Paper No. ____
`Date Filed: November 14, 2016
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`ROXANE LABORATORIES, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01461
`
`Patent No. 9,006,224
`
`
`
`
`
`PATENT OWNER’S PRELIMINARY
`RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`

`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`The Date Of Invention ..................................................................................... 3
`
`III. The Person Of Ordinary Skill In The Art ........................................................ 4
`
`IV. Claim Construction .......................................................................................... 5
`
`A.
`
`B.
`
`The Ordinary And Customary Meaning Of “Advanced”
`Is “Metastatic Or Unresectable” ............................................................ 6
`
`The Ordinary And Customary Meaning Of “Advanced”
`Is Not “After Failure Of Cytotoxic Chemotherapy” ............................. 8
`
`V.
`
`The Board Should Deny Grounds 1 And 2 Because No
`Reference Teaches Or Suggests The Claim Element “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ................................... 13
`
`VI. The Board Should Also Deny Grounds 1 And 2 Because One
`Of Ordinary Skill Would Not Have Had A Reasonable
`Expectation That Everolimus Would Effectively Treat
`Advanced PNETs After Failure Of Cytotoxic Chemotherapy ...................... 17
`
`A.
`
`B.
`
`C.
`
`Tabernero Would Not Have Provided A Reasonable
`Expectation That Everolimus Would Effectively Treat
`Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ..................................................................................... 18
`
`Roxane’s Remaining References Would Not Have
`Provided A Reasonable Expectation That Everolimus
`Would Effectively Treat Advanced PNETs After Failure
`Of Cytotoxic Chemotherapy ............................................................... 20
`
`Roxane Ignores That Tumors That Had Failed Cytotoxic
`Chemotherapy Generally Would Be More Difficult To
`Treat ..................................................................................................... 22
`
`VII. Conclusion ..................................................................................................... 25
`
`
`
`i
`
`

`
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed Cir. 1985) .......................................................................... 8
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ..................................................................................... 6
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ....................................................................... 6
`
`InSite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ...................................................................5, 17
`
`IntelGenX Corp. v. ICOS Corp.,
`IPR2016-00678 (Patent Tr. & App. Bd. Sept. 1, 2016),
`Paper 13 .................................................................................................. 13, 17
`
`Janssen Pharmaceutica, N.V. v. Eon Labs. Mfg., Inc.,
`134 Fed. Appx. 425 (Fed. Cir. 2005) .............................................................. 9
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01633 (Patent Tr. & App. Bd. Jan. 4, 2016),
`Paper 10 ........................................................................................................... 8
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2014-01233, 2015 WL 996342 (Patent Tr. & App.
`Bd. Feb. 10, 2015) .........................................................................................13
`
`Par Pharm., Inc. v. Novartis AG,
`IPR2016-00078, 2016 WL 2849201 (Patent Tr. App. Bd.
`Apr. 28, 2016) ................................................................................................14
`
`Par Pharm., Inc. v. Novartis AG,
`IPR2016-01479 (Patent Tr. & App. Bd. July 22, 2016),
`Paper 1 ...........................................................................................................12
`
` Rules and Statutes
`
`37 C.F.R. § 42.100(b) ................................................................................................ 6
`
`ii
`
`

`
`
`
`37 C.F.R. § 42.104(b)(4) ......................................................................... 2, 13, 14, 17
`37 C.F.R. § 42.104(b)(4) ....................................................................... .. 2, 13, 14, 17
`
`37 C.F.R. § 42.65(a) ................................................................................................... 8
`37 C.F.R. § 42.65(a) ................................................................................................. ..8
`
`
`
`
`
`iii
`iii
`
`

`
`
`
`LIST OF EXHIBITS
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Expert Declaration of Matthew H. Kulke, M.D.,
`M.M.Sc.
`
`Curriculum Vitae of Matthew H. Kulke, M.D.,
`M.M.Sc.
`
`Kulke Decl.
`
`Kulke C.V.
`
`Seeley, R. R., Stephens, T.D., & Tate, P., Anatomy &
`Physiology, 3rd Edition, pages 585 – 586 (1995)
`
`Seeley
`
`2001
`
`2002
`
`2003
`
`2004
`
`Moertel, C.G., et al., “Streptozocin-Doxorubicin,
`Streptozocin-Fluorouracil, Or Chlorozotocin In The
`Treatment Of Advanced Islet-Cell Carcinoma,” New
`Engl. J. Med. 326(8):519-523 (1992)
`
`2005
`
`Laughlin, E.H., Coming To Terms With Cancer: A
`Glossary Of Cancer-Related Terms, page 4 (2002)
`
`2006
`
`Hewitt, M.R. & Yu, K., “Treatment Update For
`Metastatic Pancreatic Cancer,” Community Oncol.
`3(7):428-430 (July 2006)
`
`Moertel
`
`Laughlin
`Cancer
`Glossary
`
`Hewitt and
`Yu
`
`Yu
`
`Motzer
`
`2007
`
`2008
`
`2009
`
`Yu, K.H. & Ahman, N.A., Chapter 25, “Diagnosis
`And Evaluation Of Pancreatic Ductal
`Adenocarcinoma,” Endoscopic Oncology:
`Gastrointestinal Endoscopy And Cancer Management
`(Faigel, D.O. & Kochman, M.L., eds. 2006)
`
`Motzer, R.J. & Russo, P., “Systemic Therapy For
`Renal Cell Carcinoma,” J. Urology 163:408-417
`(2000)
`
`“Wyeth Pharmaceuticals Announces Termination Of
`Phase 3 Clinical Program With Oral Temsirolimus In
`Women With Metastatic Breast Cancer,” PR
`Newswire, AP Alert (March 16, 2006)
`
`Wyeth
`Press Release
`
`iv
`
`

`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2010
`
`2011
`
`2012
`
`Pazdur, R., et al. (eds.), Chapters 11, 14, 16, & 19,
`Cancer Management: A Multidisciplinary Approach:
`Medical, Surgical, & Radiation Oncology, 9th Edition
`(2005)
`
`Pazdur
`
`Kouvaraki, M.A. et al., “Fluorouracil, Doxorubicin,
`And Streptozocin In The Treatment Of Patients With
`Locally Advanced And Metastatic Pancreatic
`Endocrine Carcinomas,” J. Clin. Oncol. 22(23):4762-
`4771 (2004)
`
`Delaunoit, Th., et al., “The Doxorubicin-
`Streptozotocin Combination For The Treatment Of
`Advanced Well-Differentiated Pancreatic Endocrine
`Carcinoma: A Judicious Option?,” Eur. J. Cancer
`40:515-520 (2004)
`
`Kouvaraki
`
`Delaunoit
`
`v
`
`

`
`
`
`I.
`
`
`
`Introduction
`
`Novartis AG (“Novartis”) respectfully submits this Preliminary Response to
`
`the Petition of Roxane Laboratories, Inc. (“Roxane”) seeking inter partes review of
`
`claims 1 and 2 of United States Patent No. 9,006,224 (“the ’224 Patent,” Ex. 1001)
`
`on two Grounds (Paper 2, “Petition” or “Pet.”).
`
`Claims 1 and 2 of the ’224 Patent recite methods of using the compound 40-
`
`O-(2-hydroxyethyl)-rapamycin (commonly known as everolimus) as a
`
`monotherapy to treat pancreatic neuroendocrine tumors (“PNETs”) “wherein the
`
`tumors are advanced tumors after failure of cytotoxic chemotherapy.” Roxane’s
`
`Petition is fatally flawed because it effectively ignores that the claim requires the
`
`treatment of advanced PNETs after failure of cytotoxic chemotherapy.
`
`In particular, none of the references in Grounds 1 or 2, alone or in
`
`combination, teaches or suggests the claim element “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy.” Roxane alleges that the reference to
`
`“advanced solid tumors” in Tabernero (Ex. 1006) constitutes a disclosure of the
`
`“after failure of cytotoxic chemotherapy” aspect of the claim element. But this
`
`argument is unsupported. Tabernero describes a Phase I everolimus clinical trial in
`
`patients with various “advanced solid tumors,” but Tabernero does not teach or
`
`suggest that all patients enrolled in the Phase I study had previously failed to
`
`respond to cytotoxic chemotherapy, or that any of them had advanced PNETs.
`
`1
`
`

`
`
`
`There is simply no basis to conclude that the Tabernero “advanced solid tumors”
`
`were advanced PNETs, let alone that they were advanced PNETs that had
`
`previously failed to respond to cytotoxic chemotherapy. Because neither
`
`Tabernero, nor any of the other references in Grounds 1 and 2, alone or in
`
`combination, teaches or suggests the “after failure of cytotoxic chemotherapy”
`
`aspect of the claim element, Roxane’s analysis is deficient under 37 C.F.R.
`
`§ 42.104(b)(4).
`
`Roxane’s petition is also deficient for failing to establish that one of ordinary
`
`skill in the art would have had a reasonable expectation that everolimus could be
`
`used successfully to treat “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy.” The art cited by Roxane does not provide such a reasonable
`
`expectation. In addition, a person of ordinary skill would have known that patients
`
`with advanced PNETs who had previously failed treatment with cytotoxic
`
`chemotherapy generally have a more resistant or aggressive disease than those who
`
`have not failed such treatment, and thus would be more difficult to treat. In fact,
`
`after failure of cytotoxic chemotherapy, the majority of advanced PNET patients
`
`(over 80%) failed to respond to drugs with proven clinical efficacy in untreated
`
`patients. But as of November 2006, everolimus had not even demonstrated
`
`efficacy in patients with previously untreated advanced PNETs. Thus, one of
`
`ordinary skill would not have had a reasonable expectation that everolimus would
`
`2
`
`

`
`
`
`successfully treat advanced PNETs after failure of cytotoxic chemotherapy.
`
`Roxane has not provided any reasons why a person of ordinary skill would have
`
`reasonably expected success with respect to this harder-to-treat patient population.
`
`
`
`In summary, none of the prior art in Grounds 1 or 2, individually or in
`
`combination, teaches or suggests all elements of claims 1 and 2 of the ’224 Patent.
`
`And, that art would not have provided a person of ordinary skill as of November
`
`20, 2006, with a reasonable expectation that the methods of claims 1 and 2 would
`
`have been successfully practiced. Accordingly, Roxane cannot establish the
`
`obviousness of claims 1 or 2 of the ’224 Patent. Novartis respectfully requests that
`
`the Board deny the Petition.
`
`II. The Date Of Invention
`
`Roxane’s declarant Dr. Yu conducted his analysis of the art as of November
`
`20, 2006, the filing date of PCT/EP2006/068656. Ex. 1003, Yu Decl. ¶ 22. As
`
`neither Roxane’s Petition nor Dr. Yu cite any prior art dated between the ’224
`
`Patent’s earliest priority date of November 21, 2005 (see Ex. 1001, ’224 Patent,
`
`cover page) and November 20, 2006, Novartis, for the purposes of this Preliminary
`
`3
`
`

`
`
`
`Response, uses November 20, 2006 as the invention date.1 Ex. 2001, Kulke Decl.
`
`¶ 20.
`
`III. The Person Of Ordinary Skill In The Art
`
`For the purposes of this Preliminary Response, Novartis adopts Roxane’s
`
`proposed definition of a person of ordinary skill in the art, which would have been
`
`someone with: (1) a Ph.D. in biology, biochemistry, pharmaceutical sciences,
`
`molecular biology, cancer biology, or other biological sciences, and/or (2) a
`
`medical degree; as well as experience conducting preclinical, clinical, and/or
`
`laboratory research relating to cancers of the pancreas or neuroendocrine system.
`
`
`
` Should Roxane seek to rely on any patents or publications dated between
`
` 1
`
`November 21, 2005 and November 20, 2006, Novartis reserves its right to object
`
`to the untimely introduction of such references and to establish that claims 1 and 2
`
`of the ’224 Patent are entitled to the earlier priority date.
`
`4
`
`

`
`
`
`Pet. 17-18; Ex. 1003, Yu Decl. ¶ 18; Ex. 2001, Kulke Decl. ¶ 21.2 To the extent
`
`necessary, the person of ordinary skill also would have collaborated with those
`
`having ordinary skill in other areas including pharmacologists, formulators, and
`
`biochemists. Id.
`
`IV. Claim Construction
`
`Challenged claims 1 and 2 of the ’224 Patent concern the treatment of
`
`specific tumors, i.e., advanced pancreatic neuroendocrine tumors (“PNETs”), that
`
`
`
` Although not pertinent to this Preliminary Response, Roxane’s suggestion that a
`
` 2
`
`person of ordinary skill would have had experience relating to rapamycin and it
`
`analogs and experience relating to intracellular signaling pathways (Pet. 17-18; Ex.
`
`1003, Yu Decl. ¶ 18) improperly relies on hindsight to assume that a person of
`
`ordinary skill would have been interested in using rapamycin or one of its analogs
`
`and/or a therapy for the treatment for PNETs that focuses on signaling pathways.
`
`Ex. 2001, Kulke Decl. ¶ 22. These aspects of Roxane’s proposed definition should
`
`not be adopted. See InSite Vision Inc. v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir.
`
`2015) (citation omitted) (“Defining the problem in terms of its solution reveals
`
`improper hindsight in the selection of the prior art relevant to obviousness.”).
`
`5
`
`

`
`
`
`failed to respond to cytotoxic chemotherapy. Ex. 1001, ’224 Patent, col. 26, l. 66 –
`
`col. 27, l. 6; Ex. 2001, Kulke Decl. ¶ 28.
`
`Novartis agrees with Roxane (Pet. 15-17) that for the purposes of this inter
`
`partes review, the ’224 Patent claim terms should be given their broadest
`
`reasonable construction in light of the specification of the patent and assigned their
`
`ordinary and customary meaning, as would be understood by one of ordinary skill
`
`in the art at the time of the invention, in the context of the entire patent disclosure.
`
`37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016); In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`Roxane has not expressly proposed constructions for any claim terms. Pet.
`
`17. However, Roxane’s arguments are premised on an interpretation of the term
`
`“advanced” PNETs that is both unsupported and inconsistent with the ordinary and
`
`customary meaning of the term as it would be understood by those in the art.
`
`Accordingly, Novartis requests that the Board construe the term “advanced.”
`
`A. The Ordinary And Customary Meaning Of
`“Advanced” Is “Metastatic Or Unresectable”
`
`One of ordinary skill in the art in November 2006 would have understood
`
`“advanced” PNETs to mean PNETs that were metastatic or unresectable. This
`
`understanding is consistent with the ’224 Patent specification and the ordinary and
`
`customary meaning of the term as used by those in the art.
`
`6
`
`

`
`
`
`PNETs are a subset of neuroendocrine tumors (“NETs”) that arise from the
`
`endocrine (i.e., hormone-secreting) cells in the pancreas. Ex. 2001, Kulke Decl.
`
`¶ 23; Ex. 1010, Doran at 5; Ex. 1001, ’224 Patent, col. 2, ll. 54-58. PNETs were
`
`known to be relatively rare tumors, that often evolved slowly, and were frequently
`
`diagnosed only once they had widespread metastases. Ex. 2001, Kulke Decl. ¶ 23,
`
`Ex. 1013, McStay at 48-49; Ex. 1012, WHO 2004 at 188, 190, 193, 195. PNETs
`
`were known to “include islet cell tumors, APUDomas, insulinomas, glucagonomas,
`
`nonfunctioning pancreatic NETs, pancreatic NETs associated with hypercalcemia,
`
`gastrinomas, VIPomas, somatostatinomas, GRFomas.” Ex. 1001, ’224 Patent, col.
`
`2, ll. 54-58, col. 8, ll. 13-17; Ex. 2001, Kulke Decl. ¶ 29.
`
`The ’224 Patent specification explains that “advanced” PNETs are those that
`
`are “metastatic,” which means that they have spread outside of the pancreas, or
`
`“unresectable,” which means that they cannot be cured by surgery, for example,
`
`because they have spread to nearby areas (locally advanced). Ex. 1001, ’224
`
`Patent, col. 26, ll. 57-58; Ex. 2001, Kulke Decl. ¶ 30.
`
`The ’224 Patent specification’s use of the term “advanced” is consistent with
`
`its ordinary usage in the art as of November 2006 (and before) to describe tumors
`
`that had spread to nearby areas (locally advanced) or more distant areas of the
`
`body (metastatic), and both were generally unresectable (i.e., they could not be
`
`cured by surgery). Ex. 2001, Kulke Decl. ¶¶ 24, 27; Ex. 2004, Moertel at 520
`
`7
`
`

`
`
`
`(describing patients with “advanced” PNETs (referred to as islet-cell carcinomas)
`
`as having proof of “unresectable or metastatic” disease).
`
`However, the term “advanced” is not specific to PNETs. Ex. 2001, Kulke
`
`Decl. ¶ 25; Ex. 2005, Laughlin Cancer Glossary at 4 (defining “advanced cancer”
`
`as “[a] general term describing the stages of cancer in which the disease has spread
`
`from the primary site to other parts of the body. When the cancer has spread only
`
`to the surrounding areas, it is called locally advanced. If it has spread further by
`
`traveling through the bloodstream or lymph system, it is called metastatic.”)
`
`B.
`
`The Ordinary And Customary Meaning Of “Advanced”
`Is Not “After Failure Of Cytotoxic Chemotherapy”
`
`Although Roxane has not expressly proposed a construction of the claim term
`
`“advanced,” it asserts that “advanced” tumors were known to have failed to
`
`respond to cytotoxic chemotherapy, stating: “[t]ypically, patients who present with
`
`advanced solid tumors have tumors which, among other things, have not responded
`
`to cytotoxic chemotherapy.” See Pet. 38 (Ground 1), 43 (Ground 2), citing Ex.
`
`1003, Yu Decl. ¶ 37. However, neither Roxane nor Dr. Yu cites any evidence to
`
`support this conclusory assertion. It should therefore be afforded little, if any,
`
`weight. 37 C.F.R. § 42.65(a); see also Johns Manville Corp. v. Knauf Insulation,
`
`Inc., IPR2015-01633 (Patent Tr. & App. Bd. Jan. 4, 2016), Paper 10 at 13 (denying
`
`institution where Petitioner relied on expert’s unsupported assertions); Ashland
`
`Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed Cir. 1985)).
`
`8
`
`

`
`
`
`Equating “advanced” tumors with tumors that have failed to respond to
`
`cytotoxic chemotherapy, as Roxane suggests, improperly confuses the state of
`
`tumor progression with whether the patient has received and failed to respond to
`
`cytotoxic chemotherapy. Roxane’s suggestion also is inconsistent with (1) the
`
`language of the challenged claims which separately describes these two aspects of
`
`the tumors, (2) the patent specification, and (3) the ordinary and customary
`
`meaning of the term “advanced” as understood by persons of skill in the art. Each
`
`of these inconsistencies is discussed below.
`
`First, claim 1 of the ’224 Patent requires that the PNETs are “advanced
`
`tumors after failure of cytotoxic chemotherapy.” If “advanced” PNETs were those
`
`that had failed cytotoxic chemotherapy, it would have been unnecessary to
`
`separately include the language “after failure of cytotoxic chemotherapy” in the
`
`claim. Constructions that render superfluous any claim terms are disfavored.
`
`Janssen Pharmaceutica, N.V. v. Eon Labs. Mfg., Inc., 134 Fed. Appx. 425, 428
`
`(Fed. Cir. 2005).
`
`Second, the ’224 Patent specification does not describe “advanced” PNETs
`
`as PNETs that have failed to respond to cytotoxic chemotherapy. To the contrary,
`
`the specification describes “advanced” PNETs as those that are metastatic or
`
`unresectable. Ex. 1001, ’224 Patent, col. 26, ll. 57-58; Ex. 2001, Kulke Decl. ¶ 30.
`
`The specification also provides that more than half of all patients “present with
`
`9
`
`

`
`
`
`liver metastases” at the time their PNET is diagnosed. Ex. 1001, ’224 Patent, col.
`
`3, ll. 2-4; Ex. 2001, Kulke Decl. ¶ 30. Thus, the specification teaches that more
`
`than half of all patients have “advanced” (i.e., metastatic or unresectable) PNETs
`
`when they are first diagnosed. Ex. 2001, Kulke Decl. ¶ 30. Such patients could
`
`not have received any treatment, including cytotoxic chemotherapy. Ex. 2001,
`
`Kulke Decl. ¶¶ 24, 30.
`
`In addition, the ’224 Patent specification describes a clinical trial in patients
`
`with “advanced (metastatic or unresectable) [PNETs] after failure of cytotoxic
`
`chemotherapy.” Ex. 1001, ’224 Patent, col. 26, ll. 56-60. If “advanced” meant
`
`that the patients had previously failed to respond to cytotoxic chemotherapy, it
`
`would not have been necessary to specify that the patients were enrolled “after
`
`failure of cytotoxic chemotherapy.” Ex. 2001, Kulke Decl. ¶ 30. The ’224 Patent
`
`specification therefore does not support an interpretation of the term “advanced”
`
`wherein the PNETs have failed to respond to cytotoxic chemotherapy. Ex. 2001,
`
`Kulke Decl. ¶ 30.
`
`Third, Roxane’s suggestion that the term “advanced” indicates that the
`
`PNETs failed to respond to cytotoxic chemotherapy is not consistent with the
`
`ordinary and customary meaning of “advanced” as understood by those of ordinary
`
`skill. Rather, “advanced” tumors were understood to mean tumors that were
`
`metastatic or unresectable (see pages 6-8, above). And as reflected in Roxane’s
`
`10
`
`

`
`
`
`cited references, those of ordinary skill also would have understood that the
`
`majority of PNETs were “advanced” when a patient was first diagnosed with a
`
`PNET and before treatment with any therapy, including cytotoxic chemotherapy.3
`
`Roxane’s declarant’s own publications similarly use the term “advanced” to
`
`describe tumors (other than PNETs) that were metastatic or unresectable at the
`
`time of diagnosis—and not to suggest that such tumors had failed any particular
`
`
`
` See Ex. 1013, McStay at 48-49 (“[PNETs] are relatively rare tumours, often with
`
` 3
`
`a slow evolution, that are only diagnosed once they have widespread metastases.”);
`
`Ex. 1012, WHO 2004 at 188, 190, 193, 195 (reporting that significant proportions
`
`of patients with PNETs were metastatic at the time of diagnosis); Ex. 2001, Kulke
`
`Decl. ¶ 23.
`
`11
`
`

`
`
`
`treatment regimen.4 Therefore, one of ordinary skill would not have defined
`
`“advanced” PNETs as those PNETs that had failed cytotoxic chemotherapy.
`
`The ordinary and customary meaning of the term “advanced” that Novartis
`
`proposes here further is supported by the Petition filed by Par Pharmaceutical, Inc.
`
`(IPR2016-01479), which also seeks inter partes review of the ’224 Patent. In its
`
`Petition, Par states:
`
`A person of ordinary skill in the art at the time of the alleged
`
`inventions would have understood the claim term ‘advanced tumors’
`
`to have its ordinary and customary meaning in the art that is consistent
`
`with the [‘224 Patent] specification. As used by those of skill in the
`
`field of oncology, an “advanced” tumor is a tumor that is
`
`unresectable or metastatic.
`
`Par Pharm., Inc. v. Novartis AG, IPR2016-01479 (Patent Tr. & App. Bd. July 22,
`
`2016), Paper 1 at 19-20 (emphasis added). Par proposes the same ordinary and
`
`
` Ex. 1004, Yu CV at 11; Ex. 2006, Hewitt and Yu at 428 (“[M]ost patients with
`
` 4
`
`pancreatic cancer have locally advanced or metastatic disease at the time of
`
`presentation,” i.e., at the time of diagnosis, before any treatment is received.); Ex.
`
`2007, Yu et al. (“[B]ecause [pancreatic cancer] is usually advanced at presentation,
`
`only 10% to 20% of patients are eligible for attempted curative resection.”); Ex.
`
`2001, Kulke Decl. ¶ 26.
`
`12
`
`

`
`
`
`customary meaning of the term “advanced tumors” that Novartis proposes here,
`
`and, notably, does not include any reference to prior failure of cytotoxic
`
`chemotherapy.
`
`For the above reasons, there is no support in either the ’224 Patent or the art
`
`to equate the terms “advanced” and “after failure of cytotoxic chemotherapy.”
`
`These terms were used to describe two different aspects of the tumors and should
`
`not be conflated as Roxane suggests. The plain and ordinary meaning of
`
`“advanced” PNETs, as understood by one of ordinary skill in the art, would be
`
`PNETs that were metastatic or unresectable.
`
`V. The Board Should Deny Grounds 1 And 2
`Because No Reference Teaches Or Suggests The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
`
`To succeed on obviousness, a petitioner must “explain adequately how the
`
`references teach or render obvious the [claim] limitation[s].” NetApp Inc. v.
`
`Crossroads Sys., Inc., IPR2014-01233, 2015 WL 996342, at *5 (Patent Tr. & App.
`
`Bd. Feb. 10, 2015). In particular, a petition “must specify where each element of
`
`the claim is found in the prior art patents or printed publications relied upon.” 37
`
`C.F.R. § 42.104(b)(4). Ignoring a claim element is a basis to deny institution. See
`
`IntelGenX Corp. v. ICOS Corp., IPR2016-00678 (Patent Tr. & App. Bd. Sept. 1,
`
`2016), Paper 13 at 6-7 (denying institution where petitioner ignored claim
`
`element); see also Par Pharm., Inc. v. Novartis AG, IPR2016-00078, 2016 WL
`
`13
`
`

`
`
`
`2849201, at *6 (Patent Tr. App. Bd. Apr. 28, 2016) (denying institution where
`
`petitioner failed to indicate why disclosure in prior art reference taught claim
`
`element).
`
`Contrary to 37 C.F.R. § 42.104(b)(4), Roxane’s Petition fails to specify
`
`where the prior art teaches or suggests the claim element “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy,” and the art cited in Grounds 1 and 2 fails to
`
`provide this teaching or suggestion.
`
`Roxane’s Petition mentions “failure of cytotoxic chemotherapy” only when
`
`discussing Tabernero (Ex. 1006). See Pet. 38 (Ground 1), 43 (Ground 2).
`
`According to Roxane, Tabernero taught that “everolimus monotherapy is a safe
`
`and effective treatment for advanced solid tumors which have not responded to
`
`cytotoxic chemotherapy….” See Pet. 38 (Ground 1), 43 (Ground 2). But Roxane
`
`does not contend that Tabernero identifies any of the patients as having advanced
`
`PNETs, or advanced PNETs that failed to respond to cytotoxic chemotherapy. Ex.
`
`2001, Kulke Decl. ¶ 32. Instead, Roxane suggests that Tabernero’s statement that
`
`the patients had “advanced solid tumors” (none of which was stated to be PNETs)
`
`means the patients had tried and failed cytotoxic chemotherapy, stating:
`
`“[t]ypically, patients who present with advanced solid tumors have tumors which
`
`… have not responded to cytotoxic chemotherapy.” See Pet. 38 (Ground 1), 43
`
`(Ground 2), citing Ex. 1003, Yu Decl. ¶ 37. Roxane’s contention is unsupported.
`
`14
`
`

`
`
`
`It is also inconsistent with the prior art.
`
`Tabernero is an abstract that describes a Phase I everolimus clinical trial.
`
`Ex. 1006, Tabernero at 193S; Ex. 2001, Kulke Decl. ¶ 32. None of the Tabernero
`
`patients is stated to have advanced PNETs, which the prior art recognized was a
`
`rare tumor type (see page 7). Id. Rather, Tabernero states that the trial involved
`
`patients with advanced solid tumors of the colon, kidney (renal cell carcinoma),
`
`breast, and other unspecified tissues. Id. Tabernero also does not teach or suggest
`
`that the enrolled patients all had been previously treated with and failed to respond
`
`to cytotoxic chemotherapy; patients could readily have been enrolled in the study
`
`without having been previously treated with cytotoxic chemotherapy. Id.
`
`Tabernero does describe the patients’ tumors as “advanced.” However, as
`
`discussed above (see pages 6-13), those of ordinary skill used the term “advanced”
`
`to refer to tumors that were metastatic (i.e., they had spread to other parts of the
`
`body) or unresectable (i.e., they could not be cured by surgery)—not to indicate
`
`they had failed to respond to cytotoxic chemotherapy. Ex. 2001, Kulke Decl. ¶ 33.
`
`In addition, one of ordinary skill would not have understood that the Tabernero
`
`patients had been previously treated with cytotoxic chemotherapy because, in
`
`addition to not mentioning it, cytotoxic chemotherapy was not always used to treat
`
`15
`
`

`
`
`
`all tumor types, including those specifically identified in Tabernero.5 Ex. 2001,
`
`Kulke Decl. ¶ 34. Thus, there is no basis to conclude that the “advanced solid
`
`tumors” of the patients enrolled in the Tabernero study had all previously failed to
`
`respond to cytotoxic chemotherapy, let alone that any of the tumors were advanced
`
`PNETs, or advanced PNETs that had previously failed to respond to cytotoxic
`
`chemotherapy. Ex. 2001, Kulke Decl. ¶ 35.
`
`Roxane does not rely on any reference other than Tabernero as evidence that
`
`the prior art taught or suggested the claim element “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy.” And, none of the references in Roxane’s
`
`Grounds 1 or 2, alone or in combination, provides this teaching or suggestion. Ex.
`
`2001, Kulke Decl. ¶¶ 32, 36-41. As a result of its failure to establish that this claim
`
`element was taught in the prior art, Roxane cannot establish the unpatentability of
`
`the challenged claims of the ’224 Patent and its Petition should be dismissed. 37
`
`
`
` For example, renal cell carcinoma was known to be generally resistant to
`
` 5
`
`cytotoxic chemotherapy. Ex. 2008, Motzer at 409 (“Studies continue to show that
`
`renal cell carcinoma is resistant to cytotoxic chemotherapy.”); Ex. 2001, Kulke
`
`Decl. ¶ 34.
`
`16
`
`

`
`
`
`C.F.R. § 42.104(b)(4); see IntelGenX Corp., IPR2016-00678, Paper 13 at 6-7; Par
`
`Pharm., Inc., 2016 WL 2849201, at *6.
`
`VI. The Board Should Also Deny Grounds 1 And 2 Because
`One Of Ordinary Skill Would Not Have Had A Reasonable
`Expectation That Everolimus Would Effectively Treat
`Advanced PNETs After Failure Of Cytotoxic Chemotherapy
`
`Roxane’s Petition should be dismissed for a second, independent reason:
`
`Roxane has failed to establish that one of ordinary skill would have had a
`
`reasonable expectation that everolimus would effectively treat patients with
`
`advanced PNETs after failure of cytotoxic chemotherapy. See InSite Vision Inc. v.
`
`Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015) (“The obviousness inquiry entails
`
`consideration of whether a person of ordinary skill in the art … would have had a
`
`reasonable expectation of success [of achieving the claimed invention].” (citation
`
`omitted)).
`
`As discussed above (see pages 13-17), none of the references in Grounds 1
`
`and 2, alone or in combination, teaches or suggests the claim element “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy.” Moreover, as discussed below,
`
`that art would not have provided a person of ordinary skill with a reasonable
`
`expectation that everolimus would be effective for the treatment of advanced
`
`PNETs in the subset of patients who had tried and failed to respond to cytotoxic
`
`chemotherapy.
`
`17
`
`

`
`
`
`A. Tabernero Would Not Have Provided A Reasonable
`Expectation That Everolimus Would Effectively Treat
`Advanced PNETs After Failure Of Cytotoxic Chemotherapy
`
`As noted above, Tabernero is the sole reference cited by Roxane when
`
`discussing tumors that failed to respond to cytotoxic chemotherapy. But Tabernero
`
`would not have provided one of ordinary skill with a reasonable expectation that
`
`everolimus would be effective in patients with advanced PNETs after failure of
`
`cytotoxic chemotherapy. As discussed above, there is no evidence the Tabernero
`
`patients with “advanced solid tumors” had advanced PNETs, let alone advanced
`
`PNETs that had previously failed to respond to cytotoxic chemotherapy. See pages
`
`13-17.
`
`Tabernero’s results in patients with colon cancer, renal (kidney) cell cancer
`
`and breast cancer6 would not have provided a reasonable expectation that
`
`everolimus would be effective to treat advanced PNETs, including advanced
`
`PNETs after failure of cytotoxic chemotherapy. A person of ordinary skill would
`
`have known that no drug is effective against all types of tumors because of
`
`important differences between tumor types. See, e.g., Ex. 2009, Wyeth Press
`
`Release 2006 (“[I]t is unfortunately not unusual for cancer drugs to work in some
`
`
` Tabernero reported “one partial response (colon cancer) and 2 stabilizations of >4
`
` 6
`
`months (renal cell and breast cancer).” Ex. 1006, Tabernero.
`