen employed with Lovaza/Omacor” similarly fails to meet the
`disclosure requirements of the Nevada Local Patent Rules, and fails to provide any motivation to combine these
`references. See Defendants’ Joint Invalidity Contentions at 799.
`6364 Defendants’ bare assertion that “the motivation or reason to combine or modify the prior art to create
`invalidating combinations under 35 U.S.C. §103 can be found in the references identified above in Section III.C,”
`and that “[c]ommon sense, design incentives. Market forces, and the background knowledge possessed by a person
`having ordinary skill in the art provide the reasons or rationales for combining the teachings of multiple references
`or modifying references to render obvious the claimed inventions of the asserted claims,” fails to meet the disclosure
`requirements of the Nevada Local Patent Rules. See Defendants’ Joint Invalidity Contentions at 790-91.
`6365 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) (stating that 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,” which turns on the known “properties
`and limitations 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).
`6366 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”).
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`CONFIDENTIAL
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`2341
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 2341 of 2444
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`that it teaches.6367 Accordingly, Defendants fail to meet their burden to establish prima facie
`
`obviousness.
`
`WO ‘118 is directed at the composition containing EPA for the purpose of preventing the
`
`occurrence of cardiovascular events in multiple risk patients. Further, the invention of WO ‘118
`
`is directed, “in particular, [to] preventing occurrence of cardiovascular events in
`
`hypercholesterolemia patients who have been treated with HMG-CoA RI but still suffer from the
`
`risk of the cardiovascular events.”6368 Contrary to Defendants’ assertion that WO ‘118 discloses
`
`“the administration of 4 g of pure EPA with no DHA,”6369 WO ’118 fails to disclose the claimed
`
`subject with the specified very high TG levels (at least 500 mg/dL) who does not receive
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`concurrent lipid altering therapy, the claimed pharmaceutical composition with the specified
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`fatty acid compositions or dosage, or the claimed method to effect the specified TG reduction
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`without substantially increasing LDL-C. WO ‘118 discloses a composition with a wide range of
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`possible EPA content, dosages, and teaches that DHA is a “preferable fatty acid” to include in
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`the disclosed composition.6370
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`WO ’118 does not disclose administration of highly-purified ethyl-EPA to the target
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`population of the claimed invention. The asserted claims are directed to persons with severe
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`hypertriglyceridemia (i.e. TG level above 500 mg/dL). WO ’118 on the other hand only
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`discloses administration of EPA to persons with triglyceride of at least 150 mg/dL.6371 WO
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`’118’s emphasis on reducing cardiovascular events suggests that its disclosure is directed to
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`6367 Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1305 (Fed. Cir. 2011)
`6368 WO ‘118 at 9.
`6369 Defendants’ Joint Invalidity Contentions at 800.
`6370 WO ‘118 at 22-23.
`6371 WO ’118 at 8.
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`CONFIDENTIAL
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`2342
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 2342 of 2444
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`patients with borderline-high to high TG levels, since the primary goal for patients with very-
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`high TG is to prevent acute pancreatitis by decreasing TG levels.6372
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`WO ’118 also does not distinguish EPA from DHA in its disclosures regarding the
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`effectiveness of the substances for treating hypertriglyceridemia.6373 WO ’118 states that
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`“[a]nother preferable fatty acid . . . is DHA-E,” and that “the compositional ratio of EPA-
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`E/DHA-E, content of EPA-E and DHA-E . . . in the total fatty acid, and dosage of (EPA-E +
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`DHA-E) are not particularly limited as long as intended effects of the present invention are
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`attained.”6374 It further states that “the composition is preferably the one having a high purity of
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`EPA-E and DHA-E.”6375 Further, WO ’118 does not disclose EPA’s effect on LDL-C, VLDL-C,
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`Apo-B, or Lp-PLA2.
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`WO ‘900 is directed to a process for producing purified EPA from a culture of micro-
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`organisms. WO ‘900 fails to disclose the claimed subject with the specified very high TG levels
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`(at least 500 mg/dL) who does not receive concurrent lipid altering therapy, the claimed
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`pharmaceutical composition with the specified dosage or administration period, or the claimed
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`method to effect the specified TG reduction without substantially increasing LDL-C. WO ‘900
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`only discloses the method of producing purified EPA for therapeutic use, it does not teach
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`administration of pure EPA. WO ‘900 has no discussion, for example, regarding claimed patient
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`population or method of treatment.
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`6372 See Section III.
`6373 WO ’118 at 11, 13, 16-21 (“the composition containing at least EPA-E and/or DHA-E as its effective
`component”).
`6374 WO ’118 at 22-23.
`6375 WO ’118 at 23.
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`CONFIDENTIAL
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`2343
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 2343 of 2444
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` WO ‘900 does not teach administration of pure EPA to treat hypertriglyceridemia. It
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`lists more than 30 diseases that can be treated with pure EPA, but hypertriglyceridemia is not one
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`of them.6376 Moreover, WO ‘900 does not teach the desired effect of EPA other than
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`commenting generally that it “may promote health and ameliorate or even reverse the effects of a
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`range of common diseases.”6377 It has no discussion, for example, on any TG-lowering effect of
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`EPA. Although WO ‘900 identifies DHA as an “undesired molecule”, it does not identify the
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`specific undesired effect of DHA or other impurities it is trying to prevent other than
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`commenting generally that “the desired effects of EPA may be limited or reversed” by them.6378
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`It has no discussion related to any LDL-C effects caused by DHA.
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`The proposed combination does not render the independent claims of the ’594 Patent
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`obvious and Defendants’ burden to prove otherwise is especially difficult because the PTO
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`considered WO ‘118, WO ‘900, Mori 2000, and Lovaza (both generally and the Lovaza package
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`insert specifically) during prosecution.6379, 6380
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`6376 See, e.g., ’900 Pub. at 16-17.
`6377 ’900 Pub. at 5.
`6378 ’900 Pub. at 39.
`6379 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”).
`6380 Defendants also argue that “[t]he administration of 2500 mg to 5000 mg of ethyl eicosapentaenoate would have
`been obvious to one of skill in the art based on the teaching of Kris-Etherton that effective doses of omega-3 fatty
`acids range from 3 to 5 grams per day, which can only be obtained consistently by supplementation.” They are
`incorrect. Kris-Etherton teaches that patients in need of TG lowering should consume “two to four grams of
`EPA+DHA per day.” Kris-Etherton at 9. Kris-Etherton does not distinguish between EPA and DHA and in fact
`recommends the administration of EPA and DHA together. Kris-Etherton does not provide any teaching related to
`the administration of EPA alone. In addition, Defendants have offered no specific combination of references that
`includes Kris-Etherton and accordingly have not met the requirements of the Local Patent Rules and the law of
`obviousness.
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`CONFIDENTIAL
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`2344
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1019, p. 2344 of 2444
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`The analysis of the independent claims of the ‘594 patent is incorporated into all asserted
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`claims that depend from those claims.
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`(a)
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`Leigh-Firbank and Mori 2000 Do
`Not Disclose Purported Knowledge
`that DHA was Responsible for the
`Increase in LDL-C
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`Defendants contend that a “person of ordinary skill in the art would have been motivated
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`to administer pure EPA to severely hypertriglyceridemic patients according to Lovaza’s known
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`regimen, particularly in light of the knowledge that DHA is responsible for the increase in LDL-
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`C levels as evidenced by Leigh-Firbank or Mori 2000.”6381
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`Defendants fail to identify a specific motivation to combine WO ‘118 or WO ‘900 with
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`the treatment regimen of Lovaza, as evidenced by the Lovaza PDR. Although Defendants need
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`not point to an explicit statement in the prior art motivating the combination of these references,
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`any assertion of an “apparent reason” to combine must find a basis in the factual record.6382
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`Defendants’ unsupported cobbling of selective disclosures represents hindsight
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`reconstruction.6383 Defendants’ contentions are no more than an assertion that certain claim
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`6381 Defendants’ Joint Invalidity Contentions at 800.
`6382 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 hinds