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Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals International Ltd.

United States District Court, D. Delaware

December 14, 2017


          Daniel M. Silver, MCCARTER & ENGLISH, LLP, Wilmington, DE; Nicholas N. Kallas, Charlotte Jacobsen, Christina L. Schwarz, Susanne Flanders, Jared Stringham, and Laura Fishwick, FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY. Attorneys for Plaintiffs.

          David E. Moore and Bindu A. Palapura, POTTER ANDERSON & CORROON LLP, Wilmington, DE; Keith A. Zullow, Michael B. Cottier, Natasha Daughtrey, Cindy Chang, and Steven J. Bernstein, GOODWIN PROCTER LLP, New York, NY. Attorneys for Defendant.



         Plaintiffs brought this patent infringement action against Roxane Laboratories, Inc.[1] in 2015. (D.I. 1). Roxane (now West-Ward) filed Abbreviated New Drug Application ("ANDA") No. 207486, seeking to engage in the commercial manufacture, use, and sale of generic versions of Novartis's Afinitor product. (D.I. 68-1 at 7-8). The parties have stipulated that this ANDA infringes claims 1-3 of U.S. Patent No. 8, 410, 131 ("the '131 patent") and claim 1 of U.S. Patent No. 9, 006, 224 ("the '224 patent"). (D.I. 66 at ¶¶ 3-4).

         At issue in this case are methods for using everolimus to treat advanced renal cell carcinoma ("RCC") and advanced pancreatic neuroendocrine tumors ("PNETs"). Everolimus, which has the formula 40-O-(2-hydroxyethyl)-rapamycin, is a derivative of rapamycin and is the active ingredient in Novartis's Afinitor product. Everolimus itself is claimed in U.S. Patent No. 5, 665, 772 ("the '772 patent"), which is not at issue in this case.

         Rapamycin has long been known to have beneficial medicinal properties, such as immunosuppressive activity and anticancer activity. (Trial Transcript ("Tr.") 74:11-16).[2] Despite these beneficial properties, rapamycin is recognized as having limited utility in pharmaceutical applications as it has low bioavailability, high toxicity, and poor solubility. ('772 patent at 1:36-40; Tr. 74:16-21). Rapamycin derivatives such as everolimus, however, have been shown to have better stability and bioavailability, making them more desirable for pharmaceutical preparations. ('772 patent at 1:41-45). Ternsirolimus, another rapamycin derivative, was a subject of active investigation to treat various cancers as of the priority date. (Tr. 58:12-19).

         The Court held a bench trial on September 13-15, 2017. Defendant argues that the asserted claims of the '131 and '224 patents are invalid as obvious. The '131 patent is directed to the use of rapamycin derivatives to treat solid tumors. ('131 patent at Abstract). Asserted claims 1-3 of the '131 patent require administering a therapeutically effective amount of everolimus to inhibit the growth of solid excretory system tumors, including advanced solid excretory system tumors and kidney tumors. (Id. at claims 1-3). Claims 1-3 of the '131 patent read as follows:

         Claim 1

         1. A method for inhibiting growth of solid excretory system tumors in a subject, said method consisting of administering to said subject a therapeutically effective amount of a compound of formula

         (Image Omitted.)


         R1 is CH3,

         R2 is -CH2-CH2-OH, and

         X is =O.

         Claim 2

         2. The method of claim 1 wherein the solid excretory system tumor is an advanced solid excretory system tumor.

         Claim 3

         3. The method of claim 1 wherein the solid excretory system tumor is a kidney tumor.

         (Id. at claims 1-3).

         The '224 patent is directed to treating endocrine tumors with an mTOR inhibitor as a monotherapy or in combination with another drug. ('224 patent at Abstract). Asserted claim 1 of the '224 patent reads as follows:

1. A method for treating pancreatic neuroendocrine tumors, comprising administering to a human subject in need thereof a therapeutically effective amount of 40-O-(2-hydroxyethyl)-rapamycin as a monotherapy and wherein the tumors are advanced tumors after failure of cytotoxic chemotherapy.

(Id. at claim 1).


         A patent claim is invalid as obvious under 35 U.S.C. § 103 "if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains." 35 U.S.C. § 103; see also KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406-07 (2007). The determination of obviousness is a question of law with underlying factual findings. See Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342, 1360 (Fed. Cir. 2012). "The underlying factual inquiries include (1) the scope and content of the prior art; (2) the differences between the prior art and the claims at issue; (3) the level of ordinary skill in the art; and (4) any relevant secondary considerations .. .." Western Union Co. v. MoneyGram Payment Sys., Inc., 626 F.3d 1361, 1369 (Fed. Cir. 2010) (citing Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)).

         A court is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a "check against hindsight bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1077-79 (Fed. Cir. 2012). Relevant secondary considerations include commercial success, long felt but unsolved needs, failure of others, praise, unexpected results, and copying, among others. Graham, 383 U.S. at 17-18; Ruiz v. A.B. Chance Co., 234 F.3d 654, 662-63 (Fed. Cir. 2000); Tex. Instruments, Inc. v. U.S. Int'l Trade Comm 'n, 988 F.2d 1165, 1178 (Fed. Cir. 1993). Secondary considerations of nonobviousness are important because they "serve as insurance against the insidious attraction of the siren hindsight...." W.L. Gore &Assocs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983).

         A patentee is not required to present evidence of secondary considerations. See Prometheus Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092, 1101-02 (Fed. Cir. 2015). There must be enough evidence, however, for a finding that a given secondary consideration, if presented, exists by a preponderance of the evidence. See Apple Inc. v. Samsung Elec. Co., Ltd., 839 F.3d 1034, 1053 (Fed. Cir. 2016) (en banc). If there is, then the probative value of each secondary consideration will be considered in light of the evidence produced. That does not mean, though, that the burden of persuasion on the ultimate question of obviousness transfers to the proponent of the secondary consideration. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1359 (Fed. Cir. 2007). That burden stays always with the patent challenger. Id. at 1359-60.

         A party asserting that a patent is invalid as obvious must "show by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so." Id. at 1361. That "expectation of success need only be reasonable, not absolute." Id. at 1364. "Whether an ordinarily skilled artisan would have reasonably expected success ... is measured as of the date of the invention[] . . .." Amgen Inc. v. F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1362 (Fed. Cir. 2009).


         A. Findings of Fact

         1. The person of ordinary skill in the art ("POSA") has a medical degree and/or Ph.D. in biology, biochemistry, pharmaceutical sciences, molecular biology, cancer biology, or other biological sciences, and, if necessary, collaborates with others having skills and expertise in areas such as pharmacology, drug formulation, and biochemistry.

         2. The priority date for claims 1-3 of the '131 patent is February 19, 2001. (D.I. 68-1 at 3).

         3. Hidalgo 2000, Hutchinson, the '772 patent, and U.S. Patent No. 6, 004, 973 ("the '973 patent") are prior art.

         4. Hidalgo 2000 or Hutchinson and the '772 patent or the '973 patent, in view of what was known in the art, do not teach a POSA the administration of a therapeutically effective amount of everolimus to inhibit the growth of solid excretory system tumors.

         5. Administration of a therapeutically effective amount of everolimus to treat advanced RCC would not have been obvious to a POSA.

         B. Conclusions of Law

         Defendant contends that administration of a therapeutically effective amount of everolimus to treat advanced RCC would have been obvious to a POSA. (D.I. 91 at 29). The essence of Defendant's obviousness argument is that knowledge in the art about the biology of advanced RCC, mTOR[3] inhibitors, and safe dosing ranges of everolimus, alongside phase I temsirolimus clinical trial results in advanced RCC, would have given a POSA a reasonable expectation of success of effectively treating advanced RCC with everolimus, as both everolimus and temsirolimus are mTOR inhibitors. (Id. at 14). Therefore, according to Defendant, the invention as a whole would have been obvious to a POSA.

         I. Scope and Content of the Prior Art

         i. Background

         Defendant asserts that "the prior art established a strong scientific rationale for using an mTOR inhibitor to treat advanced RCC." (Id. at 30). Plaintiffs counter that many different agents were under investigation for the treatment of advanced RCC, and that the relative success of immunotherapies would have motivated a POSA to investigate immunostimulants rather than immunosuppressants like everolimus. (D.I. 93 at 13; see, e.g., JTX-30 at pp. 869-75; PTX-79 at pp. 43-45).

         As of February 2001, clinical trials for advanced RCC treatments included immunotherapies (PTX-79 at p. 43-45), chemotherapy combinations (PTX-127 at p. 2425), and agents targeting growth factors (JTX-5 at p. 361). Temsirolimus was also in clinical trials to treat cancer at that time, but no mTOR inhibitor had been approved to treat any type of cancer (Tr. 463:6-15, 591:9-592:3), and no clinical data existed for everolimus as an antitumor agent (id. at 188:23-189:3, 464:22-24). Advanced RCC was difficult to treat (id. at 69:15-70:4), as demonstrated by clinical trial failures in immunotherapies and chemotherapy combinations (id. at 590:7-20). Despite these failures, scientists continued to develop and to test chemotherapy combination treatments for advanced RCC because they were active against a variety of cancers and many combinations were available. (D.I. 93 at 14; Tr. 461:2-462:8). Scientists continued to pursue immunotherapy treatments for advanced RCC because they had demonstrated the greatest success to date, with FDA approval for interleukin 2 ("IL-2"). (D.I. 93 at 13; Tr. 69:15-18, 431:7- II, 437:10-20). As of February 2001, there were no completed clinical trials of mTOR inhibitors for treatment of advanced RCC. (Tr. 595:13-24). The prior art also disclosed high failure rates of cancer drugs during clinical trials: more than 70% of cancer drugs failed during phase II, and a majority of cancer drugs failed during phase III. (Id. at 202:17-20, 518:18-23). I conclude that in February 2001, (1) a failure of a particular agent for treatment of advanced RCC would not have dissuaded a POSA from pursuing as a whole the class of agents to which the failed agent belonged, and (2) as a class of drugs, mTOR inhibitors represented a relatively new line of research for treatment of advanced RCC.

         Defendant asserts that the molecular biology of advanced RCC would have motivated a POSA to pursue treatment using mTOR inhibitors. (D.I. 91 at 24-28, 41; D.I. 92 at 15-16). According to Dr. Cho, the prior art established that in renal cell cancer, von Hippel-Lindau ("VHL") tumor suppressor gene function loss leads to the accumulation of hypoxia-inducible factor 1 ("HIF-1"), resulting in over-secretion of vascular endothelial growth factor ("VEGF"), which in turn leads to increased angiogenesis and cancer growth. (Tr. 127:7-128:2, 129:12-23).

         The prior art's mixed results in studies investigating the molecular biology of advanced RCC had not explained the biology as clearly as Dr. Cho stated. As of February 2001, advanced RCC tumors were known to be highly vascularized (id. at 129:14-18), and several studies had demonstrated that a majority (55-60%) of clear cell RCC patients had VHL tumor suppressor gene mutations (id. at 132:4-133:13; JTX-11 at p. 793). It was also known that HIF-1 played a role in regulating VEGF gene expression, VHL gene inactivation was associated with VEGF gene expression, and VEGF gene expression correlated with blood vessel density in many tumor types. (JTX-29 at p. 76). The prior art also linked VHL-defective RCC cell lines to HIF-1 activation, hypothesizing that HIF-1 activation "may underlie the angiogenic phenotype of VHL-associated tumors, " but also cautioning that HIF-1 activation may not be a "sufficient explanation for oncogenesis." (JTX-20 at pp. 271, 274). Immunohistochemical studies spanning multiple types of cancer cells had demonstrated HIF-1 a overexpression in only one of the two samples of human advanced RCC cells studied. (Tr. 137:11-138:21; JTX-36 at pp. 5831-32, 5834).

         The prior art also implicated multiple pathways in HIF-1 activation in human cancer (JTX-29 at p. 90 Fig. 4), and noted inconsistent results for HIF-la expression across RCC biopsies and RCC cell lines (id. at p. 81). Reviewing studies of HIF-1 in human cancer, the Semenza paper was optimistic about the future "potential efficacy of combination therapy utilizing an angiogenesis inhibitor and a HIF-1 inhibitor" (id. at p. 89 (citations omitted)), but concluded that "the role of HIF-la expression in [RCC] requires further analysis" (id. at p. 81; accord JTX-7 at p. 809 ("However, there is still much to learn on, firstly, the exact mechanisms by which mTOR controls the Gl/S transition and, secondly, on any other cellular targets of rapamycin.")). Therefore, although the prior art provided a working hypothesis for the molecular biology of advanced RCC, it revealed multiple potential targets in the mTOR pathway, and scientists acknowledged that the precise role of HIF-1 in the molecular biology of advanced RCC was not completely understood.

         Similarly, as of the priority date, some evidence existed to support the hypothesis that HIF-la overexpression was related to the mTOR pathway, but the precise mechanism of action underlying that relationship was not clear. (See, e.g., JTX-37 at p. 1543). The Zhong 2000 study examined human prostate cancer cell lines and concluded that "HIF-la-dependent gene transcription and the expression of HIF-1-regulated gene product are modulated by the activity of the PI3K/AKT/FRAP pathway" in prostate cancer cells. (Id. at p. 1543; see also Id. at p. 1545). From this, the authors further concluded that increased HIF-la expression can be induced by both genetic mutations and physiological stimulation, and that HIF-1 expression "may play a major role in promoting angiogenesis and metabolic adaptation in [prostate cancer] and other common solid tumors." (Id. at p. 1545). The authors demonstrated correlations between treatment with either rapamycin or a phosphoinositide 3-kinase ("PI3K") inhibitor and reduced HIF-la expression and VEGF secretion in the prostate cancer cell lines. (Tr. 140:8-20; JTX-37 at pp. 1543, 1544). Based on these results and prior data, the authors hypothesized that "pharmacological inhibition of HIF-1 activity may represent a useful treatment strategy, " and that "the effect of PI3K/AKT/FRAP pathway inhibitors on HIF-la expression may provide a basis for therapeutic efficacy." (JTX-37 at p. 1545).

         The Zhong 2000 authors cautioned, however, that additional studies would be required to determine the precise mechanism of action of the PBK/protein kinase B ("AKT")/FKBP12 rapamycin-associated protein ("FRAP") pathway as it related to HIF-la expression. (Id. at p. 1543; accord JTX-27 at p. 3512 ("Clearly, additional experiments are required to establish the relationship between deregulated PI3K-AKT activity and rapamycin sensitivity in human cancer cells."); JTX-29 at p. 91 ("[T]he accelerating pace of discovery [regarding the role of HIF-1 in cancer biology] hopefully will provide sufficient momentum for the transition from basic science to clinical application in the near future.")).

         Finally, Defendant asserts that the prior art established a clear preference for an orally-administered cancer treatment. (D.I. 91 at 28 (citing JTX-10 at Abstract (identifying pharmacoeconomic principles, patient preference, and improved quality of life as driving the pursuit of oral formulations, and noting bioavailability and patient compliance concerns as limitations to oral chemotherapy formulations))). Plaintiffs disagree, arguing that "whether a drug [c]an be administered intravenously or by subcutaneous injection or by orally is not one of the important points for both physicians and patients in choosing a therapy." (Tr. 477:13-17). Whereas Plaintiffs' argument rests on their expert's experience, Defendant's argument finds support in the prior art. I agree with Defendant that the prior art established a general preference for orally-administered cancer treatments.

         In light of the preference for oral cancer treatments, the molecular biology of advanced RCC, and the prior art relating to mTOR inhibitors, Defendant argues a POSA would have been motivated to pursue everolimus to treat advanced RCC with a reasonable expectation of success. (D.I. 91 at 29). The prior art disclosed general antiproliferative properties of everolimus, and that oral administration of everolimus was safe and tolerable in treating renal and liver transplant patients. (JTX-19 at p. 160; JTX-22 at p. 694). According to Dr. Cho, since everolimus and rapamycin both target the mTOR pathway, a POSA would reasonably expect everolimus to have the same antiproliferative effect in advanced RCC patients that rapamycin had in prostate cancer cells. (D.I. 91 at 27; Tr. 139:20-140:1). This assertion is undermined, however, by Dr. Cho's admission that a POSA would not generalize results of a particular treatment across different cancer models. (Tr. 203:16-22). Additionally, although they are related compounds, rapamycin, temsirolimus, and everolimus differ in various pharmacological properties such as their binding affinities for FKBP-12 (id. at 523:18-524:4 (citing JTX-25 at p. 38)), elimination half-lives (Tr. 526:24-527:20 (citing JTX-22 at p. 703)), and the correlation between dose and drug duration in the bloodstream (Tr. 526:1-22 (citing JTX-22 at p. 702)). Therefore, the prior art at most would have identified an oral formulation of everolimus as one of many potential treatment options for advanced RCC.

         Collectively, the background prior art disclosed a variety of approaches under development to treat advanced RCC, including the use of temsirolimus, an mTOR inhibitor, which was in the early stages of clinical development. It cautioned, however, that the role of HIF-1 and the mTOR pathway in the molecular biology of advanced RCC was not completely understood, and that cancer treatments generally demonstrated high failure rates at phase II and phase III clinical trials. The prior art also taught a preference for oral formulations for cancer treatments.

         ii. Asserted ...

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