Paper No. __
`Date Filed: September 5, 2017
`
`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
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`Case IPR2016-01479
`Patent No. 9,006,224
`
`NOVARTIS’S PATENT OWNER SURREPLY
`
`
`Date Filed: September 5, 2017
`
`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
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`Case IPR2016-01479
`Patent No. 9,006,224
`
`NOVARTIS’S PATENT OWNER SURREPLY
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`TABLE OF AUTHORITIES
`
`Cases
`Allergan, Inc. v. Apotex, Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .........................................................................3
`
`Genzyme Therapeutic Prods. Ltd. P'ship v. BioMarin Pharm.
`Inc.,
`825 F.3d 1360 (Fed. Cir. 2016) .......................................................................3
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966).............................................................................................4
`
`Intelligent Bio-Systems v.Illumina Cambridge Ltd.,
`IPR2013-00517, Paper 87 (P.T.A.B. Feb. 11, 2015), aff’d
`821 F.3d 1359 (Fed. Cir. 2016) ...................................................................1, 5
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................4
`
`W.L. Gore & Assocs. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................5
`
`Statutes, Regulations, And Other Authorities
`
`35 U.S.C. § 103......................................................................................................3, 4
`
`35 U.S.C. § 112..........................................................................................................3
`
`35 U.S.C. § 312(a)(3).................................................................................................2
`
`37 C.F.R. § 42.104(b) ................................................................................................2
`
`37 C.F.R. § 42.23(b) ..................................................................................................1
`
`37 C.F.R. § 42.24(c)(1)..............................................................................................5
`
`37 C.F.R. § 42.6(a)(3)............................................................................................1, 5
`
`M.P.E.P. § 2107.03(IV) .............................................................................................3
`
`i
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`TABLE OF ABBREVIATIONS
`
`’224 Patent
`
`Ex. 1001, U.S. Patent No. 9,006,224
`
`De Jong
`
`Duran
`
`Ex. 1010, De Jong, M., et al., “Therapy Of Neuroendocrine
`Tumors With Radiolabeled Somatostatin-Analogues,” Q.J.
`Nucl. Med. 43(4):356-66 (1999)
`
`Ex. 1011, Duran, I., et al., “A Phase II Trial Of Temsirolimus
`In Metastatic Neuroendocrine Carcinomas (NECs),” J. Clinical
`Oncology 23(16S):215S (2005)
`
`Ex. 2111
`
`Transcript of the August 28, 2017 Deposition of Mark J. Ratain
`
`Longnecker 1979 Ex. 2038, Longnecker, D.S. et al., “Transplantation of
`Azaserine-Induced Carcinomas Of Pancreas In Rats,” Cancer
`Letters, 7:197-202 (1979)
`
`NCI
`
`NETs
`
`Pet. __
`
`National Cancer Institute
`
`neuroendocrine tumors
`
`Petition for Inter Partes Review of U.S. Patent No. 9,006,224
`in Par Pharm., Inc. v. Novartis AG, IPR2016-01479, Paper 1
`(filed July 22, 2016)
`
`Öberg 2004
`
`Ex. 1027, Öberg, K., “Treatment Of Neuroendocrine Tumours
`Of The Gastrointestinal Tract,” Oncología 27(4):185-89 (2004)
`
`PNET
`
`POR __
`
`Reply __
`
`SSA
`
`SSTRs
`
`pancreatic neuroendocrine tumor
`
`Novartis’s Patent Owner Response in Par Pharm., Inc. v.
`Novartis AG, IPR2016-01479, Paper 17 (filed May 11, 2017)
`
`Petitioner’s Reply in Par Pharm., Inc. v. Novartis AG,
`IPR2016-01479, Paper 21 (filed Aug. 3, 2017)
`
`somatostatin analog
`
`somatostatin receptors
`
`ii
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`Novartis respectfully requests rejection of Par’s Reply—or at least the new
`
`arguments and references identified below—as procedurally improper and
`
`substantively meritless. Intelligent Bio-Sys. v. Illumina Cambridge Ltd., IPR2013-
`
`00517, Paper 87 at 14-16 (P.T.A.B. Feb. 11, 2015), aff’d, 821 F.3d 1359 (Fed. Cir.
`
`2016) (reply violated 37 C.F.R. §§ 42.6(a)(3) and 42.23(b) where it offered “a
`
`distinct new line of reasoning,” presented “a number of additional new arguments,”
`
`cited multiple new references not in the petition, and “relie[d] extensively” on new
`
`expert declaration arguments, but did not include those arguments “with nearly the
`
`same degree of specificity”).
`
`(1) Par’s Petition alleged that CA20948 is “a specific line of pancreatic
`
`NETs.” Pet. 32. Par now admits that CA20948 is an adenocarcinoma of the
`
`exocrine pancreas—a tumor distinct from PNETs in multiple respects, including
`
`responses to therapies (POR 11-12)—but newly alleges CA20948 was a model for
`
`all NETs. Reply 17. Par cites Dr. Ratain’s new declaration, which cites a new
`
`PubMed search. Ex. 1119 ¶47; Ex. 1075. That search is incomplete and unreliable
`
`as it omits at least Longnecker 1979, which explains that CA20948 is an exocrine
`
`cell line. POR 31; Ex. 2111, 81:14-82:11. Only two titles mention CA20948; none
`
`describes it as a PNET model. Ex. 2111, 77:5-16, 78:8-10. And only the De Jong
`
`title mentions NETs, but De Jong does not indicate that CA20948 is similar to
`
`PNETs in any way other than both express SSTRs. POR 31-37; Ex. 2111, 74:5-9,
`
`1
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`74:23-75:3 (all but one paper in Ex. 1075, including De Jong, relate to receptor-
`
`targeted therapy). Expression of SSTRs is not relevant here because Dr. Ratain
`
`admitted that mTOR is not involved in SSTR-signaling. Ex. 2111, 80:5-8.
`
`(2) Par newly relies on another exocrine cell line, AR42J, to suggest that
`
`CA20948 is a NET model. Reply 17-18. But AR42J and CA20948 were different
`
`cell lines (Ex. 2111, 82:18-83:23): unlike CA20948, AR42J was culturable in vitro
`
`(id. 88:9-21; Ex. 1005, p. 253) and responded to octreotide (Ex. 1053, p. 15; Ex.
`
`2041 ¶140). Par has no prior art showing that AR42J was a PNET model. Ex. 1053
`
`describes AR42J as an “exocrine pancreatic tumor.” Ex. 1053, p. 15. Ex. 1085
`
`distinguishes “pancreatic tumors” from “neuroendocrine tumors,” of which PNETs
`
`are a type, and describes AR42J as a “pancreatic tumor model.” Ex. 1085, pp. 3,
`
`12; Ex. 2111, 90:21-91:6, 93:18-23. Ex. 1089 is not prior art, and describes
`
`quantifying radioactive SSA binding to SSTRs in AR42J cells (Ex. 2111, 232:13-
`
`234:12); it does not teach that AR42J was a model for PNET responses to non-
`
`SSTR-targeted therapies in 2005. POR 37 n.11; Ex. 2041 ¶¶150-152.
`
`(3) Par’s Petition only cites Öberg 2004 in Grounds 1-2 and Duran in
`
`Grounds 3-4. Pet. 4. On reply, Par combines Öberg 2004 and Duran. Reply 4, 13-
`
`16, 18-20. That new combination is improper. 35 U.S.C. § 312(a)(3); 37 C.F.R. §
`
`42.104(b). It is also ineffectual: neither reference, alone or in combination,
`
`provides a motivation to select everolimus or reasonable expectation of its success
`
`2
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`in treating the claimed PNETs. POR 26-30, 48-55. Par’s reliance on Allergan, Inc.
`
`v. Apotex Inc., and Genzyme Therapeutic Prods. L.P. v. Biomarin Pharm. Inc., is
`
`misplaced. Allergan found a method of treating hair loss using a “broad genus” of
`
`PGF analogs obvious, where the prior art taught their efficacy for that purpose. 754
`
`F.3d 952, 961-66 (Fed. Cir. 2014). Genzyme concerned selection of “biweekly
`
`dosing” from a previously suggested range. 825 F.3d 1360, 1365, 1373 (Fed. Cir.
`
`2016). Here, the claims recite a method of treating a specific tumor (PNET) using a
`
`specific compound (everolimus). No prior art reasonably suggested that efficacy.
`
`And M.P.E.P. § 2107.03(IV) that Par cites concerns utility of a patent application
`
`under § 112, not obviousness under § 103 in light of prior art like Duran, an
`
`abstract with interim observations from an uncontrolled Phase II trial of
`
`temsirolimus in NETs, not the claimed PNETs. POR 48-55.
`
`(4) Par newly alleges that there was a sufficient “connection” between NETs
`
`and mTOR for the NCI to sponsor the Duran Phase II temsirolimus trial. Reply 16
`
`(citing 5 pages of Ex. 1119 discussing 10 (2 new) exhibits without reproducing the
`
`analysis). But new Ex. 1104 does not disclose the basis for the NCI funding, and
`
`Dr. Ratain has never seen the funding application. Ex. 2111, 140:10-142:16, 144:4-
`
`9. New Ex. 1072 does not report a loss of PTEN in PNETs. Ex. 2111, 185:5-23.
`
`Here, NCI funding reflects the undisputed need for new treatments, not a
`
`reasonable expectation of success. Ex. 2111, 135:8-136:11 (NCI funded multiple
`
`3
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`trials), 13:5-17, 20:25-21:5 (NCI funded failed trial (Ex. 1112)); Exs. 2015 & 2085
`
`(same). As of 2005, 70% of oncology drugs failed Phase II trials, no drug had
`
`proven effective for advanced PNETs in over 20 years, and no drug was effective
`
`in advanced PNETs after failure of cytotoxic chemotherapy. POR 39, 65-66.
`
`(5) Par newly relies on the ’224 specification. Reply 12-13, 19. Such
`
`reliance is foreclosed by §103 and Graham v. John Deere Co., 383 U.S. 1, 17-18
`
`(1966), which require comparison of the “differences between the claimed
`
`invention and the prior art”—not the specification and prior art. The Federal
`
`Circuit in Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364 (Fed. Cir. 2005),
`
`could not overrule the Supreme Court or Statute, and did not prescribe that the
`
`’224 Patent include specific data. Merck is also factually distinguishable. Pet. 46-
`
`47 (Merck concerned a “claim limitation regarding dosage”). The Merck prior art
`
`taught all claim elements, including efficacy, but proposed a higher dose. 395 F.3d
`
`at 1373-75. The Court only considered the patent specification when rejecting a
`
`teaching away argument because there was no evidence, in the prior art or patent
`
`specification, that safety concerns taught away from the claimed dose. Id. Here, no
`
`teaching away is alleged, and the case does not turn on dose selection.
`
`(6) Par improperly relies on the ’224 specification (Ex. 1119 ¶59) and new
`
`Exs. 1123 and 1124 to assert that mTOR inhibitors are interchangeable. Reply 8-
`
`10. But a POSA in 2005 knew that rapamycin, temsirolimus, and everolimus were
`
`4
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`different in ways that could affect their anticancer potential. POR 28, 53-56. Exs.
`
`1123 and 1124 contain no antitumor data nor any comparison of the antitumor
`
`activity of these mTOR inhibitors. Ex. 2111, 156:8-157:6, 160:22-162:2. And the
`
`’224 Patent contains no admissions that the cited excerpts in cols. 7, 9, 10, and 26
`
`are prior art. Instead, those excerpts concern what the inventors “found” (e.g., Ex.
`
`1001, 7:10-53), and cannot be used for obviousness absent an admission that the
`
`disclosure is prior art. W.L. Gore & Assocs. v. Garlock, Inc., 721 F.2d 1540, 1553
`
`(Fed. Cir. 1983).
`
`(7) Par alleges that prior cytotoxic chemotherapy is irrelevant to
`
`everolimus’s expected efficacy because the prior art trials enrolled patients with
`
`and without prior cytotoxic chemotherapy. Reply 11-12. But the fact that every
`
`cited clinical trial in NETs disclosed whether patients received prior cytotoxic
`
`chemotherapy indicates that such prior therapy was important when analyzing the
`
`results. E.g., Ex. 1011; Ex. 1090; Ex. 1112, pp. 6112-13 (Table 1); Ex. 2047, pp.
`
`3100, 3102; Ex. 2049; Ex. 2099.
`
`(8) Par’s Reply fails to cite, let alone explain the significance of, new Exs.
`
`1066-69, 1071-73, 1075, 1077-79, 1081-83, 1085, 1089-92, 1097-98, 1100-02,
`
`1104, 1106-09, 1111, 1114, 1116, 1118, 1120-22. Any attempt to incorporate these
`
`exhibits by reference to Ex. 1119 is improper. 37 C.F.R. §§ 42.6(a)(3), 42.24(c)(1);
`
`Intelligent Bio-Sys., IPR2013-00517, Paper 87 at 14-16.
`
`5
`
`
`
`Dated: September 5, 2017
`
`Paper No. __
`Date Filed: September 5, 2017
`
`/ Nicholas N. Kallas /
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`6
`
`
`
`Paper No. __
`Date Filed: September 5, 2017
`
`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing Novartis’s Patent Owner Surreply was
`
`served on September 5, 2017 by causing it to be sent by email to counsel for
`
`Petitioner at the following email addresses:
`
`Daniel G. Brown (daniel.brown@lw.com)
`
`Jonathan M. Strang (jonathan.strang@lw.com)
`
`Brenda L. Danek (brenda.danek@lw.com)
`
`Dated: September 5, 2017
`
`/ Nicholas N. Kallas /
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`1
`
`
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