Trials@uspto.gov
`571-272-7822
`
`Paper 61
`Date: October 5, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICAL LLC,
`Petitioner,
`v.
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-014791
`Patent 9,006,224 B2
`
`
`
`
`
`
`
`
`
`Before CHRISTOPHER L. CRUMBLEY, ROBERT A. POLLOCK, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`CRUMBLEY, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`1 This proceeding as initially filed named Par Pharmaceutical, Inc. as the
`sole Petitioner. Argentum Pharmaceutical LLC was joined as a party to this
`proceeding via a Motion for Joinder in IPR2017-01063; West-Ward
`Pharmaceuticals International Limited was joined as a party via a Motion for
`Joinder in IPR2017-01078. Subsequently, Par and West-Ward separately
`requested termination of their participation in the proceeding pursuant to
`settlement. Argentum Pharmaceutical LLC is the sole remaining Petitioner.
`
`
`
`

`

`IPR2016-01479
`Patent 9,006,224 B2
`
`INTRODUCTION
`I.
`In this inter partes review, instituted pursuant to 35 U.S.C. § 314,
`Argentum Pharmaceutical LLC (“Argentum”) challenges the patentability of
`claims 1–3 of U.S. Patent No. 9,006,224 B2 (Ex. 1001, “the ’224 patent”),
`owned by Novartis AG (“Novartis”).
`We have jurisdiction under 35 U.S.C. § 6. This Final Written
`Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73,
`addresses issues and arguments raised during trial. For the reasons
`discussed below, we determine that Argentum has not shown by a
`preponderance of the evidence that claims 1–3 of the ’224 patent are
`unpatentable.
`A. Procedural History
`On July 22, 2016, Par Pharmaceutical, Inc. (“Par”) filed a Petition
`requesting an inter partes review of claims 1–3 of the ’224 patent. Paper 1
`(“Pet.”). Novartis filed a Preliminary Response. Paper 7. On February 14,
`2017, we instituted an inter partes review of the challenged claims. Paper 8
`(“Dec.”). Subsequent to institution, Argentum and West-Ward
`Pharmaceuticals International Limited (“West-Ward”) filed separate
`petitions and motions for joinder with the instant proceeding. IPR2017-
`01063, Papers 1, 3; IPR2017-01078, Papers 1, 3. On September 25, 2017,
`we granted both motions for joinder, joining Argentum and West-Ward as
`petitioners to this inter partes review. Paper 33. As we noted at the time,
`both Argentum and West-Ward stated that their petitions include the same
`
`2
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`IPR2016-01479
`Patent 9,006,224 B2
`grounds and arguments2 as those in the Par proceeding, and both parties rely
`on the same evidence including the same expert witness testimony. Id. at 5.
`Following institution, Novartis filed a Patent Owner Response (Paper
`17, “PO Resp.”) and Argentum filed a Reply (Paper 21, “Reply”). We
`granted Novartis authorization to file a Surreply (Paper 26, “Surreply”) to
`address alleged new arguments made in Argentum’s Reply, and permitted
`Argentum to file a short Response (Paper 29).
`Argentum relies upon the declaration testimony of Dr. Mark J. Ratain
`(Ex. 1003), and with its Reply submitted a Supplemental Declaration of
`Dr. Ratain (Ex. 1119). Novartis took cross-examination of Dr. Ratain via
`deposition following the submission of each declaration, and filed the
`transcripts (Exs. 2040, 2111). Novartis filed observations on the cross-
`examination of Dr. Ratain (Paper 34) and Argentum filed a response to the
`observations (Paper 42).
`Novartis relies upon the declaration testimony of Dr. Matthew H.
`Kulke. Ex. 2041. Argentum took cross-examination of Dr. Kulke via
`deposition and submitted the transcript. Ex. 1070.
`Novartis filed a Motion to Exclude certain evidence submitted by
`Argentum (Paper 35, “Mot. Exclude”), after which Argentum filed an
`Opposition (Paper 41, “Opp. Exclude”) and Novartis filed a Reply (Paper
`43, “Reply Exclude”).
`
`
`2 For this reason, although we cite to Par’s Petition in this decision because it
`is of record in this proceeding, we attribute all the contentions made therein
`to Argentum as the sole remaining Petitioner.
`
`3
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`IPR2016-01479
`Patent 9,006,224 B2
`Oral argument was requested by both parties. Papers 31, 36.
`Argument was heard on November 1, 2017, and a transcript has been
`entered into the record. Paper 49 (“Tr.”).
`On January 23, 2018, Par and Novartis filed a joint motion to
`terminate Par as a petitioner due to settlement (Paper 50), which we granted
`on February 6, 2018 (Paper 52).
`On February 14, 2018, counsel for Argentum contacted the Board via
`e-mail, requesting that the Board hold the Final Written Decision in
`abeyance in order to facilitate ongoing settlement discussions with Novartis.
`Ex. 3002. We notified the parties that, in light of the parties’ request and
`because the proceedings involve joinder, pursuant to 35 U.S.C. § 316(a)(11)
`and 37 C.F.R. § 42.100(c) we would adjust the time for issuing a Final
`Written Decision. Counsel for West-Ward3 e-mailed a similar request on
`February 15, 2018. Ex. 3003. West-Ward continued to provide updates to
`the Board via e-mail to notify us that settlement negotiations were ongoing
`and to request that we continue to hold this Decision in abeyance.
`On October 2, 2020, West-Ward and Novartis jointly requested to
`terminate West-Ward as a petitioner due to settlement (Paper 57), which we
`granted (Paper 60). Argentum is the sole remaining Petitioner in this
`proceeding.
`
`
`3 West-Ward updated its Mandatory Notices on January 8, 2019, notifying
`us that it changed its name to Hikma Pharmaceuticals International Limited.
`IPR2017-01078, Paper 11. Because the majority of the filings in this case
`were made prior to the name change, for clarity of this Decision we will
`refer to the company using its prior name, West-Ward.
`
`4
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`IPR2016-01479
`Patent 9,006,224 B2
`B. Related Proceedings
`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.
`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.
`While this inter partes review was pending, the District Court entered
`a decision in the former case, finding no invalidity of claim 1 the ’224
`patent, on December 14, 2017. Novartis Pharm. Corp. v. West-Ward
`Pharm. Int’l Ltd., 287 F. Supp. 3d 505 (D. Del. 2017) (“District Court
`Decision”). That decision also found that certain claims of a related patent,
`U.S. Patent No. 8,410,131 (“the ’131 patent”) were not invalid. Id. West-
`Ward appealed the District Court’s decision as to the ’131 patent to the
`United States Court of Appeals for the Federal Circuit, but did not appeal the
`District Court’s decision regarding the ’224 parent at issue here. On May
`13, 2019, the Federal Circuit affirmed. Novartis Pharm. Corp. v. West-Ward
`Pharm. Int’l Ltd., 923 F.3d 1051 (Fed. Cir. 2019) (“Federal Circuit
`Decision”).
`C. 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,
`codes (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
`
`5
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`IPR2016-01479
`Patent 9,006,224 B2
`rapamycin derivative is 40-O-(2-hydroxyethyl)-rapamycin, also known as
`everolimus. Id. at 1:46–47, 11:50–51.
`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 such tumors 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 3:9–12.
`The ’224 patent describes a method of treatment using mTOR
`inhibitors, specifically with everolimus (also called “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.
`D. The Challenged Claims
`Claim 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-O-(2-hydroxyethyl)-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.
`
`6
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`IPR2016-01479
`Patent 9,006,224 B2
`E. The Instituted Grounds
`We instituted an inter partes review of all claims challenged in the
`Petition on the following grounds of unpatentability, each alleging
`obviousness of the claims under 35 U.S.C. § 103(a)4:
`Claim(s)
`Challenged
`1–3
`
`Öberg 2004,5 Boulay 2004,6 and O’Donnell7
`
`References
`
`2
`
`1–3
`
`Öberg 2004, Boulay 2004, O’Donnell, and Tabernero8
`
`Boulay 2004, O’Donnell, and Duran9
`
`
`4 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.
`5 K. Öberg, Treatment of neuroendocrine tumors of the gastrointestinal
`tract, 27 ONCOLOGIA 57 (2004) (Ex. 1027).
`6 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).
`7 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).
`8 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
`tumors, 23 J. CLINICAL ONCOLOGY 3007 (2005) (Ex. 1038).
`9 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).
`
`7
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`

`IPR2016-01479
`Patent 9,006,224 B2
`Claim(s)
`Challenged
`2
`
`References
`
`Boulay 2004, O’Donnell, Duran, and Tabernero
`
`
`
`II. ANALYSIS
`
`A. Legal Standards
`To prevail in challenging Novartis’s claims, Argentum must
`demonstrate by a preponderance of the evidence that the claims are
`unpatentable. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). A claim is
`unpatentable under 35 U.S.C. § 103(a) if the differences between the
`claimed subject matter and the prior art are such that the subject matter, as a
`whole, would have been obvious at the time of the invention to a person
`having ordinary skill in the art. KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398,
`406 (2007). The question of obviousness is resolved on the basis of
`underlying factual determinations including: (1) the scope and content of
`the prior art; (2) any differences between the claimed subject matter and the
`prior art; (3) the level of ordinary skill in the art; and (4) objective evidence
`of nonobviousness, i.e., secondary considerations.10 See Graham v. John
`Deere Co., 383 U.S. 1, 17–18 (1966). The level of ordinary skill in the art
`may be reflected by the prior art of record. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001).
`B. Claim Construction
`In an inter partes review based on a petition filed prior to November
`13, 2018, the Board interprets claim terms in an unexpired patent according
`to their broadest reasonable construction in light of the specification of the
`
`
`10 The record does not contain evidence or argument regarding objective
`evidence of non-obviousness.
`
`8
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`IPR2016-01479
`Patent 9,006,224 B2
`patent in which they appear. 37 C.F.R. § 42.100(b) (2016).11 Under that
`standard, we interpret claim terms using “the broadest reasonable meaning
`of the words in their ordinary usage as they would be understood by one of
`ordinary skill in the art, taking into account whatever enlightenment by way
`of definitions or otherwise that may be afforded by the written description
`contained in the applicant’s specification.” In re Morris, 127 F.3d 1048,
`1054 (Fed. Cir. 1997). Only those terms which are in controversy need to be
`construed and only to the extent necessary to resolve the controversy. See
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013,
`1017 (Fed. Cir. 2017); see also U.S. Surgical Corp. v. Ethicon, Inc., 103
`F.3d 1554, 1568 (Fed. Cir. 1997) (holding claim construction is not
`necessary when it is not “directed to, or has been shown reasonably to affect,
`the determination of obviousness”).
`In its Petition, Argentum proffered constructions for four claim terms:
`“pancreatic neuroendocrine tumor,” “advanced tumors,” “unit dose,” and
`“islet cell tumor.” Pet. 18–21. Novartis’s Preliminary Response addressed
`only the construction of “advanced tumors,” agreeing that the term should be
`construed to refer to a tumor that is unresectable or metastatic. Prelim.
`Resp. 7–8. Novartis also asked that we state that “advanced” does not mean
`“after failure of cytotoxic chemotherapy,” though this is not a construction
`any petitioner asserted. Id. at 9–11.
`
`
`11 An amendment to this rule does not apply here because the Petition was
`filed prior to November 13, 2018. See Changes to the Claim Construction
`Standard for Interpreting Claims in Trial Proceedings Before the Patent Trial
`and Appeal Board, 83 Fed. Reg. 51340 (Oct. 11, 2018) (amending 37 C.F.R.
`§ 42.100(b) effective November 13, 2018) (now codified at 37 C.F.R.
`§ 42.100(b) (2019)).
`
`9
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`IPR2016-01479
`Patent 9,006,224 B2
`In our Institution Decision, we agreed with the parties that the
`broadest reasonable interpretation of “advanced” tumors, when viewed in
`light of the ’224 patent specification, is “metastatic or unresectable.” Dec. 6.
`But we declined to incorporate in our construction a requirement that
`“advanced” does not means “after failure of cytotoxic chemotherapy,” as
`Novartis requested. Id. We did not consider it necessary to construe any
`other terms from the challenged claims. During the instituted trial, neither
`party asked that we revisit the construction of “advanced,” or argued that we
`should render any further constructions. In view of the complete record, we
`reaffirm our prior construction of “advanced tumor,” and do not consider
`further constructions of any claim term to be necessary.
`C. Obviousness over Öberg 2004, Boulay 2004, and O’Donnell
`Argentum 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. Argentum relies upon the
`Declaration of Mark J. Ratain, M.D. (Ex. 1003) to support its positions.
`1. The Prior Art
`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
`following figure, which discloses an algorithm for the therapy of
`neuroendocrine tumors:
`
`10
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`IPR2016-01479
`Patent 9,006,224 B2
`
`
`
`Figure 1 of Öberg 2004, shown above, 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 Argentum, “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
`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
`
`11
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`IPR2016-01479
`Patent 9,006,224 B2
`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.
`2. The Proposed Combination
`Argentum 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,
`such as everolimus, with similar biological activity to rapamycin. Id.
`According to Argentum, that reason would have been further strengthened
`by Boulay 2004’s disclosure of everolimus’ activity in treating a rat
`
`12
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`IPR2016-01479
`Patent 9,006,224 B2
`pancreatic tumor model, and O’Donnell’s disclosure that administration of
`everolimus to human cancer patients was effective and safe. Pet. 43–44.
`Argentum 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, Argentum
`concedes that O’Donnell and Boulay 2004 do not specify 10 mg/day.
`Pet. 46. Nevertheless, Argentum 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.
`3. Reason to Select Everolimus
`Novartis contends that the combined art fails to render the claims
`obvious, because Argentum “provides no credible reason why a [person of
`ordinary skill in the art] would have been motivated to select everolimus
`over other prior art compounds to treat advanced PNETs after failure of
`cytotoxic chemotherapy.” PO Resp. 23–24. Novartis contends that, at the
`time of the invention, numerous compounds were being developed to treat
`cancer generally, and many of those compounds were in more advanced
`stages of clinical development than everolimus. Id. at 24. For example,
`Novartis observes that small molecule tyrosine kinase inhibitors (e.g.,
`gefitinib, erlotinib, SU101, sorafenib, imatinib mesylate, and sunitinib
`malate), and anti-receptor antibodies (e.g., cetuximab and trastuzumab) had
`reached at least Phase III clinical trials in human cancers, and sorafenib had
`completed Phase II clinical trials in NETs (including advanced PNETs). Id.
`(citing Ex. 2041 ¶113; Ex. 2043, 361–66; Ex. 1037, S42–S43; Ex. 2061,
`1248; Ex. 2072, 2270; Ex. 2051, 7484). Novartis asserts that a person of
`
`13
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`IPR2016-01479
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`ordinary skill in the art would have favored any of these various compounds
`over everolimus, given the limited state of knowledge as to its efficacy at the
`time. Id. at 25.
`Novartis argues that unless Argentum can prove that the skilled
`artisan would have selected everolimus from among the possible treatments
`available, its obviousness case must fail. PO Resp. 23. To support this
`proposition, Novartis cites Insite Vision Inc. v. Sandoz, Inc., 783 F.3d 853,
`861 (Fed. Cir. 2015), as holding that “[i]n cases involving a new method of
`treatment using a known compound, the Board should consider whether the
`prior art as a whole would have motivated a [person of ordinary skill in the
`art] to select the claimed compound over other prior art compounds.” PO
`Resp. 23. We disagree with Novartis’ interpretation of Insite Vision.
`The Federal Circuit’s decision in appeal from the related District
`Court case is instructive on this point. In that case, just as in this one,
`Novartis argued that claim 1 of the ’224 patent was nonobvious because the
`skilled artisan would not have been motivated to select everolimus over
`other prior art compounds. District Court Decision, 287 F. Supp. 3d at 527.
`The District Court accepted that argument as one basis for finding that the
`claims were not invalid. Id. But the Federal Circuit found this conclusion to
`be in error. Federal Circuit Decision, 923 F.3d at 1059 (“[O]ur case law
`does not require that a particular combination must be the preferred, or the
`most desirable, combination described in the prior art in order to provide
`motivation for the current invention.”) (quoting In re Fulton, 391 F.3d 1195,
`1200 (Fed. Cir. 2004)). While the Federal Circuit found that such
`considerations may be appropriate when evaluating a “lead compound”
`obviousness challenge, the combination asserted in the District Court (and
`mirrored here) does not involve such an analysis. Id. at 1060. The Federal
`
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`IPR2016-01479
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`Circuit concluded that the proper inquiry in cases such as the present one is
`whether a person of ordinary skill in the art would have been motivated to
`modify the prior art to arrive at the claimed method of treatment. Id. “This
`question was answered affirmatively when the district court found that a
`person of ordinary skill ‘would have been motivated to pursue everolimus as
`one of several potential treatment options.’” Id.
`Judged by the correct standard, the evidence leaves little doubt that a
`person of ordinary skill in the art would have been motivated to pursue
`everolimus as a potential treatment option for advanced PNETs after failure
`of cytotoxic chemotherapy. Novartis does not seriously contend otherwise,
`focusing its arguments instead on whether the motivation to pursue
`everolimus was greater than the motivation to pursue other possible
`treatments. Not only does Öberg 2004 discusses rapamycin as an
`“interesting new compound” that suggests clinical trials with rapamycin in
`combination with cytotoxic chemotherapy, it specifically provides a
`treatment algorithm that shows rapamycin among the potential
`“experimental therapies” following failure of cytotoxic chemotherapy.
`Ex. 1027, 60, Fig 1. And O’Donnell specifically demonstrates that
`administration of everolimus to human cancer patients was safe. Ex. 1029,
`200. We credit Dr. Ratain’s testimony 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. Given the difference
`in information on everolimus and rapamycin, we find that the skilled artisan
`would have been motivated to pursue everolimus as an alternative to the
`rapamycin disclosed in Öberg 2004.
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`4. Reasonable Expectation of Success
`Even if a person of ordinary skill would have had reason to pursue
`everolimus, however, our inquiry does not end there. Argentum must also
`prove that the 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.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007).
`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).
`Again, review of the District Court’s decision in the related case, as
`well as the Federal Circuit’s decision on appeal, is instructive.12 The District
`Court found that, as of 2001, there were no clinical trials of everolimus and
`that another rapamycin derivative, temsirolimus,13 had only undergone
`
`
`12 We recognize that the Federal Circuit Decision applies to the ’131 patent,
`and was rendered on a different factual basis than the prior art at issue before
`us. For example, the critical date for the ’131 patent is approximately four
`years earlier than that of the ’224 patent, requiring a different evaluation of
`the state of the art. In addition, we recognize that a district court’s decision
`regarding whether a patent would have been obvious is rendered under a
`different standard of proof—clear and convincing evidence—than is
`required here. Therefore, the court’s determination on reasonable
`expectation of success is not directly determinative of our decision here.
`Nevertheless, we find the court’s analysis of the caselaw, and what factual
`inquiries are relevant to the question of reasonable expectation of success,
`instructive.
`13 Temsirolimus, also known as CCI779 or 40-(3-hydroxy-2-
`(hydroxymethyl)-2-methylpropanoate)-rapamycin (Ex. 1001, 2:11–12),
`differs from everolimus by the substituent groups attached to the rapamycin
`backbone. Both the district court defendant and Argentum have relied on
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`Phase I study. District Court Decision, 287 F. Supp. 3d at 512. The court
`also noted that everolimus and temsirolimus differ in pharmacological
`properties relevant to treatment (id. at 517), and that PNETs were known to
`differ from carcinoids in behavior, incidence, molecular genetics, and
`responses to pharmacotherapies. Id. at 519. Noting the high rate of failure
`for potential cancer treatments, especially among hard-to-treat cancers like
`PNET, the court found that this would have diminished any expectation that
`everolimus would be effective in PNETs. Id. at 529.
`Reviewing the District Court’s findings as to the ’131 patent, the
`Federal Circuit affirmed. Federal Circuit Decision, 923 F.3d 1051, 1061
`(Fed. Cir. 2019) (“We conclude that the district court did not clearly err in
`finding that West-Ward’s asserted prior art combination . . . failed to provide
`clear and convincing evidence of a reasonable expectation of success.”).
`Among the District Court’s findings noted by the appeals court were the fact
`that the phase I data resulted from small sample sizes and studies that were
`designed to test safety, not efficacy. Id. The court also noted that the
`studies in the prior art did not disclose the number of patients enrolled who
`had advanced RCC, as well as the findings regarding the pharmacological
`differences between temsirolimus and everolimus. Id. The court concluded
`that “[t]he district court reviewed the above evidence, determined that the
`molecular biology of advanced RCC was not fully understood, recognized
`the limitations in the temsirolimus phase I data, and found that such data did
`not provide a person of ordinary skill with a reasonable expectation of
`success. . . . We hold that the district court did not err.” Id. at 1062.
`
`
`clinical trials of temsirolimus as relevant to the reasonable expectation of
`success in treating patients with everolimus.
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`We are presented with similar facts in the case at hand. O’Donnell,
`the only prior art clinical trial of everolimus presented to us, was a Phase I
`trial designed to test dosages, not efficacy. Ex. 1029, 803. While Öberg
`2004 does disclose the promise of rapamycin, we agree with the District
`Court that at the time of the invention the mTOR pathway was insufficiently
`understood, such that a person of ordinary skill in the art would not have
`reasonably expected rapamycin’s “promise,” as reported in Öberg 2004, to
`translate to everolimus. Ex. 1027, 60. And in regard to Boulay 2004,
`Novartis argues that the record lacks sufficient evidence to support
`Argentum’s contention that the CA20948 rat pancreatic tumor model
`described therein was applicable to the treatment of PNETs. Ex. 1005, 253.
`On this point, again we agree with the District Court. District Court
`Decision, 287 F. Supp. 3d at 526 (“I find that Defendant has failed to
`establish by clear and convincing evidence that CA20948 is a PNET
`model.”). Upon evaluating the full record before us, we find that the
`CA20948 tumor model line originated from a pancreatic adenocarcinoma,
`which is distinct from a neuroendocrine tumor (NET). Ex. 2038, 197–99;
`Ex. 2041 ¶¶ 132–134. We credit and rely on Dr. Kulke’s testimony that
`pancreatic adenocarcinomas and PNETs were known to differ in their origin,
`incidence, clinical behavior, molecular genetics, and responses to
`pharmacotherapies. Ex. 2041 ¶¶ 57, 135–136.
`Argentum does not dispute the distinction between CA20948 and
`PNETs, but instead argues that tests performed on CA20948 would
`nevertheless be understood to be applicable to PNETs. Reply 17–18.
`Argentum’s primary support for this argument derives from the De Jong
`reference, which discloses the use of the CA20948 pancreatic tumor line in a
`study of the treatment of neuroendocrine tumors. Ex. 1010, Abstract. As
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`Novartis correctly observes, however, the De Jong study involved radiation-
`based treatment of tumors using radioactive somatostatin-analogues. PO
`Resp. 33; Ex.1010, 356–58. Both neuroendocrine tumors and CA20948
`express somatostatin receptors; it is this commonality that made CA20948
`useful as a model for NETs in De Jong’s study of radiation treatment.
`Ex. 2041 ¶¶ 139, 141. But just because some features of a cell line make it
`useful in studies of tumors where those features are relevant, it does not
`necessarily follow that the cell line is relevant to all studies of those tumors.
`See Tr. 14:15–25. As Dr. Kulke credibly explains, the person of ordinary
`skill in the art would not have understood from the De Jong radiation
`treatment study that CA20948 could be used as a mod