Case 1:14-cv-02758-PAC Document 111 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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`i 
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`Kowa Company, Ltd. et al.,
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`
`Plaintiffs,
`
`v.
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`Amneal Pharmaceuticals LLC,
`
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`Defendant.
`
`Kowa Company, Ltd. et al.,
`
`
`Plaintiffs,
`
`v.
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`Orient Pharma Co., Ltd.,
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`Defendant.
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`Kowa Company, Ltd. et al.,
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`
`Plaintiffs,
`
`v.
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`Zydus Pharmaceuticals (USA) Inc. et al.,
`
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`Defendants.
`
`Kowa Company, Ltd. et al.,
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`Plaintiffs,
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`Defendants.
`
`
`Apotex, Inc. et al.,
`
`
`v.
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`Case 1:14-cv-02758-PAC Document 111 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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`
`
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`v.
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`Lupin Ltd. et al.,
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`Civil Action No. 15-cv-3935 (PAC)
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`
`
`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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`TABLE OF CONTENTS
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`Page
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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
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`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
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`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
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`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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`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
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`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
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`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
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`6.
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`Commercial success is a secondary indicia of non-obviousness. The patentee
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`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
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`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.
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`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
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`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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`commercialized) using "hard" evidence (In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1995), and (2)
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`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.
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`Musland, 847 F.2d 1573, 1582 (Fed. Cir. 1988). That is the patentee must make a “prima facie
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`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).
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`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
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`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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`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.
`
`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 &
`
`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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`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®
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`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
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`(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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`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.)
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`27.
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`Certainly by February 12, 2003, the earliest possible priority date of U.S. Patent
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`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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`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.)
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`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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`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
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`testimony of Dr. Zusman.)
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`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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`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
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`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
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`problems. (DTX-0941 at KN002700505; Anticipated testimony of Drs. Hay and Zusman.)
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`35.
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`Livalo® is not indicated in its currently-available labelling for any of the
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`particular patient populations urged in Plaintiffs’ Expert's Reports. (DTX-1546; Anticipated
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`testimony of Dr. Zusman.)
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`36.
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`Plaintiffs have failed to demonstrate that the elderly, patients of Asian descent,
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`patients with renal dysfunction, pre-diabetic, and diabetics were not receiving safe and effective
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`treatment for high cholesterol and related diseases using the treatment options available as of 1987
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`and 2003, including statins On the contrary, patients of Asian descent and the elderly were
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`receiving safe and effective treatment for high cholesterol and related diseases using the treatment
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`options available as of 1987 and 2003, including statins such as Lipitor and Zocor, each of which
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`were safely and effectively prescribed in these types of patients. (Anticipated testimony of Dr.
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`Zusman; DTX-1558; DTX-1559; DTX-1560; DTX-1561; DTX-1562; DTX-1563; DTX-1564.)
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`37.
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`Certainly, doses of drugs and polypharmacy can be employed in populations that
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`metabolized certain statins suboptimally. In regard to the elderly, patients with renal dysfunction,
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`patients having diabetes and pre-diabetes, and patients intolerant to statins, the Livalo®
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`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
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`of patients intolerant to statins. With respect to patients suffering renal dysfunction, it suggests
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`that “Livalo® should be administered with caution in patients with impaired renal function.”
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`(DTX-0287; Anticipated testimony of Dr. Zusman.)
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`38.
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`Indeed, the Chamberlin reference cited by Plaintiffs to support of its argument that
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`pitavastatin has particular use in the elderly, specifically notes that it has “limited subgroup
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`analysis data … to those patients aged 65 or older.” (DTX-1208.) The Corsini article cited by
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`plaintiffs to support pitavastatin use in patients intolerant to statins, actually suggests that the drug
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`has only comparable use to atorvastatin and rosuvastatin in patients intolerant to statins. (DTX-
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`1489.) Furthermore, the Hollaway reference does not support plaintiff's position in respect of
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`some unique use of pitavastatin in statin intolerant patients, as such reference only involved 40
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`individuals, did not define statin intolerance, and nearly one-third of the total patients involved
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`were not able to tolerate pitavastatin. (DTX-1587.) In regard to renal dysfunction, the Barrios
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`2013 reference specifically states that there is need for specifically designed clinical trials to show
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`that pitavastatin can improve cardiovascular prognosis in patients with renal dysfunction. (DTX-
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`1585.) The Crestor® Prescribing information suggests that the drug may be used in patients of
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`Asian Descent, but the dose may optimally be reduced to 5mg (DTX-1286; Anticipated testimony
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`of Dr. Zusman.)
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`39.
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`Nor have plaintiff's demonstrated that Livalo® meets an unmet need in
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`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
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`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
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`/ “pilot in nature” or still ongoing and/or (iii) contain (potential for) bias and/or conflicts of
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`interest—so in other words, studies having little, if any, statistical significance and little
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`relevance or weight to support Plaintiffs’ position. (Anticipated testimony of Dr. Zusman.)
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`41.
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`National guidelines concerning the detection, evaluation and treatment of high
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`cholesterol and related-diseases further support my position that Livalo® fails to satisfy some
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`unmet need,” including in the special patient populations identified by Plaintiffs’ experts. (See
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`DTX-1570 at MYLAN(Pitav) 076354, (referencing pitavastatin only to note that it is one of
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`several low- or moderate-intensity statins).)
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`42.
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`In sum, as of the earliest filing date of the ’336 patent there was no long-felt or
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`unmet need that has been met by Livalo®. Instead, other more potent statins were already known
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`in the art, and the particularized benefits Plaintiffs point to were already present in other statins
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`such as pravastatin. Indeed, even to the extent that there was a long felt need, all of the experts
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`agree that this need still exists, thus supporting that Livalo® has not met any such need.
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`Plaintiffs Have Failed to Demonstrate Any Unexpected Results
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`43.
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`In attempting to overcome the clear case of prima facie obviousness, Plaintiffs
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`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-
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`Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (citations
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`omitted); see also Koa Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006) (“[W]hen
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`unexpected results are used as evidence of nonobviousness, the results must be shown to be
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`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.
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`For example, for the ’336 patent the closest prior art relates other salts of
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`pitavastatin. And for the ’993 patent, the closest prior art relates to a crystalline form of
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`pitavastatin nearly identical (if not identical) to Form A as claimed by the ’993 patent. Plaintiffs
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`offer no evidence that the calcium salt has better, and unexpected properties than these other salt
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`forms. Instead, the majority of Plaintiffs arguments are about pitavastatin having unexpected
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`results as compared to other statins. The same is true for the ’993 patent. Plaintiffs do not point
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`to any unexpected properties of claimed Form A that are superior to the crystalline form disclosed
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`by the EP ’406 reference, but again claim unexpected results as compared to other statins. But
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`these other statins are not the closest prior art, and thus Plaintiffs arguments fail. Bristol-Myers
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`Squibb Co., 752 F.3d at 977 (Fed. Cir. 2014).
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`45.
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`In addition, the alleged unexpected results that Plaintiffs point to do not show that
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`Livalo® has superior properties over the other statins as is required for a finding of unexpected
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`results. In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (When a patentee attempts to rely on
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`the unexpected benefits of a claimed invention, the patentee must “show that the claimed invention
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`exhibits some superior property or advantage that a person of ordinary skill in the relevant are
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`would have found surprising or unexpected.”). For instance, Plaintiffs allege that Livalo® exhibits
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`unexpectedly greater efficacy because it is allegedly “more potent than other statins and thus more
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`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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`14
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 18 of 30
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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.
`
` 
`
`15
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 19 of 30
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`
`Livalo®, which has been on the market in Japan since 2003, underwent six years of post-marketing
`
`studies there. These studies concluded that there were no new or unexpected safety findings for
`
`Livalo®. (DTX-0214 at KN002391256.) This is consistent with clinical experience of Livalo®
`
`in the U.S. (Anticipated testimony of Dr. Zusman.) Additionally, Plaintiffs’ internal documents
`
`indicate that in 2011, their sales force was reporting that physicians felt that Livalo® had a safety
`
`and tolerability profile at parity to pravastatin and Crestor. (DTX-0301, Livalo – Executive
`
`Committee February 16, 2012, Kowa-Lilly," KN0028800628-663.) Thus, there is nothing
`
`unexpected about Livalo®’s tolerability-its tolerability is in line with other statins marketed long
`
`before Livalo®.
`
`49.
`
`75.
`
`Plaintiffs also assert that pitavastatin, unexpectedly has surprising results in
`
`HIV patients and diabetic patients, and less drug-drug interactions. But unfortunately, Livalo®
`
`has not been demonstrated to possess any of these benefits over the prior art. The studies that
`
`Plaintiffs’ point to for support are largely “pilot in nature” or contain limitations that render the
`
`results unreliable or at least not clinically significant (e.g., limited population (small in size and/or
`
`not diverse), short duration, uncontrolled study, ongoing investigation, (potential for) bias and/or
`
`conflicts of interest). (Anticipated testimony of Dr. Zusman.)
`
`50.
`
`Consistent with this understanding, Livalo® is only indicated for:
`
`DTX-0287, Livalo label (revised Oct. 2013).
`
`51.
`
`The currently available Livalo® label has no indications for use in any specific
`
`populations, including diabetic patients, HIV patients, or patients treated with polypharmacy. (Id.)
`
`
`
` 
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`16
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 20 of 30
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`
`Without FDA-approved indications, it would be illegal off-label promotion for Kowa to market
`
`Livalo® as superior (or even non-inferior) to other treatments for these population sub-groups.
`
`(Anticipated testimony of Dr. Hay.)
`
`53.
`
`Similarly, the Livalo® Prescribing Information does not support Plaintiffs’ claim
`
`that Livalo® has an unexpected effect on patients with pre- or type II diabetes, including those
`
`with renal deficiency. The label recommends that “Livalo® should be administered with caution
`
`in patients with impaired renal function,” disclosing warnings and dose restrictions for renal
`
`impairment patients. (DTX-0287, Livalo label, revised Oct. 2013.) In addition, Livalo®’s label
`
`indicates that Livalo® has been found to be inferior to atorvastatin for patients with type II
`
`diabetes. (Id.)
`
`54. With regard to having surprising results regarding a lack of interactions with other
`
`drugs, this result is not surprising, since other statins behave similarly. For example, pravastatin,
`
`like Livalo®, avoids metabolization by the cytochrome-P isoenzymes and the isoenzyme
`
`cytochrome CYP3A4 and CYP2C9 pathways to any appreciable extent, which minimizes
`
`interactions with drugs that are metabolized through these pathways. (DTX-1489, Corsini, A et
`
`al., (1999). "New insights into the pharmacodynamic and pharmacokinetic properties of statins".
`
`Pharmacology & Therapeutics 84 (3): 413–428.) Thus, nothing about Livalo®’s metabolism was
`
`surprising because the same is seen in statins that pre-date Livalo®. Further, Livalo® is still
`
`known to have some drug-drug interactions. For example, the Livalo® Prescribing Information
`
` 
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`17
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 21 of 30
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`
`contains a warning for co-administration of Livalo® and P450-metabolized drugs. (DTX-0287,
`
`Livalo label, revised Oct. 2013.)
`
`55.
`
`“patients receiving warfarin should have their PT and INR monitored when
`
`pitavastatin is added to their therapy”
`
`56.
`
`“[i]n patients taking erythromycin, a dose of LIVALO® 1 mg once daily should
`
`not be exceeded”
`
`57.
`
`“LIVALO® should be administered with caution in patients with impaired renal
`
`function in . . . when used concomitantly with fibrates or lipid-modifying doses of niacin”).
`
`58.
`
`Other literature also contains warnings for co-administration of Livalo® and P450-
`
`metabolized drugs:
`
`DDIs between pitavastatin and, among others, cyclosporine,
`erythromycinrifampin, atazanavir,
`lopinavir/ritonavir,
`fenofibrate,
`gemfibrozil, ezetimibe, enalapril, digoxin, itraconazole, warfarin and
`grapefruit juice)
`“it is recommended that pitavastatin should be discontinued when
`treatment with erythromycin (or other macrolide antibiotics).”
`
`(See, e.g., DTX-1590, KN001590858-69, Anthony M. Gotto Jr., Pitavastatin for the Treatment of
`
`Primary Hyperlipidemia and Mixed Dyslipidemia, 8 EXPERT REV. CARDIOVASCULAR THERAPY
`
`1079, 1085-86 (2010); DTX-1585, KN001597899-914, Vivencio Barrios et al., Searching the
`
`Place of Pitavastatin in the Current Treatment of Patients with Dyslipidemia, 11 EXPERT REV.
`
`CARDIOVASCULAR THERAPY 1597, 1599 (2013) (“Barrios 2013”).)
`
` 
`
`18
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 22 of 30
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`
`60.
`
`Finally, even if one takes Plaintiffs argument as true, the alleged unexpected results
`
`are merely a difference in degree rather than a difference in kind. Such a difference is insufficient
`
`to rebut a showing of obviousness. In re Merck & Co., Inc., 800 F.2d 1091, 1099 (Fed. Cir. 1986)
`
`(finding that finding that the difference in properties between the claimed compounds were “a
`
`matter of degree rather than kind,” and “in the absence of evidence to show that the properties of
`
`the compounds differed in such an appreciable degree that the difference was really unexpected,”
`
`the evidence was insufficient to rebut the prima facie case of obviousness.); see also Hoffmann-La
`
`Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1334 (Fed. Cir. 2014) cert. denied, 135 S. Ct. 878, 190
`
`(2014) (finding that even where the comparative tolerability of the claimed dosage over the prior
`
`art was demonstrated to be unexpected, such evidence was not probative of non-obviousness when
`
`the unexpected result was merely a difference in degree, rather than a difference in kind.).
`
`61.
`
`Plaintiffs’ allegations of unexpected results are not compelling and are insufficient
`
`to overcome the prima facie case of obviousness discussed above. See, e.g., DyStar, 464 F.3d at
`
`1371 (“[S]econdary considerations of nonobviousness are insufficient as a matter of law to
`
`overcome our conclusion that the . . . claim [at issue] would have been obvious.”).
`
`
`
`Plaintiffs Have Failed to Demonstrate Licensing of Livalo® as a Secondary
`Consideration Supporting Non-Obviousness
`
`62.
`
`One of the rarely-used secondary considerations used to rebut obviousness is the
`
`acquiescence of others in the industry, primarily shown through licensing of the patented
`
` 
`
`19
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`Case 1:14-cv-02758-PAC Document 111 Filed 12/16/16 Page 23 of 30
` 
`
`invention, based on the understanding that one would not take a license to a product that was
`
`against their interest. Iron Grip Barbell Co. v. USA Sports, Inc., 392 F