Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 1 of 30
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF NEW YORK
`
`Civil Action No. 14-CV-2758 (PAC)
`
`
`
`Civil Action No. 14-CV-2759 (PAC)
`
`
`
`Civil Action No. 14-CV-2760 (PAC)
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`
`
`Civil Action No. 14-cv-7934 (PAC)
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`
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`
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`i 
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`Kowa Company, Ltd. et al.,
`
`
`Plaintiffs,
`
`v.
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`Amneal Pharmaceuticals LLC,
`
`
`Defendant.
`
`Kowa Company, Ltd. et al.,
`
`
`Plaintiffs,
`
`v.
`
`Orient Pharma Co., Ltd.,
`
`
`Defendant.
`
`Kowa Company, Ltd. et al.,
`
`
`Plaintiffs,
`
`v.
`
`Zydus Pharmaceuticals (USA) Inc. et al.,
`
`
`Defendants.
`
`Kowa Company, Ltd. et al.,
`
`
`Plaintiffs,
`
`Defendants.
`
`
`Apotex, Inc. et al.,
`
`
`v.
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` 
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`

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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 2 of 30
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`Kowa Company, Ltd. et al.,
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`Plaintiffs,
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`
`
`
`
`
`
`
`v.
`
`
`Lupin Ltd. et al.,
`
`
`Civil Action No. 15-cv-3935 (PAC)
`
`
`
`Defendants.
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`DEFENDANTS’ PROPOSED FINDINGS AND CONCLUSIONS RE:
`
`SECONDARY CONSIDERATIONS OF OBVIOUSNESS REGARDING THE ’336 AND
`’993 PATENTS
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`PRESENTED ON BEHALF OF ALL DEFENDANTS
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`ii 
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 3 of 30
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`TABLE OF CONTENTS
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`Page
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`iii
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 4 of 30
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`Non-obviousness is Not Supported by Any Secondary Indicia of Non-obviousness
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`1.
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`Secondary indicia of non-obviousness are case law derived circumstantial evidence
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`that shed light on the obviousness determination by drawing inferences from underlying facts.
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`They are found to be probative of whether an invention was obvious or not in that they "inoculate
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`the obviousness inquiry against hindsight." Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1377-
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`79 (Fed. Cir. 2012).
`
`2.
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`In Graham v. John Deere Co. of Kansas, 383 U.S. 1, 17-18 (1966), the U.S.
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`Supreme Court stated that secondary considerations can include commercial success, long-felt but
`
`unsolved need, and the failure of others. Other factors recognized by the Federal Circuit after
`
`Graham include whether the invention received industry acclamation, the prior art teaches away
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`from the invention, or others have copied the invention. See, e.g., Ecolochem, Inc. v. Southern
`
`California Edison Co., 227 F.3d 1361, 1381 (Fed. Cir. 2000), cert. denied, 532 U.S. 974 (2001).
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`Simultaneous invention can argue against any secondary indicia of obviousness. Ecolochem at
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`1379; Lindemann Maschinenfabrik GMBH v. American Hoist and Derrick Co., 730 F.2d 1452,
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`1460 (Fed. Cir. 1984).
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`3.
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`While the overall burden in respect of obviousness remains on the challenger, in
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`respect of secondary considerations, the patentee must establish the existence of a secondary
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`consideration supporting non-obviousness. In re Cyclobenzaprine Hydrochloride Extended-
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`Release Capsule Patent Litig., 676 F.3d 1063, 1081 n.8 (Fed. Cir. 2012) (burden of establishing
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`nonobviousness does not shift to patentee, but patentee could not rely on unexpected results
`
`because it “failed to offer adequate proof”); Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
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`683 F.3d 1356, 1363 (Fed. Cir. 2012) (“to show that the cooling effects of the combination of WS-
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`23 and menthol was unexpected, [the patentee] needed to demonstrate that the results were
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`1
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 5 of 30
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`unexpected to a significant degree beyond what was already known about the effect of combining
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`WS-3 and menthol”).
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`4.
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`The burden is also on the patentee to demonstrate a nexus between the secondary
`
`indicia of non-obviousness relied upon and the particular claimed invention. See, e.g., Asyst
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`Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir. 2008) (although embodiments of the
`
`invention may have enjoyed commercial success, patentee failed to link the commercial success
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`to the patented features).
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`5.
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`Secondary considerations of non-obviousness cannot overcome a strong showing
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`of obviousness. Tokai Corp. v. Easton Enterprises, 632 F.3d 1358, 1371(Fed. Cir. 2011). Here,
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`none of the secondary considerations identified by Plaintiffs overcome the strong case obviousness
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`set forth by Defendants.
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`
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`Plaintiffs Have Failed to Demonstrate the Commercial Success of Livalo® and to
`Make a Nexus Between the Purported Commercial Success and the Calcium Salt
`Form of Pitavastatin Which Comprises Livalo®1
`
`6.
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`Commercial success is a secondary indicia of non-obviousness. The patentee
`
`carries the burden of demonstrating that what is “commercially successful is the invention
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`disclosed and claimed in the patent.” Demarco Corp. v. F. Von Langsdorff Licensing Ltd., 851
`
`F.2d 1387, 1392 (Fed. Cir. 1988).
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`7.
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`To prove commercial success, the patent most establish both: (1) that the product
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`embodying the patented invention is commercially successful (Cf. Applied Materials Inc. v.
`
`Advanced Semiconductor Materials America Inc., 98 F.3d 1563, 1570 (Fed. Cir. 1966) –
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`"[A]patentee need not show that all possible embodiments within the claims were successfully
`
`commercialized in order to rely on the success in the marketplace of the embodiment that was
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`                                                            
`1 The entire discussion of the lack of Livalo®’s commercial success will be supported by the
`anticipated testimony of Drs. Hay and Bell.
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`2
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 6 of 30
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`commercialized) using "hard" evidence (In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1995), and (2)
`
`there is a "nexus" between the claimed, patentable features of the invention and the commercial
`
`success of the product. In re GPAC, Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995).
`
`8.
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`Success is not relevant if it is the result of non-patented features. Sjolund v.
`
`Musland, 847 F.2d 1573, 1582 (Fed. Cir. 1988). That is the patentee must make a “prima facie
`
`case of nexus" when asserting commercial success between the product its sells and the patented
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`invention. Crocs, Inc. v. International Trade commission, 598 F.3d 1294 (Fed. Cir. 2010).
`
`9.
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`Hard evidence of commercial success may comprise a high volume of first-year
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`sales coupled with articles in the trade praising the invention (In re McLaughlin, 443 F.2d 1391.
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`1396 (C.C.P.A. 1971)), and a high volume of products sold coupled with evidence of increasing
`
`market share (Ashland Oil Inc. v. Delta Resins & Refractories Inc., 776 F.2d 281, 291 (Fed. Cir.
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`1985)).
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`10.
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`Beyond establishing a nexus between the commercial product and the patented
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`product, and hard evidence of commercial success, the patentee bears the burden to demonstrate
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`that “[t]he asserted commercial success of the product [is] … due to the merits of the claimed
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`invention beyond what was readily available in the prior art.” J.T. Eaton & Co. v. Atl. Paste &
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`Glue Co., 106 F.3d 1563, 1571 (Fed. Cir. 1997); Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299,
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`1312 (Fed. Cir. 2006); Sparton Corp. v. United States, 89 Fed. Cl. 196, 239 (Ct. Cl. 2009). Gross
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`sales figures alone are insufficient to demonstrate commercial success. Kansas Jack, Inc. v. Kuhn,
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`719 F.2d 1144, 1150-51 (Fed. Cir. 1983) (where alleged “commercial success consist[s] solely of
`
`number of units sold,” with “no evidence of market share . . . [or] nexus,” a finding of obviousness
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`is proper).
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 7 of 30
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`11.
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`Commercial success is a secondary consideration because it may indicate that there
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`was an economic incentive to make the claimed invention. However, if the incentive to make the
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`invention was blunted, due for example other products, or factors that would deter or prevent others
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`from developing the same, such success is not probative. See Merck & Co. Inc. v. Teva Pharms.
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`USA, Inc., 395 F.3d 1364, 1376–77 (Fed. Cir. 2005) and Syntex (U.S.A.) LLC v. Apotex, Inc., 407
`
`F.3d 1371, 1383 (Fed. Cir. 2005) (existing prior patents prevented others from attempting to make
`
`claimed invention; patentees’ commercial success therefore not relevant); see also Procter &
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`Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 998 n.2 (Fed. Cir. 2009) (commercial
`
`success accorded “little weight” where at the time of the patented invention, the prior art over
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`which obviousness was asserted was available to patentee but not to the public).
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`12.
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`Plaintiffs have failed to prove that Livalo® has been commercially successful as a
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`commercial product, as set forth below.
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`13.
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`Livalo® sales in the United States do not support that Livalo® has achieved
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`commercial success here. Indeed the Dyslipidemia Product Demand Quantitative Market
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`Research Report, generated by a market research firm hired by Kowa, suggested that Livalo®
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`would achieve a 7% peak market share of prescriptions in the dyslipidemia market place. (DTX-
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`0910 at KN001541095.) Nevertheless, in 2014 (four (4) years after launch) Kowa’s internal
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`documents show that Livalo® was still only at less than 0.5% of the total prescriptions. (DTX-
`
`0930 at KN002477920.) Indeed IMS Health data confirms that Livalo® was never able to reach
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`0.5% of U.S. statin prescriptions at any point after launch. (DTX-1167.)
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`14.
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`This performance by Livalo® has fallen well below Plaintiffs’ internal revenue
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`forecasts expectations. On November 17, 2009, before market launch of Livalo®, Kowa
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`Pharmaceuticals America (“KPA”) projected peak annual Livalo® sales of $700M in 2016 with
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 8 of 30
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`2015 sales of $645M. (DTX-0224, KN002056495-608 at KN002056500; see also DTX-0849,
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`KN001346601-02 at KN001346601.) Yet, Plaintiffs admit that sales are now estimated to be
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`closer to the $200M range for 2016. (Anticipated testimony of G. Gordon.) Even just five months
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`after launch at a November 8, 2010 Livalo® sales meeting, Kowa expressed concern that Livalo®
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`sales “… are not living up to expectations,” and Livalo®’s failure to meet internal forecasts has
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`continued throughout its sales history. (DTX-0224, KN002056495-608 at KN002056509.)
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`Indeed IMS data shows that Livalo® had captured less than 1.8% of the cholesterol drug market
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`sales revenue by 2015, five years after launch. (DTX-1166.)
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`15.
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`Japanese sales of $3.3 billion for pitavastatin between 2003 and 2012 (See DTX-
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`1231, Presentation for Investors at PITADEF00020828-PITADEF00020897) do not provide a
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`basis for an assertion of commercial success either, as it is well known that Japanese regulators
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`and prescribers have a strong preference for Japanese-manufactured medications (DTX-1231 at
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`PITADEF00020914-926). Livalo® is also the only domestically-manufactured statin in Japan.
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`Indeed, even if one were to consider Japanese sales in the calculus of commercial success,
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`Livalo®'s global statin market share is only 0.21% of the $312.53 billion worldwide statin sales,
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`which is even smaller than the market share Livalo® has achieved in the U.S. statin market. (DTX-
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`1181 at Exhibit D-1 of Bell Expert Report.)
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`16.
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`The market for cholesterol-lowering drugs was saturated at the time of Livalo®’s
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`FDA approval in 2009. By the time Livalo® entered the market in 2010, the market also included
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`at least Lipitor® (atorvastatin), Crestor® (rosuvastatin), generic and branded simvastatin
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`(Zocor®), Vytorin® (ezetimibe/simvastatin), generic and branded pravastatin (Pravachol®),
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`Zetia® (ezetimibe), Lesco®l (fluvastatin) and Mevacor® (lovastatin) Lescol® (fluvastatin), and
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`Mevacor® (lovastatin)., as well as other non-statin agents used to reduce cholesterol. (DTX-0941
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`5
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 9 of 30
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`KN002700481-519 at KN002700493; DTX-1065, KN002020984-1029 at KN002021028.)
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`Livalo® also faced further competition from lower-cost generic versions of popular statins.
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`17.
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`Support for the lack of commercial success is seen in Kowa’s difficulty in obtaining
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`a marketing partner for Livalo® and in its eventual partner Eli Lilly's decision to terminate a co-
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`promotion with Kowa/Nissan of the drug, based on its poor performance in the market, with Lilly
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`loosing over 100 million dollars on the deal. (DTX-220). Kowa recognized that “only hope [it]
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`had to sell [Livalo®] is to put a lot of marketing muscle around it, something Kowa itself will
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`never do enough of.” (DTX-1227, KN000910922-25.) However, companies, including Sciele
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`Pharma, Sanofi and Forest declined to enter into an agreement with Kowa for Livalo® because
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`they did not see Livalo® as a promising market opportunity (See DTX-1200, KN002566752-53;
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`DTX-1537, KN002020763-73 at KN002020765-67.)
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`18.
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`And although in 2009, Kowa entered into a co-promotion agreement with Eli Lilly
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`and Co. (“Lilly”), (DTX-0008, KN000759781-851) the Kowa/Eli Lilly alliance was short-lived.
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`In August 2012, after nearly two years of selling Livalo® in the United States, Lilly expressed that
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`it was “unhappy with the sales performance of Livalo® since Lilly had spent approximately $226
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`million on Livalo®, with projected net sales to Lilly of approximately $68 million, leaving Lilly
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`with a deficit of $158 million.” (DTX-0215, KN002624623-25.) Based on the poor sales
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`performance of Livalo® and Lilly’s intention to drastically reduce the sales force for co-promotion
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`because of that poor performance, the Kowa and Lilly co-promotion agreement was terminated on
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`June 30, 2013. (DTX-0827, KN001382854-70 (Mutual Dissolution Agreement dated March 25,
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`2013).)
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 10 of 30
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`19.
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`Indeed, Kowa financial records show that Livalo® was not only unprofitable for
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`Lilly, but also for Kowa, who suffered net losses on Livalo® every year until 2013, and is expected
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`to show cumulative net losses through 2020. (DTX-1028.)
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`20.
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`There is no basis for the assertion that the avoidance of the most commonly used
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`metabolic pathway by Livalo® has a nexus with commercial sales particularly with respect to
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`statin-intolerant patients, pre-diabetes patients, patients with type II diabetes, and patients who
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`need to take protease inhibitors such as those infected by HIV and HCV. Indeed, the fact that
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`physicians do not have a Livalo® label with any indications for use in such patient populations
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`belies such statements. (DTX-1202.) Nor does the patent specification say anything about its
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`metabolic pathway, drug-drug interactions, or its use to treat any specific patient sub-population.
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`21.
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`Plaintiffs have not only failed to make out a case for commercial success, but have
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`also failed to prove a nexus between the sales of pitavastatin calcium containing drugs and the
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`calcium salt claimed in the '336 patent or the polymorphs of the calcium salt of the '993 patent.
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`See In re Paulsen, 30 F.3d 1475, 1482 (Fed. Cir. 1994); In re Huang, 100 F.3d 135, 140 (Fed. Cir.
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`1996) (sales must be a direct result of the unique characteristics of the claimed invention). Here,
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`Plaintiffs are not entitled to a presumption of nexus in light of the several patents listed in the
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`Orange Book as covering Livalo®. See Therasense, Inc. v. Becton, Dickinson & Co., 593 F.3d
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`1289, 1299 (Fed. Cir. 2010), reh’g en banc granted, opinion vacated on other grounds, 374 F.
`
`App’x 35 (Fed. Cir. 2010), and opinion reinstated in part, 649 F.3d 1276 (Fed. Cir. 2011) (Where
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`a “product embodie[s] at least two patents,” the patentee is not entitled to a presumption of nexus
`
`because that is “not a situation where the success of a product can be attributed to a single patent.”).
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`And without this presumption, Plaintiffs have not provided sufficient evidence to tie any alleged
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`success to the patented features of the asserted patent claims.
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`7
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 11 of 30
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`Plaintiffs Have Failed to Demonstrate Any Long-Felt But Unmet Need for Livalo®
`and to Make a Nexus Between Any Purported Long-Felt Need and Its Resolution by
`the Introduction of the Calcium Salt Form of Pitavastatin Which Comprises Livalo®
`
`22.
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`To establish a long-felt need as supporting a secondary indicia of non-obviousness,
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`one needs to demonstrate with objective evidence that the art at the time of the invention
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`recognized a problem for a long period of time without solution, In re Gershon, 372 F.2d 535, 539
`
`(C.C.P.A. 1967), and actually attempted to solve the same, Orthopedic Equipment Co., Inc. v. All
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`Orthopedic Appliances, Inc., 707 F.2d 1376, 1382 (Fed. Cir. 1983) (Although the claimed
`
`invention achieved the desirable result of reducing inventories, there was no evidence of any prior
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`unsuccessful attempts to do so). It must then be shown that the invention actually satisfied the
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`long-felt need, In re Cavanagh, 436 F.2d 491, 496 (C.C.P.A. 1971), and that another did not do so
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`before the invention date. Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768 (Fed. Cir.
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`1988).
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`23.
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`To determine if the need was long-felt, the date of the problem's identification is
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`determined and the length of time over which efforts were made to solve the problem is taken into
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`account. Texas Instruments Inc. v. Int'l Trade Comm'n, 988 F.2d 1165, 1178 (Fed. Cir. 1993).
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`The case law has not set in stone how long a time is long for this secondary indicia of non-
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`obviousness. The failure of others to meet such a long-felt need is supportive of non-obviousness.
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`Graham v. John Deere Co. of Kansas, 383 U.S. 1, 17 (1966).
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`24.
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`To establish that an invention meet a particular need, one must show that the
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`claimed invention achieved a result superior to the prior art. Iron Grip Barbell Co. v. USA Sports,
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`Inc., 392 F.3d 1317, 1325 (Fed. Cir. 2004) (“[t]he mere passage of time without the claimed
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`invention is not evidence of non-obviousness”); Caldwell v. U.S., 481 F.2d 898, 903-5 (Ct. Cl.
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`1973); In re Cavanagh, 436 F.2d 491, 496 (C.C.P.A. 1971).
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`8
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 12 of 30
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`25.
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`Factors that may argue against a long-felt need in the face of technical know-how
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`to make the invention include a lack of interest in the problem, regulatory regulations arguing
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`against marketing, or the lack of appreciation of the marketability of invention. Environmental
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`Designs, Ltd. v. Union Oil Co. of Cal., 713 F.2d 693, 698 (Fed. Cir. 1983); Scully Signal Co. v.
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`Electronics Corp. of America, 570 F.2d 355, 361-62 (1st Cir. 1977).
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`26.
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`By August 1987, there was no long felt need for yet another HMB-CoA reductase
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`inhibitor statin to be developed. At the time there was one drug that was to be imminently
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`marketed lovastatin (which received its final FDA approval on September 1, 1987), and
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`certainly was marketed before August 19 1988 (the priority date asserted by defendants).
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`Lovastatin was already being reported as a potent inhibitor of HMG CoA reductase and that
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`adverse effects were infrequent. (DTX-1491). There were four other drugs, mevastatin,
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`simvastatin, eptastatin (pravastatin), and fluvastatin moving through clinical trials which had
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`numerous publications associated with them and seminal patents thereon had been published
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`(DTX-1485 at ¶¶ 36, 63). Furthermore, numerous companies had already filed patent
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`applications on new HMG-CoA reductase inhibitor statins, including Pfizer on atorvastatin,
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`which would later be marketed by it as Lipitor®. (Id.; Anticipated testimony of Drs. Hay and
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`Zusman.)
`
`27.
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`Certainly by February 12, 2003, the earliest possible priority date of U.S. Patent
`
`No. 8,557,933, there was no clinical need for Livalo®. Many of the alleged needs for which
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`Livalo® was purported developed, including as concerns the treatment of patients with
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`hyperlipidemia, hyperlipoproteinemia or atherosclerosis, had been met already by the time
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`Livalo® was approved, numerous FDA-approved statin products marketed, inter alia, in the
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`U.S. prior to 2003, Pravachol® (DTX-1530); Zocor® (DTX-1531); Lescol® (DTX-1532);
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`9
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 13 of 30
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`Lipitor® (DTX-1533); Lescol XL® (DTX-1534); Altoprev® (DTX-1535); see also WO
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`03/016317 Al (“WO ’317”) ( D T X - 1 5 1 4 at p p . 1, 11, 29-32 ( disclosing available statins
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`as of February 2002); Anticipated testimony of Dr. Zusman.)
`
`28.
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`The FDA approved Livalo® for the U.S. market in August 2009, however it failed
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`to launch until July 2010. (Anticipated testimony of H. Iwasaki; DTX-1160.) The lengthy delay
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`supports that there was no real need for yet another statin in an already saturated statin marketplace
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`when Livalo® was ready to be introduced. (Anticipated testimony of Dr. Hay.)
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`29.
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`In fact when Plaintiffs commissioned circa October 2009 "The Link Group" to
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`make a competitive assessment of Livalo® against the other statins available at the time via a web-
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`based survey of primary care providers and cardiologists, the majority physician opinion was that
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`“Livalo® Has No Reason for Being: No advantages in efficacy, safety or cost.” (DTX-0941 at
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`KN002700485-486, KN002700488; Anticipated testimony of Drs. Hay and Zusman.)
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`30.
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`As set forth above in respect of the allegation of commercial success, Livalo®'s
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`insignificant market share in the statin market, whether adjudged from a U.S. only perspective, or
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`worldwide, is further evidence that there was no long-felt, unmet need.
`
`31. While plaintiffs assert some advantage in terms of drug-drug interaction, the FDA
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`labeling still provided drug interaction warnings, and monitoring requirements, some of which
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`were more burdensome than those for existing statins. (DTX-0941 at KN002700506; Anticipated
`
`testimony of Dr. Zusman.)
`
`32.
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`Even before August 1987, two HMG-CoA reductase inhibitors were moving
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`through clinical trials that were not significantly metabolized by the CYP3A4 system. (DTX-
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`1485 at ¶ 65.)
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`10
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`Case 1:14-cv-02758-PAC Document 109 Filed 12/16/16 Page 14 of 30
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`33.
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`Furthermore, Livalo®, unlike many other statins, had no clinical trial data showing
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`significant and substantial reductions in hard cardiovascular endpoints, such as cardiovascular
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`mortality, myocardial infarction, stroke etc. (DTX-0941 at KN002700512; Anticipated testimony
`
`of Drs. Zusman and Hay.)
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`34.
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`Indeed, Kowa's market research indicated physicians viewed Livalo®’s so-called
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`safety advantages as tenuous and unlikely to be convincing to providers that had successfully
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`prescribed existing statins for decades to millions of patients with minimal adverse events or safety
`
`problems. (DTX-0941 at KN002700505; Anticipated testimony of Drs. Hay and Zusman.)
`
`35.
`
`Livalo® is not indicated in its currently-available labelling for any of the
`
`particular patient populations urged in Plaintiffs’ Expert's Reports. (DTX-1546; Anticipated
`
`testimony of Dr. Zusman.)
`
`36.
`
`Plaintiffs have failed to demonstrate that the elderly, patients of Asian descent,
`
`patients with renal dysfunction, pre-diabetic, and diabetics were not receiving safe and effective
`
`treatment for high cholesterol and related diseases using the treatment options available as of 1987
`
`and 2003, including statins On the contrary, patients of Asian descent and the elderly were
`
`receiving safe and effective treatment for high cholesterol and related diseases using the treatment
`
`options available as of 1987 and 2003, including statins such as Lipitor and Zocor, each of which
`
`were safely and effectively prescribed in these types of patients. (Anticipated testimony of Dr.
`
`Zusman; DTX-1558; DTX-1559; DTX-1560; DTX-1561; DTX-1562; DTX-1563; DTX-1564.)
`
`37.
`
`Certainly, doses of drugs and polypharmacy can be employed in populations that
`
`metabolized certain statins suboptimally. In regard to the elderly, patients with renal dysfunction,
`
`patients having diabetes and pre-diabetes, and patients intolerant to statins, the Livalo®
`
`Prescribing Information recommends that “LIVALO® should be administered with caution in …
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`elderly patients,” and says nothing in support of its use in pre-diabetics or diabetics, or in respect
`
`of patients intolerant to statins. With respect to patients suffering renal dysfunction, it suggests
`
`that “Livalo® should be administered with caution in patients with impaired renal function.”
`
`(DTX-0287; Anticipated testimony of Dr. Zusman.)
`
`38.
`
`Indeed, the Chamberlin reference cited by Plaintiffs to support of its argument that
`
`pitavastatin has particular use in the elderly, specifically notes that it has “limited subgroup
`
`analysis data … to those patients aged 65 or older.” (DTX-1208.) The Corsini article cited by
`
`plaintiffs to support pitavastatin use in patients intolerant to statins, actually suggests that the drug
`
`has only comparable use to atorvastatin and rosuvastatin in patients intolerant to statins. (DTX-
`
`1489.) Furthermore, the Hollaway reference does not support plaintiff's position in respect of
`
`some unique use of pitavastatin in statin intolerant patients, as such reference only involved 40
`
`individuals, did not define statin intolerance, and nearly one-third of the total patients involved
`
`were not able to tolerate pitavastatin. (DTX-1587.) In regard to renal dysfunction, the Barrios
`
`2013 reference specifically states that there is need for specifically designed clinical trials to show
`
`that pitavastatin can improve cardiovascular prognosis in patients with renal dysfunction. (DTX-
`
`1585.) The Crestor® Prescribing information suggests that the drug may be used in patients of
`
`Asian Descent, but the dose may optimally be reduced to 5mg (DTX-1286; Anticipated testimony
`
`of Dr. Zusman.)
`
`39.
`
`Nor have plaintiff's demonstrated that Livalo® meets an unmet need in
`
`polypharmacy patients as the Livalo® Prescribing Information contains warnings for co-
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`administration of Livalo® and P450-metabolized drugs, erythromucin, and in respect of patients
`
`with impaired renal function, fibrates and lipid-modifying doses of niacin. (DTX-0287.)
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`4 0 . Other references upon which Plaintiffs’ experts rely similarly set out the results of
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`studies that are (i) based upon a small and/or non-diverse subject population, (ii) short in duration
`
`/ “pilot in nature” or still ongoing and/or (iii) contain (potential for) bias and/or conflicts of
`
`interest—so in other words, studies having little, if any, statistical significance and little
`
`relevance or weight to support Plaintiffs’ position. (Anticipated testimony of Dr. Zusman.)
`
`41.
`
`National guidelines concerning the detection, evaluation and treatment of high
`
`cholesterol and related-diseases further support my position that Livalo® fails to satisfy some
`
`unmet need,” including in the special patient populations identified by Plaintiffs’ experts. (See
`
`DTX-1570 at MYLAN(Pitav) 076354, (referencing pitavastatin only to note that it is one of
`
`several low- or moderate-intensity statins).)
`
`42.
`
`In sum, as of the earliest filing date of the ’336 patent there was no long-felt or
`
`unmet need that has been met by Livalo®. Instead, other more potent statins were already known
`
`in the art, and the particularized benefits Plaintiffs point to were already present in other statins
`
`such as pravastatin. Indeed, even to the extent that there was a long felt need, all of the experts
`
`agree that this need still exists, thus supporting that Livalo® has not met any such need.
`
`
`
`Plaintiffs Have Failed to Demonstrate Any Unexpected Results
`
`43.
`
`In attempting to overcome the clear case of prima facie obviousness, Plaintiffs
`
`assert that pitavastatin has certain, unexpected properties. But in order to be probative, the
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`unexpected results must be compared to the closest prior art, which Plaintiffs fail to do. Bristol-
`
`Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (citations
`
`omitted); see also Koa Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006) (“[W]hen
`
`unexpected results are used as evidence of nonobviousness, the results must be shown to be
`
`unexpected compared with the closest prior art.”); accord In re Baxter Travenol Labs., 952 F.2d
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`388, 392 (Fed. Cir. 1991) (same).
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`44.
`
`For example, for the ’336 patent the closest prior art relates other salts of
`
`pitavastatin. And for the ’993 patent, the closest prior art relates to a crystalline form of
`
`pitavastatin nearly identical (if not identical) to Form A as claimed by the ’993 patent. Plaintiffs
`
`offer no evidence that the calcium salt has better, and unexpected properties than these other salt
`
`forms. Instead, the majority of Plaintiffs arguments are about pitavastatin having unexpected
`
`results as compared to other statins. The same is true for the ’993 patent. Plaintiffs do not point
`
`to any unexpected properties of claimed Form A that are superior to the crystalline form disclosed
`
`by the EP ’406 reference, but again claim unexpected results as compared to other statins. But
`
`these other statins are not the closest prior art, and thus Plaintiffs arguments fail. Bristol-Myers
`
`Squibb Co., 752 F.3d at 977 (Fed. Cir. 2014).
`
`45.
`
`In addition, the alleged unexpected results that Plaintiffs point to do not show that
`
`Livalo® has superior properties over the other statins as is required for a finding of unexpected
`
`results. In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (When a patentee attempts to rely on
`
`the unexpected benefits of a claimed invention, the patentee must “show that the claimed invention
`
`exhibits some superior property or advantage that a person of ordinary skill in the relevant are
`
`would have found surprising or unexpected.”). For instance, Plaintiffs allege that Livalo® exhibits
`
`unexpectedly greater efficacy because it is allegedly “more potent than other statins and thus more
`
`effective at lower dosing regiments” as compared to other statins. (Anticipated testimony of Drs.
`
`Miller, Gotto, Davidson, and Sponseller.) However, Plaintiffs appear to be conflating two issues:
`
`potency and efficacy. A person of ordinary skill in the art would have understood that potency of
`
`dosage strength does not dictate efficacy. (Anticipated testimony of Dr. Zusman.) For example,
`
`atorvastatin (40 mg and 80 mg) and rosuvastatin (10 mg, 20 mg and 40 mg) are more effective at
`
`lowering a patient’s LDL-C than pitavastatin (4 mg):
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`
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`(PTX-1215, Cobble 2013.)
`
`46.
`
`Rather than a highly effective statin, pitavastatin calcium is understood to be one
`
`of several “moderate-intensity” statins available to physician and those of ordinary skill in the art.
`
`(DTX-1578, AAFP 2014;1 see also DTX-1572, ACC/AHA 2013 at 25.)
`
`47.
`
`This is supported by Livalo®’s label, which does not indicate any clinical studies
`
`that show Livalo® is superior in a general population with primary hyperlipidemia or mixed
`
`dyslipidemia to any other statin. (DTX-0287, Livalo label (revised Oct. 2013).) At best, Livalo®
`
`was seen as only possibly useful as a second-line statin in patients already on atorvastatin or
`
`simvastatin (two statins primarily metabolized by CYP450), in patients who suffer from CYP-450
`
`isoenzyme abnormality. (DTX-0214, Lilly Due Diligence Assessment – Summary Presentation
`
`to Kowa, November 30, 2009, KN002391253-262 at KN002391255.) However, pravastatin was
`
`found to have a similar profile to Livalo® in this regard. (Id.; Anticipated testimony of Dr.
`
`Zusman.) Accordingly, there is nothing superior or otherwise unexpected about the efficacy of
`
`pitavastatin over that of the closest prior art.
`
`48.
`
`74.
`
`Plaintiffs also appear to claim that Livalo®’s tolerability is unexpected.
`
`But, statins as a class have proven to be well tolerated, highly effective and safe. (DTX-0560;
`
`DTX-1244; Anticipated testimony of Dr. Zusman.) Plaintiffs’ own research illustrates Livalo®’s
`
`potential for adverse events and reported side effects is similar to statins as a drug class overall.
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