Case 1:15-cv-00474-RGA Document 100 Filed 12/14/17 Page 1 of 46 PageID #: 2879
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS AG,
`
`Plaintiffs;
`
`v.
`
`WEST-WARD PHARMACEUTICALS
`INTERNATIONAL LIMITED,
`
`Defendant.
`
`Civil Action No. 15-cv-4 74-RGA
`
`TRIAL OPINION
`
`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. Cottler, Natasha Daughtrey, Cindy Chang, and
`Steven J. Bernstein, GOODWIN PROCTER LLP, New York, NY.
`
`Attorneys for Defendant.
`
`December\~ 2017
`
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`Plaintiffs brought this patent infringement action against Roxane Laboratories, Inc. 1 m
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`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 iii! 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,
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`which has the formula 40-0-(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). Temsirolimus, another rapamycin derivative, was a subject of active
`
`investigation to treat various cancers as of the priority date. (Tr. 58:12-19).
`
`1 On February 27, 2017, Defendant Roxane Laboratories, Inc. filed an unopposed motion to substitute West-Ward
`Pharmaceuticals International Limited to replace Roxane Laboratories, Inc., which the Court granted. (D.I. 55, 56).
`Defendant West-Ward is now the owner of the ANDA at issue in this litigation and has not contested jurisdiction of
`this Court. (D.1. 55 at 'IJ'll 5-6).
`2 The trial transcript is available on the docket at D.I. 97-99. It is consecutively paginated.
`
`1
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`The Court held a bench trial on September 13-15, 2017. Defendant argues that the asserted
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`claims of the '131 and '224 patents are invalid as obvious. The '131 patent is directed to the use
`
`ofrapamycin 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 I
`
`41
`
`33
`
`0
`
`OH
`
`24
`
`18
`20
`17~ ~ ~ 23
`19
`21
`
`-
`
`13
`
`15
`
`wherein
`R1 is CH3,
`R1 is -CH2-CH2-0H, and
`Xis=O.
`
`Claim 2
`
`2. The method of claim 1 wherein the solid excretory system tumor is an advanced
`solid excretory system tumor.
`
`2
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`Claim 3
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`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:
`
`tumors, compnsmg
`treating pancreatic neuroendocrine
`1. A method for
`administering to a human subject in need thereof a therapeutically effective amount
`of 40-0-(2-hydroxyethyl)-rapamycin as a monotherapy and wherein the tumors are
`advanced tumors after failure of cytotoxic chemotherapy.
`
`(Id. at claim 1 ).
`
`I.
`
`LEGAL ST AND ARDS
`
`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
`
`3
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`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. ... " WL. Gore & Assocs., Inc. v.
`
`Garlock, Inc., 721F.2d1540, 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 bane). 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.
`
`4
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`F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1362 (Fed. Cir. 2009).
`
`II.
`
`A.
`
`VALIDITY OF THE '131 PATENT
`
`Findings of Fact
`
`I. 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. (DJ. 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, mTOR3 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.
`
`3 mTOR stands for the "mammalian target ofrapamycin."
`
`5
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`1.
`
`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 m TOR 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 forinterleukin 2 ("IL-2"). (D.I. 93 at 13; Tr. 69: 15-18, 431 :7-
`
`11, 437:10-20). As of February 2001, there were no completed clinical trials ofmTOR 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
`
`6
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`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 Rippel-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).
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`7
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`The prior art also implicated multiple pathways in HIF-1 activation in human cancer (JTX-
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`29 at p. 90 Fig. 4 ), and noted inconsistent results for HIF-1 a expression across RCC biopsies and
`
`RCC cell lines (id. at p. 81). Reviewing studies ofHIF-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 G 1/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 ofHIF-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(cid:173)
`
`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-1 a-dependent gene
`
`transcription and the expression of HIF-1-regulated gene product are modulated by the activity of
`
`the PBK/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 ("PBK") 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
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`8
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`on these results and prior data, the authors hypothesized that "pharmacological inhibition of HIF-
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`1 activity may represent a useful treatment strategy," and that "the effect of PI3K/AKT/FRAP
`
`pathway inhibitors on HIP-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 PI3K/protein kinase B ("AKT")/FKBP12
`
`rapamycin-associated protein ("FRAP") pathway as it related to HIP-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(cid:173)
`
`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
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`9
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`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 ofHIF-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.
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`ii.
`
`Asserted Prior Art References
`
`(a) Hidalgo 2000
`
`The Hidalgo 2000 reference discusses the clinical development of rapamycin and
`
`temsirolimus as anti-cancer agents and the rapamycin-sensitive signal transduction pathways
`
`underlying rapamycin' s anti tumor mechanisms of action. (JTX-14 at pp. 6680, 6683; Tr. 82:4-7).
`
`Hidalgo 2000 includes summaries of the preliminary results of two phase I temsirolimus dose-
`
`finding studies (Hidalgo Abstract (JTX-15) and Raymond Abstract (JTX-24)) designed to
`
`determine the maximum tolerated dose of temsirolimus in patients with a variety of solid tumors.
`
`(JTX-14 at p. 6683; Tr. 83:18-84:13, 206:16-19, 209:10-13). Based on promising preliminary
`
`results that temsirolimus "consistently induced tumor regressions at relatively nontoxic doses in
`
`the phase I studies," Hidalgo 2000 notes, "Disease-directed efficacy studies of [temsirolimus] in a
`
`broad range of tumor types will be initiated following the completion of the phase I studies." ( JTX-
`
`14 at p. 6683; Tr. 85:6-11). It is undisputed that Hidalgo 2000 does not provide any information
`
`regarding the use of everolimus to treat any form of cancer. (Tr. 202:24-203:3). It is further
`
`undisputed that Hidalgo 2000 does not suggest that rapamycin had demonstrated preclinical
`
`activity in RCC (id. at 203: 10-15), and that both the Hidalgo Abstract study (id. at 209:4-17; JTX-
`
`15) and the Raymond Abstract study (Tr. 206:8-23; JTX-24) were not limited to patients with
`
`advanced RCC.
`
`(b) Hutchinson
`
`Hutchinson is a December 2000 publication that summarizes the clinical development of
`
`temsirolimus, and includes a review of updated results from the same phase I temsirolimus studies
`
`described in Hidalgo 2000. (JTX-16 at p. 198; Tr. 98:15-99:7). More specifically, Hutchinson
`
`notes one partial response, two minor responses, and three minor responses or prolonged stable
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`disease in patients with RCC across both phase I studies, and further states that a phase II
`
`temsirolimus trial in advanced RCC was underway in the United States. (JTX-16 at p. 198; Tr.
`
`201:21-202:1). It is not disputed that Hutchinson was not formally peer reviewed and does not
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`discuss everolimus. (JTX-16 at p. 198; Tr. 196:17-197:5).
`
`( c) '772 Patent
`
`U.S. Patent No. 5,665,772 issued on September 9, 1997. The '772 patent discloses certain
`
`novel derivatives of rapamycin (id. at 1:41-2:19), including everolimus; notes the general
`
`antitumor activity of rapamycin (id. at 1 :34-36, 4: 1-2); lists everolimus as a preferred compound
`
`for immunosuppressive use (id. at 2:55-56); and discloses various dosages of everolimus (see, e.g.,
`
`id. at 4:29-48). The '772 patent further claims inducing an immunosuppressant effect by
`
`administering everolimus in an effective amount. (Id. at 22: 19-22 ). It is undisputed that the '772
`
`patent does not contain any preclinical or clinical data demonstrating an antitumor effect of
`
`everolimus or any explicit disclosure that everolimus would be effective to treat advanced RCC.
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`(Tr. 193:3-195:9).
`
`(d) '973 Patent
`
`U.S. Patent No. 6,004,973 issued on December 21, 1999. The '973 patent discloses oral
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`formulations of rapamycin derivatives useful for treating, among other things, organ or tissue
`
`transplant rejection, autoimmune disease, asthma, multi-drug resistance, proliferative disorders
`
`such as tumors, fungal infections, inflammation, and infection. (Id. at 4:60-5:47). The '973 patent
`
`further discloses everolimus as a preferred compound and discloses various oral dose ranges for
`
`everolimus.
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`(Id. at 2:5-11; 5:48-55).
`
`It is undisputed that the '973 patent does not contain
`
`preclinical or clinical data demonstrating any antitumor effect of everolimus, and does not suggest
`
`that everolimus would be effective to treat advanced RCC. (Tr. 196:4-14).
`
`12
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`NOVARTIS EXHIBIT 2117
`Par v. Novartis, IPR 2016-01479
`Page 13 of 46
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`Case 1:15-cv-00474-RGA Document 100 Filed 12/14/17 Page 14 of 46 PageID #: 2892
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`2.
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`Comparing Prior Art and Claimed Subject Matter
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`Defendant's expert, Dr. Cho, opines that a POSA would have been motivated to administer
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`therapeutically effective amounts of everolimus to inhibit the progression of advanced RCC with
`
`a reasonable expectation of success. (Id. at 60:8-15). According to Dr. Cho, the claimed invention
`
`would have been obvious over the teachings of Hidalgo 2000 or Hutchinson in combination with
`
`the '973 patent or the '772 patent, in view of the general knowledge in the art.
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`Specifically, Dr. Cho stated that the prior art references Hidalgo 2000 and Hutchinson
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`showed that temsirolimus monotherapy had promising clinical activity in advanced RCC in phase
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`I clinical trials. (Id. at 84:20-85:11, 97:12-98:4). According to Dr. Cho, a then-ongoing phase II
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`clinical trial of temsirolimus in advanced RCC patients would have indicated to a POSA that the
`
`phase I results demonstrated unusually high activity in advanced RCC patients relative to patients
`
`with other cancers because the advanced RCC phase I results were sufficient to justify a phase II
`
`trial in advanced RCC. (Id. at 97:22-98:14 (discussing JTX-16)). Therefore, Defendant argues,
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`either one of these prior art references, combined with the '772 or the '973 patents' disclosures of
`
`general antitumor properties of and oral dose ranges for pharmaceutical compositions of
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`everolimus, would lead a POSA to believe everolimus could be administered in a therapeutically
`
`effective amount as a monotherapy to treat advanced RCC. (Tr. 108: 12-20, 111 :11-112:5, 157:17-
`
`159:5). Dr. Cho further opined that a POSA would be able to arrive at the claimed therapeutically
`
`effective dose of everolimus through routine experimentation. (Id. at 155:4-13). Thus, Defendant
`
`contends that combining these references in view of what was known in the art about advanced
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`RCC would suggest to a POSA all limitations of claims 1-3 of the' 131 patent. (D.I. 91 at 32-33).
`
`The parties do not dispute that a POSA would have recognized the need for an effective
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`treatment for advanced RCC, as it was difficult to treat and the available treatments had
`
`shortcomings. (Id. at 29; D.I. 93 at 11; Tr. 69:15-70:4, 439:7-21). The parties disagree, however,
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`13
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`Case 1:15-cv-00474-RGA Document 100 Filed 12/14/17 Page 15 of 46 PageID #: 2893
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`over whether the prior art as a whole would have motivated a POSA to start with mTOR inhibitors,
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`including everolimus, to treat advanced RCC. (Tr. 159:10-160: 1, 428:23-429:3; D.I. 93 at 17).
`
`Plaintiffs assert that because Dr. Cho restricted his review and analysis to art regarding mTOR
`
`inhibitors, he failed to consider the full scope of the relevant prior art, and Defendant has failed to
`
`prove obviousness because it has failed to prove a motivation to select everolimus over other
`
`compounds.
`
`(D.1. 93 at 12 (citing Tr. 71:24-72:14)). Defendant counters that Plaintiffs'
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`interpretation improperly requires Defendant to prove that everolimus was a preferred compound.
`
`(D.I. 92 at 10-11 (citing Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369,
`
`1376 (Fed. Cir. 2013) ("[A] finding that the prior art as a whole suggests the desirability of a
`
`particular combination need not be supported by a finding that the prior art suggests that the
`
`combination claimed ... is the preferred, or most desirable, combination."))).
`
`I find that the relevant prior art would have included art relating to treatments beyond
`
`mTOR inhibitors. Against the backdrop of a strong desire to find an effective advanced RCC
`
`treatment and the general preference for orally-administered cancer treatments, promising
`
`temsirolimus phase I data, and shared properties of temsirolimus and everolimus, a POSA would
`
`have been motivated to pursue everolimus as one of several potential treatment options for
`
`advanced solid tumors, including advanced RCC. Dr. Cho acknowledged that, in addition to
`
`mTOR inhibitors, a POSA would have considered the many other options for the treatment of
`
`advanced RCC then under development, including immunotherapies and a wide variety of
`
`chemotherapy combinations. (Tr. 176:17-177:8, 447:6-448:3, 452:6-12, 461: 17-462:4). Rather
`
`than reviewing references covering the entire scope of the prior art, Dr. Cho restricted his review
`
`to references concerning the mTOR pathway. (Id. at 71:24-72:14). To support the limited scope
`
`of Dr. Cho's prior art review, Defendant cites the failures associated with immunotherapies and
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`14
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`Case 1:15-cv-00474-RGA Document 100 Filed 12/14/17 Page 16 of 46 PageID #: 2894
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`chemotherapies, the molecular biology of RCC, and active research regarding the mTOR pathway.
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`(D.1. 92 at 12; Tr. 72:15-73:7). The prior art, however, taught that failures with a particular type
`
`of treatment category, such as immunotherapies, would not necessarily deter future development
`
`of treatments within that category. (Tr. 461 :2-462:8, 590:7-20). This, along with the variety of
`
`treatments in development to treat advanced RCC, and the knowledge gaps in the molecular
`
`biology of advanced RCC, would have led a POSA searching for an advanced RCC treatment to
`
`consider prior art references beyond those involving the mTOR pathway. By limiting the scope
`
`of his prior art review to references regarding the mTOR pathway, Dr. Cho allowed hindsight bias
`
`to inform his analysis. Defendant has failed to prove by clear and convincing evidence that a
`
`POSA would have been motivated to select everolimus.
`
`Even if a POSA would have been motivated to select everolimus to treat advanced RCC, I
`
`find that the asserted combinations would not have provided a POSA a reasonable expectation of
`
`success in using everolimus to treat advanced RCC. Defendant asserts that since there are no
`
`inconsistent clinical results in the use of mTOR inhibitors to treat advanced RCC, the hypothesis
`
`that mTOR inhibitors would be effective to treat advanced RCC is supported by a reasonable
`
`expectation of success. (D.I. 92 at 13-14). Dr. Cho admitted, however,