Trials@uspto.gov
`571-272-7822
`
`
` Paper 8
`
`Entered: February 15, 2017
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`____________
`
`Case IPR2016-01479
`Patent 9,006,224 B2
`____________
`
`
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`CRUMBLEY, Administrative Patent Judge.
`
`
`
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a) and 37 C.F.R. § 42.108
`
`
`
`
`571-272-7822
`
`
` Paper 8
`
`Entered: February 15, 2017
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`____________
`
`Case IPR2016-01479
`Patent 9,006,224 B2
`____________
`
`
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`CRUMBLEY, Administrative Patent Judge.
`
`
`
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a) and 37 C.F.R. § 42.108
`
`
`
`
`
`IPR2016-01479
`Patent 9,006,224 B2
`
`
`I. INTRODUCTION
`
`Par Pharmaceutical, Inc. filed a Petition requesting an inter partes
`
`review of claims 1–3 of U.S. Patent No. 9,006,224 B2 (Ex. 1001, “the ’224
`
`patent”). Paper 1 (“Pet.”). Novartis AG, the owner of the ’224 patent, filed
`
`a Preliminary Response to the Petition. Paper 7 (“Prelim. Resp.”).
`
`Pursuant to 35 U.S.C. § 314(a), an inter partes review may not be
`
`instituted unless the information presented in the Petition and any
`
`Preliminary Response shows “there is a reasonable likelihood that the
`
`petitioner would prevail with respect to at least 1 of the claims challenged in
`
`the petition.” Taking into account the information presented, we conclude
`
`that the record establishes a reasonable likelihood that Par will prevail in
`
`proving that claims 1–3 of the ’224 patent are unpatentable. Accordingly,
`
`we institute an inter partes review of these claims.
`
`A. Related Matters
`
`We are informed that the ’224 patent has been asserted in two patent
`
`infringement actions in the United States District Court for the District of
`
`Delaware: Novartis Pharm. Corp. et al. v. Roxane Labs., Inc., No. 15-474-
`
`RGA, and Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 15-475-
`
`RGA. Pet. 3; Paper 4, 2–3. Claims 1 and 2 of the ’224 patent were
`
`challenged by a different petitioner in IPR2016-01461; the Board denied
`
`institution of trial in that proceeding.
`
`B. The ’224 Patent
`
`The ’224 patent, titled “Neuroendocrine Tumor Treatment,” issued
`
`April 14, 2015, from U.S. Patent Application No. 12/094,173. Ex. 1001,
`
`
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`2
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`IPR2016-01479
`Patent 9,006,224 B2
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`(54), (45), (21). The patent describes treating neuroendocrine tumors using
`
`mTOR (mammalian target of rapamycin) inhibitors, including rapamycin
`
`and its derivatives. Id. at 1:2–5, 1:17–43. One specifically listed rapamycin
`
`derivative is 40-O-(2-hydroxyethyl)-rapamycin, also known as everolimus.
`
`Id. at 1:46–47; 11:50.
`
`The ’224 patent discloses that mTOR inhibitors have activity as
`
`immunosuppressants, and have also been found useful for the treatment of
`
`solid tumors, particularly advanced solid tumors, including pancreatic
`
`neuroendocrine tumors (PNETs). Id. at 2:35–67. PNETs are particularly
`
`lethal, having a 5-year patient survival rate of 55.3%; the ’224 patent states
`
`that most are malignant at the time of diagnosis, and 60% or more present
`
`with liver metastases. Id. at 3:1–10. The ’224 patent concludes that there is
`
`an unmet need for treatment of PNETs in patients whose disease has
`
`progressed following one or more courses of chemotherapy. Id. at 3:10–12.
`
`The ’224 patent describes a method of treatment using mTOR
`
`inhibitors, specifically with everolimus (“compound A”). Id. at 11:66–67.
`
`The patent proposes a clinical study in which patients with advanced PNETs
`
`are treated with 10 mg/day of everolimus after failure of cytotoxic
`
`chemotherapy. Id. at 26:56–60.
`
`C. Illustrative Claim
`
`
`
`Of the challenged claims, claims 1 is independent and illustrative of
`
`the challenged claims:
`
`1. A method for treating pancreatic neuroendocrine tumors,
`comprising administering to a human subject in need thereof a
`therapeutically effective amount of 40-0-(2-hydroxyethyl)-
`
`
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`3
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`IPR2016-01479
`Patent 9,006,224 B2
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`rapamycin as a monotherapy and wherein the tumors are
`advanced tumors after failure of cytotoxic chemotherapy.
`
`Ex. 1001, 26:66–27:4. Claim 2 specifies a unit dose of 10 mg/day, and claim
`
`3 requires that the tumor be an islet cell tumor. Id. at 27:5–8.
`
`D. Asserted Grounds of Unpatentability
`
`
`
`Par challenges claims 1–3 of the ’224 patent on the following grounds
`
`of unpatentability:
`
`References
`
`Öberg 2004,2 Boulay 2004,3 and
`O’Donnell4
`
`Basis1
`
`Challenged Claims
`
`§ 103(a) 1–3
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero5
`
`§ 103(a) 2
`
`
`
`1 The relevant sections of the Leahy-Smith America Invents Act (“AIA”),
`Pub. L. No. 112–29, took effect on March 16, 2013. Because the application
`from which the ’224 patent issued was filed before that date, our citations to
`Title 35 are to its pre-AIA version.
`
`2 K. Öberg, Treatment of neuroendocrine tumors of the gastrointestinal
`tract, 27 ONCOLOGIA 57 (2004) (Ex. 1027).
`
`3 A. Boulay et al., Antitumor efficacy of intermittent treatment schedules
`with the rapamycin derivative RAD001 correlates with Prolonged
`Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood
`Mononuclear Cells, 64 CANCER RES. 252 (2004) (Ex. 1005).
`
`4 A. O’Donnell et al., A phase I study of the oral mTOR inhibitor RAD001 as
`a monotherapy to identify the optimal biologically effective dose using
`toxicity, pharmacokinetic (PK) and pharmacodynamics (PD) endpoints in
`patients with solid tumors, 22 PROC. AM. SOC’Y OF CLINICAL ONCOLOGY
`200(803ab) (2003) (Ex. 1029).
`
`5 J. Tabernero et al., A phase I study with tumor molecular
`pharmacodynamics (MPD) evaluation of dose and schedule of the oral
`mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid
`4
`
`
`
`
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`IPR2016-01479
`Patent 9,006,224 B2
`
`
`References
`
`Basis1
`
`Challenged Claims
`
`Boulay 2004, O’Donnell, and Duran6
`
`§ 103(a) 1–3
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`§ 103(a) 2
`
`
`
`Par contends that Öberg 2004, Boulay 2004, and O’Donnell are prior
`
`art to the ’224 patent under 35 U.S.C. § 102(b), whereas Duran and
`
`Tabernero are prior art under 35 U.S.C. § 102(a). Pet. 29–36. Novartis does
`
`not, at this stage of the proceeding, challenge the prior art status of any
`
`reference.
`
`II. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, we construe claims by applying the broadest
`
`reasonable interpretation in light of the specification. 37 C.F.R. § 42.100(b);
`
`see also In re Cuozzo Speed Techs., LLC, 136 S. Ct. 2131, 2144–46 (2016).
`
`Under the broadest reasonable interpretation standard, and absent any
`
`special definitions, claim terms are given their ordinary and customary
`
`meaning, as would be understood by one of ordinary skill in the art in the
`
`context of the entire disclosure. In re Translogic Tech. Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007). Any special definitions for claim terms or phrases
`
`
`
`tumors, 23 J. CLINICAL ONCOLOGY 3007 (2005) (Ex. 1038).
`
`6 I. Duran et al., A Phase II Trial of Temsirolimus in Metastatic
`Neuroendocrine Carcinomas (NECs), 23 SUPPLEMENT TO J. CLINICAL
`ONCOLOGY 3096 (2005) (Ex. 1011).
`
`
`
`5
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`Patent 9,006,224 B2
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`must be set forth with reasonable clarity, deliberateness, and precision. In re
`
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`Par proffers constructions for four claim terms: “pancreatic
`
`neuroendocrine tumor,” “advanced tumor,” “unit dose,” and “islet cell
`
`tumor.” Pet. 18–21. Novartis addresses only the construction of “advanced
`
`tumor,” agreeing with Par that the term should be construed to refer to a
`
`tumor that is unresectable or metastatic. Prelim. Resp. 7–8. Novartis also
`
`asks that we state that “advanced” does not mean “after failure of cytotoxic
`
`chemotherapy,” though this is not a construction Par asserts. Id. at 9–11.
`
`We agree with the parties that the broadest reasonable interpretation
`
`of “advanced” tumors, when viewed in light of the ’224 patent specification,
`
`is “metastatic or unresectable.” The specification refers to “patients with
`
`measurable advanced (metastatic or unrese[c]table) pancreatic
`
`neuroend[o]crine tumors,” suggesting that metastatic and unresectable
`
`tumors are subsets within advanced tumors. Ex. 1001, 26:57–58. We also
`
`note that the specification discusses the use of mTOR inhibitors for cancer
`
`chemotherapy “particularly for the treatment of solid tumors, especially of
`
`advanced solid tumors,” implying that not all solid tumors are “advanced.”
`
`Id. at 2:39–40. The parties’ agreed construction is also consistent with the
`
`evidence of ordinary and customary usage, such as the Cancer Glossary
`
`published by the American Cancer Society. Ex. 2005, 3 (“advanced cancer”
`
`definition).
`
`We decline, at this stage of the proceeding, to include in our
`
`construction of “advanced” that it does not mean “after failure of cytotoxic
`
`chemotherapy,” as Novartis asks. Although we did make such a distinction
`
`
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`6
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`IPR2016-01479
`Patent 9,006,224 B2
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`in our Decision denying institution in the related case IPR2016-01461,
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`neither party has argued that the two terms are synonymous here. Though
`
`we do not consider that construction inconsistent with the one we adopt here,
`
`it is unnecessary to further complicate the construction in this case with
`
`language that is not relevant to the dispute between the parties. We,
`
`likewise, find no present need to construe the terms “unit dose,” and “islet
`
`cell tumor” as Par requests. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`
`200 F.3d 795, 803 (Fed. Cir. 1999) (stating that only claim terms which are
`
`in controversy need to be construed, and then only to the extent necessary to
`
`resolve the controversy).
`
`For these reasons, we adopt the parties’ proposed construction for
`
`“advanced,” as meaning “metastatic or unresectable.”
`
`B. Obviousness over Öberg 2004, Boulay 2004, and O’Donnell
`
`Par contends that claims 1–3 are unpatentable under 35 U.S.C.
`
`§ 103(a) as having been obvious over the combined teachings of Öberg
`
`2004, Boulay 2004, and O’Donnell. Pet. 40–47. Par relies upon the
`
`Declaration of Mark J. Ratain, M.D. (Ex. 1003) to support its positions.
`
`1. The Asserted Ground of Unpatentability
`
`Öberg 2004 discusses methods of treatment for neuroendocrine
`
`tumors of the gastrointestinal tract and pancreas. Ex. 1027, 57. Öberg 2004
`
`specifically discusses treatment of metastatic tumors, which Dr. Ratain
`
`testifies would fall within the skilled artisan’s understanding of advanced
`
`tumors. Id.; see also Ex. 1003 ¶ 101. Included in Öberg 2004 is the
`
`
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`7
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`Patent 9,006,224 B2
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`following figure, which discloses an algorithm for the therapy of
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`neuroendocrine tumors:
`
`
`
`Figure 1 of Öberg 2004 discloses an algorithm for therapy of
`
`neuroendocrine (NE) tumors beginning with surgery, radiotherapy, or
`
`embolization as a first therapy, followed by (in the case of high-proliferative
`
`tumors) cytotoxic therapy and, after failure of cytotoxic therapy,
`
`experimental therapies such as rapamycin. Ex. 1027, 60. Öberg 2004
`
`discusses rapamycin as an “interesting new compound” and suggests clinical
`
`trials with rapamycin as a single agent or in combination with cytotoxic
`
`chemotherapy. Id. According to Par, “Öberg 2004 only differs from claims
`
`1 and 3 of the ’224 patent in that it does not explicitly disclose the use of
`
`everolimus,” and, as to claim 2, it does not include a specific reference to the
`
`10 mg/day unit dose required by that claim. Pet. 31–32.
`
`Boulay 2004 is a study of the efficacy of treatment with “rapamycin
`
`derivative RAD001” (everolimus) in the CA20948 synergenic rat pancreatic
`
`tumor model. Ex. 1005, 252. According to Dr. Ratain, CA20948 is a rat
`
`
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`tumor line used as a model for PNET in laboratory studies, and a person of
`
`ordinary skill in the art would have recognized that activity in the model
`
`would support clinical development to treat human PNETs. Ex. 1003 ¶ 112.
`
`Boulay 2004 also notes that everolimus was a rapamycin derivative being
`
`clinically developed at that time, for use in treatment of human cancer. Ex.
`
`1005, 252. Boulay concludes that everolimus “displays significant
`
`antitumor activity in the synergenic CA20948 rat pancreatic tumor model,”
`
`and is “well tolerated, with no significant body weight loss or mortalities
`
`observed.” Id. at 253–54.
`
`O’Donnell is the abstract of a poster presented at the 2003 Annual
`
`Meeting of the American Society of Clinical Oncology, describing a phase I
`
`study of everolimus. Ex. 1029, 200. The study was a dose escalation study,
`
`performed “to identify the optimal biologically effective dose based on
`
`toxicity” in patients having solid tumors. Id. O’Donnell concluded that
`
`dosages of 5, 10, 20, and 30 mg weekly were “well tolerated” with only mild
`
`degrees of side effects. Id.
`
`Par contends that a person of ordinary skill in the art, seeking to treat
`
`patients with PNET after failure of cytotoxic chemotherapy, would have
`
`looked to Öberg 2004’s disclosure of rapamycin as an “interesting new
`
`compound,” and would have understood these teachings to extend to other
`
`rapamycin derivatives known to be mTOR inhibitors. Pet. 42. Dr. Ratain
`
`testifies that, by 2005, there was a “significant body” of data on the
`
`administration of everolimus to humans, but no reported clinical data on
`
`rapamycin. Ex. 1003 ¶ 135. Dr. Ratain concludes that a person of ordinary
`
`skill in the art would have had reason to administer a rapamycin derivative,
`
`
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`9
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`IPR2016-01479
`Patent 9,006,224 B2
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`such as everolimus, with similar biological activity to rapamycin. Id.
`
`According to Par, that reason would have been further strengthened by
`
`Boulay 2004’s disclosure of everolimus’ activity in treating a rat PNET
`
`model, and O’Donnell’s disclosure that administration of everolimus to
`
`human cancer patients was effective and safe. Pet. 43–44. Par also contends
`
`that this treatment would have had a reasonable expectation of success,
`
`particularly in view of Boulay 2004’s disclosure of the effectiveness in the
`
`rat model. Id. at 45.
`
`With respect to the unit dosage specified in claim 2, Par concedes that
`
`O’Donnell and Boulay 2004 do not specify 10 mg/day. Pet. 46.
`
`Nevertheless, Par contends that determining the optimal dosage would have
`
`required nothing more than routine experimentation, and Novartis has not
`
`shown any particular effectiveness of 10 mg/day as compared to other
`
`dosages. Id. at 46–47.
`
`2. Reasonable Expectation of Success
`
`Novartis argues that a person of ordinary skill in the art would not
`
`have had a reasonable expectation that everolimus would successfully treat
`
`advanced PNETs after failure of cytotoxic chemotherapy, relying on the
`
`declaration of Matthew H. Kulke, M.D. Prelim. Resp. 19–33 (citing Ex.
`
`2001). In particular, Novartis contends that—even if the art suggested
`
`treatment of advanced PNETs with everolimus—patients with advanced
`
`PNETs that had failed cytotoxic chemotherapy had a more resistant or
`
`aggressive form of the disease. Id. at 20. These resistant PNETs, according
`
`to Novartis, presented “unique challenges” and showed far lower response
`
`rates to treatment. Id. at 21.
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`10
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`In view of these hurdles to treatment, Novartis argues, the art cited by
`
`Par would not have provided a reasonable expectation of success. Novartis
`
`observes that Öberg 2004 lists rapamycin, not everolimus, as a treatment
`
`after cytotoxic chemotherapy, and recognizes rapamycin was “experimental”
`
`at the time. Id. at 24–25. With respect to Boulay 2004, Novartis contends
`
`that even if the CA20948 rat model is a model for advanced PNET in
`
`humans, it is not a model for advanced PNET after failure of cytotoxic
`
`chemotherapy and would not have provided a reasonable expectation of
`
`success in these hard-to-treat cases. Id. at 26. Finally, with respect to
`
`O’Donnell, Novartis observes that the reference does not state that the
`
`patients had advanced PNET, let alone advanced PNET after failure of
`
`cytotoxic chemotherapy. Id. at 27.
`
`
`
`At this stage of the proceedings, we cannot conclude, as Novartis
`
`asserts, that a person of ordinary skill in the art would have had no
`
`reasonable expectation of success in treating advanced PNET after failure of
`
`cytotoxic chemotherapy. Novartis’ arguments address the disclosures of
`
`each reference individually, and the expectation of success that might be
`
`drawn from each reference alone. But Par’s proposed ground of
`
`unpatentability is based in the combined disclosures of the three references,
`
`and the reasonable expectation of success must be evaluated on the basis of
`
`the prior art as a combination. To that end, Par has set forth sufficient
`
`evidence that a person of ordinary skill, viewing Öberg 2004, Boulay 2004,
`
`and O’Donnell in combination, would have had a reasonable expectation of
`
`success in treating advanced PNET after failure of cytotoxic chemotherapy.
`
`In particular, we note the testimony of Dr. Ratain supporting Par’s
`
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`11
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`assertions. See Ex. 1003 ¶ 150. Although Dr. Kulke provides testimony to
`
`the contrary (see Ex. 2001 ¶¶ 85–88), conflicting expert testimony creates a
`
`genuine issue of material facts, which we must view in the light most
`
`favorable to a petitioner when deciding whether to institute trial. See 37
`
`C.F.R. § 42.108(c).
`
`3. Secondary Considerations of Nonobviousness
`
`Par addresses secondary considerations of nonobviousness in its
`
`Petition, contending that any considerations that might be raised by Novartis
`
`in reply are insufficient to support nonobviousness. Pet. 54–55. Though Par
`
`addresses indicia such as long-felt need, commercial success, and copying, it
`
`is notably silent as to unexpected results. Id. This is significant, Novartis
`
`argues, because evidence of unexpected results was made of record during
`
`prosecution of the application that issued as the ’224 patent, and the
`
`Examiner cited those unexpected results in the Statement of Reasons for
`
`Allowance. Prelim. Resp. 40–41; Ex. 1002, 1114–16. As such, Novartis
`
`contends that Par had the burden of acknowledging this evidence in its
`
`Petition, and should have addressed unexpected results in order to establish a
`
`reasonable likelihood of success on the merits. Id. (citing Praxair Distrib.,
`
`Inc. v. INO Therapeutics, Inc., Case IPR2015-00522, 16–17 (PTAB July 29,
`
`2015) (Paper 12)).
`
`Even if it is proper, in some cases, to place the burden on a petitioner
`
`to address in its petition previously-introduced evidence of unexpected
`
`results, we do not consider it appropriate in the case at hand. It does not
`
`appear, on the present record, that the evidence of unexpected results that
`
`was before the Examiner is commensurate in scope with the claims before us
`
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`today. Notably, at the time the evidence of unexpected results was
`
`presented, the claims pending before the Office were not limited to advanced
`
`tumors after the failure of cytotoxic chemotherapy. See Ex. 1002, 935.
`
`The Declaration of Dr. Lebwohl, submitted under 37 C.F.R. § 1.132
`
`as evidence of unexpected results, is similarly not limited to treatment after
`
`failure of cytotoxic chemotherapy. See id. at 1005–08. Dr. Lebwohl’s
`
`Declaration describes the RADIANT-3 clinical study as “the first clinical
`
`study that confirmed that patients having advanced neuroendocrine tumors
`
`of pancreatic origin when treated with [everolimus] more than doubled the
`
`time without tumor growth,” but does not mention treatment following
`
`failure of cytotoxic chemotherapy. Id. at 1007, ¶ 7. Nor does the Appendix
`
`to the Declaration, a Novartis press release, mention failure of cytotoxic
`
`chemotherapy, or describe any particular results in patients who had
`
`previously undergone chemotherapy. Id. at 1009. Given the emphasis in the
`
`Preliminary Response on the failure of cytotoxic chemotherapy limitation as
`
`being central to the patentability of the claims, Novartis provides no reason
`
`why should overlook that distinction when evaluating the previously-
`
`submitted evidence of unexpected results.
`
`We note that, in its Preliminary Response, Novartis cites the Yao
`
`paper describing the RADIANT-3 study as further evidence of unexpected
`
`results. Prelim. Resp. 41–42. While Yao does note that some portion of
`
`patients in the study had previously received chemotherapy (Ex. 2022, 517–
`
`18) this evidence does not appear to have been before the Examiner during
`
`prosecution. As such, we decline to place the burden on Par to anticipate
`
`this evidence of unexpected results and address it in its Petition.
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`For these reasons, although we acknowledge Novartis’ evidence of
`
`unexpected results, the current evidence of objective indicia does not
`
`persuade us of the nonobviousness of the challenged claims. The parties
`
`will have the opportunity to further develop the record regarding unexpected
`
`results during the instituted trial.
`
`4. Conclusion
`
`We find that, at this stage of the proceeding, Par has sufficiently
`
`established a reasonable likelihood it will prevail in proving claims 1–3 to be
`
`unpatentable over Öberg 2004, Boulay 2004, and O’Donnell. With respect
`
`to claims 1 and 3, Par has made a sufficient showing that the prior art
`
`teaches the elements of the claims, there was a reason to combine the
`
`disclosures, and that there was a reasonable expectation of success. With
`
`respect to claim 2, we note that Novartis does not, at this stage of the
`
`proceeding, separately argue the claim, or contend that determining the
`
`proper dosage would not have been routine experimentation at the time of
`
`the invention.
`
`C. Obviousness over Öberg 2004, Boulay 2004, O’Donnell, and Tabernero
`
`Par also contends that, even if the dosage limitation of claim 2 is not
`
`obvious as being routine experimentation in light of Öberg 2004, Boulay
`
`2004, and O’Donnell, Tabernero explicitly teaches such a dosage. Pet. 48.
`
`Tabernero is a presentation abstract regarding a Phase I study of the
`
`use of everolimus in patients with advanced solid tumors. Ex. 1038.
`
`Tabernero discloses that everolimus inhibits mTOR, a protein kinase
`
`involved in “the regulation of cell growth, proliferation, and survival.” Id.
`
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`Tabernero recommends further Phase II–III development of everolimus, at a
`
`dosage of 10 mg daily, as a single agent tumor treatment. Id.
`
`
`
`Novartis does not separately address this ground, or contend that
`
`Tabernero does not teach a 10mg/day unit dose of everolimus. We are
`
`persuaded, on this record, that Par has sufficiently established that a person
`
`of ordinary skill in the art would have had reason to administer such a
`
`dosage of everolimus in view of Tabernero and the other cited prior art.
`
`D. Obviousness over Boulay 2004, O’Donnell, and Duran
`
`Par also contends that claims 1–3 would have been obvious over the
`
`combined disclosures of Boulay 2004, O’Donnell, and Duran. Pet. 49–52.
`
`The disclosures of Boulay 2004 and O’Donnell relied upon by Par are set
`
`forth above.
`
`Duran discusses the administration of the rapamycin derivative
`
`temsirolimus to patients having metastatic neuroendocrine carcinomas
`
`(NECs), which Dr. Ratain testifies are a subset of advanced NETs.
`
`Ex. 1011, 215s; Ex. 1003 ¶ 129. Specifically, Duran notes islet cell
`
`carcinomas as a subset of the treated NECs. Ex. 1011, 215s. Of the 23
`
`patients in the study, 11 had undergone prior chemotherapy. Id. Duran
`
`concludes that temsirolimus appears to have antitumor activity in NECs. Id.
`
`Par contends that Duran teaches that temsirolimus, which is related to
`
`everolimus, had been shown to be safe and effective as monotherapy in
`
`patients with advanced NET previously treated with cytotoxic
`
`chemotherapy. Pet. 49. This, combined with Boulay 2004’s teaching that
`
`everolimus was successful in a rat pancreatic NET model, and O’Donnell’s
`
`disclosure that everolimus was tolerated and effective in humans, allegedly
`
`
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`15
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`IPR2016-01479
`Patent 9,006,224 B2
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`would have led a person of ordinary skill in the art to administer everolimus
`
`to a patient having advanced NETs after failure of cytotoxic chemotherapy.
`
`Id. at 49–50. Relying on the testimony of Dr. Ratain, Par contends that such
`
`a treatment would have had a reasonable expectation of success. Id. at 50
`
`(citing Ex. 1003 ¶ 167).
`
`With respect to claim 2, Par again contends that the dosage limitation
`
`would have been the result of routine experimentation. Pet. 51–52. As with
`
`the prior ground, Novartis does not address claim 2 separately or contend at
`
`this stage of the proceeding that the proper dosage would not have been
`
`determined via routine experimentation.
`
`Novartis again argues that Par has failed to establish a reasonable
`
`expectation of success in using everolimus to treat advanced PNET after
`
`failure of cytotoxic chemotherapy, and also notes the alleged unexpected
`
`results of the invention. Prelim. Resp. 33–38, 40–45. We find these
`
`arguments unpersuasive at this stage of the proceeding, for the reasons
`
`discussed in the prior ground.
`
`Novartis also argues that institution of this ground of unpatentability
`
`should be denied, because the three cited references do not disclose
`
`treatment after failure of cytotoxic chemotherapy. Id. at 11–19. With
`
`respect to Duran,7 Novartis contends that because not all NECs are advanced
`
`PNETs, there is no way to know from Duran’s disclosure whether any of the
`
`
`
`7 Though Novartis also addresses Boulay 2004, O’Donnell, and Tabernero in
`its Preliminary Response (Prelim. Resp. 11–15, 17–18), we understand Par’s
`contention to be that Duran alone teaches treatment after cytotoxic
`chemotherapy.
`
`16
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`IPR2016-01479
`Patent 9,006,224 B2
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`treated patients had advanced PNETs. Id. at 15–16. Similarly, Novartis
`
`contends that Duran does not specify whether any of the patients previously
`
`treated with chemotherapy had advanced PNETs, and cites Dr. Kulke’s
`
`testimony that a person of ordinary skill would have understood the Duran
`
`patients who underwent chemotherapy did not have advanced PNETs. Id. at
`
`16 (citing Ex. 2001 ¶ 43).
`
`Though we agree with Novartis that Duran does not explicitly specify
`
`treatment of patients with advanced PNET after failure of cytotoxic
`
`chemotherapy, we do not find this fatal to the Petition at this stage of the
`
`proceeding. Duran does disclose the treatment of patients with advanced
`
`NEC, and that some of the patients had previously undergone chemotherapy.
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`Par’s contention that this disclosure would have suggested temsirolimus to a
`
`person of ordinary skill in the art seeking to treat advanced PNET after
`
`failure of cytotoxic chemotherapy is reasonable on the present record.
`
`Given this suggestion, we also find it reasonable that the skilled artisan
`
`would have investigated other rapamycin derivatives, including everolimus
`
`in light of Boulay 2004 and O’Donnell.
`
`For the foregoing reasons, we find that Par has sufficiently established
`
`a reasonable likelihood it will prevail in proving claims 1–3 to be
`
`unpatentable over Boulay 2004, O’Donnell, and Duran.
`
`E. Obviousness over Boulay 2004, O’Donnell, Duran, and Tabernero
`
`As with the prior ground involving Öberg 2004, Par contends that
`
`even if Boulay 2004, O’Donnell, and Duran do not teach or suggest claim
`
`2’s dosage limitation of 10 mg/day, this dosage is explicitly set forth by
`
`Tabernero. Pet. 53. Again, Novartis does not address this ground separately
`
`
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`17
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`IPR2016-01479
`Patent 9,006,224 B2
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`or contend that Tabernero does not disclose this dosage of everolimus. We
`
`conclude, for the reasons stated above, that Par has established a reasonable
`
`likelihood of prevailing on this ground.
`
`III. CONCLUSION
`
`Upon consideration of the Petition and the Preliminary Response, and
`
`for the reasons set forth above, we conclude that Par has demonstrated a
`
`reasonable likelihood that claims 1–3 of the ’224 patent are unpatentable.
`
`Accordingly, we institute inter partes review with respect to these claims as
`
`set forth in the following Order.
`
`IV. ORDER
`
`Accordingly, it is
`
`ORDERED that, pursuant to 35 U.S.C. § 314, an inter partes review
`
`is instituted on the following grounds, the trial commencing as of the date of
`
`this Decision:
`
`(1) Whether claims 1–3 are unpatentable under 35 U.S.C. § 103(a) as
`having been obvious over the combined disclosures of Öberg 2004,
`Boulay 2004, and O’Donnell;
`
`(2) Whether claim 2 is unpatentable under 35 U.S.C. § 103(a) as
`having been obvious over the combined disclosures of Öberg 2004,
`Boulay 2004, O’Donnell, and Tabernero;
`
`(3) Whether claims 1–3 are unpatentable under 35 U.S.C. § 103(a) as
`having been obvious over the combined disclosures of Boulay 2004,
`O’Donnell, and Duran;
`
`(4) Whether claim 2 is unpatentable under 35 U.S.C. § 103(a) as
`having been obvious over the combined disclosures of Boulay 2004,
`O’Donnell, Duran, and Tabernero; and
`
`
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`18
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`IPR2016-01479
`Patent 9,006,224 B2
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`FURTHER ORDERED that no ground other than those specifically
`
`granted above are authorized for inter partes review as to the claims of the
`
`’224 patent.
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`19
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`IPR2016-01479
`Patent 9,006,224 B2
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`For PETITIONER:
`
`Daniel Brown
`Daniel.brown@lw.com
`
`Jon Strang
`Jonathan.strang@lw.com
`
`
`For PATENT OWNER:
`
`Nicholas Kallas
`nkallas@fchs.com
`
`Raymond Mandra
`rmandra@fchs.com
`
`
`
`
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`20
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