Ute Hoch et al.Download PDFPatent Trials and Appeals BoardMay 11, 202014354080 - (D) (P.T.A.B. May. 11, 2020) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/354,080 04/24/2014 Ute Hoch SHE0431.00 9685 21968 7590 05/11/2020 NEKTAR THERAPEUTICS 455 Mission Bay Blvd., South, Suite 100 San Francisco, CA 94158 EXAMINER OLSON, ERIC ART UNIT PAPER NUMBER 1623 MAIL DATE DELIVERY MODE 05/11/2020 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte UTE HOCH, MICHAEL A. ELDON, and ABRAHAM C.F. LEUNG ____________ Appeal 2019-004329 Application 14/354,080 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appellant1 seeks our review,2 under 35 U.S.C. § 134(a), of the Examiner’s decision to reject claims 1 and 5–14. (Appeal Br. 4.) We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Nektar Therapeutics. (See Appeal Br. 1.) 2 We consider the Non-Final Office Action issued August 23, 2017 (“Non- Final Act.”), the Appeal Brief filed December 7, 2018 (“Appeal Br.”), the Examiner’s Answer issued on March 12, 2019 (“Ans.”), and the Reply Brief filed May 13, 2019 (“Reply Br.”). Appeal 2019-004329 Application 14/354,080 2 INTRODUCTION Appellant’s Specification is directed to a method of treating cancer by administering a long-acting topoisomerase I inhibitor and a long-acting topoisomerase II inhibitor. (Specification dated April 24, 2014 (“Spec.”) ¶ 10.) The long-acting topoisomerase I inhibitor may include a pentaerythritol-based multi-arm polymer conjugate of irinotecan (“PBMAPCI”) as described in U.S. Patent No. 7,744,861. (Id. ¶ 33.) The Specification reports that the effective half-life of a long-acting irinotecan polymer conjugate is about 50 days as compared about two days for unmodified irinotecan. (Id. ¶ 31.) The long-acting topoisomerase II inhibitor may include doxorubicin HCl liposome injection, commercially available as DOXIL®. (Id. ¶ 35.) Appellant’s claim 1 recites: A method for treating a patient suffering from a cancer, the method comprising the steps of: (a) administering to the patient a topoisomerase II- inhibiting amount of doxorubicin HCl liposome injection; and (b) administering to the patient a topoisomerase I- inhibiting amount of a composition comprising a long-acting topoisomerase I inhibitor having a structure: Appeal 2019-004329 Application 14/354,080 3 wherein each n is an integer ranging from 40 to about 500, and pharmaceutically acceptable salts thereof, and further wherein: the topoisomerase I-inhibiting amount in step (b) is greater than 100 mg/m2 based on irinotecan equivalents, the cancer is selected from the group consisting of ovarian cancer, colorectal cancer, breast cancer, lymphoma cancers, leukemia cancers, rhabdomyosarcoma and neuroblastoma; and the long-acting topoisomerase I inhibitor has an effective half-life of from about 5 days to about 60 days. (Appeal Br. 15–16.) The Examiner rejected the claims as follows: Appeal 2019-004329 Application 14/354,080 4 Claims Rejected 35 U.S.C. § Reference(s)/Basis Non-Final Office Action 1, 5, 7, 8, 10–14 103(a) Morgensztern,3 Zhao4 2–4 6 103(a) Morgensztern, Zhao, Wilailak5 4 9 103(a) Morgensztern, Zhao, Gatti6 5 1, 5–14 103(a) Morgensztern, Chong7 5–6 ANALYSIS As the Examiner finds, Morgensztern teaches a method of treating cancer by administering irinotecan and pegylated-liposomal doxorubicin (PLD) injection. (See Morgensztern 442, see Non-Final Act. 3.) Morgensztern teaches administering chemotherapy over a 21-day cycle by administering PLD on day 1, and administering 100 mg/m2 irinotecan immediately following PLD infusion on days 1 and 8. (See Morgensztern 442, see Non-Final Act. 3.) Morgensztern teaches treating ovarian, colorectal, and breast cancer with the combination therapy. (See Morgensztern 443, see Non-Final Act. 3.) Morgensztern teaches that administering the two agents together “would take advantage of combined topoisomerase targeting” similar to other pre-clinical studies showing 3 Morgensztern et al., “A Phase I Study of Pegylated Liposomal Doxorubicin and Irinotecan in Patients with Solid Tumors,” 55 Chemotherapy 441–445 (2009). 4 Zhao et al., US 7,744,861 B2, issued June 29, 2010. 5 Wilailak et al., “A Study of Pegylated Liposomal Doxorubicin in Platinum- Refractory Epithelial Ovarian Cancer,” 57 Oncology, 183–186 (2004). 6 Gatti et al., US 4,946,831, issued August 7, 1990. 7 Chong et al., WO 2011/063158 A1, published May 26, 2011. Appeal 2019-004329 Application 14/354,080 5 synergism when administering irinotecan together with doxorubicin. (See Morgensztern 441–442, see Non-Final Act. 7.) The Examiner acknowledges that Morgensztern does not disclose a long-acting irinotecan, having a half-life between 5 and 60 days. (See Non- Final Act. 3.) The Examiner cites Zhao or Chong for teaching the instantly claimed long-acting pentaerythritol-based multi-arm polymer conjugate of irinotecan (“PBMAPCI”). (See id. at 3, 5.) Zhao teaches PBMAPCI is more effective in suppressing tumor growth than unmodified irinotecan over the course of 60 days. (See Zhao 51:1–17; 52:21–30; see Non-Final Act. 3.) Zhao further teaches that multi- armed prodrug conjugates demonstrate additional improvements over unmodified active compounds, including increased tumor retention time, reduced clearance rate, and reduced adverse side effects. (See Zhao 7:1–12; see Ans. 8.) The Examiner finds that Zhao’s dosing range of 40–90 mg/kg PBMAPCI would correspond to an amount greater than 100 mg/m2 for an adult human. (See Zhao 44:1–7; see Non-Final Act. 4.) The Examiner determines a person of ordinary skill in the art would have been motivated by Zhao’s teachings to substitute PBMAPCI for Morgensztern’s unmodified irinotecan, thus arriving at the method of claims 1, 5, 7, 8, and 10–14. (Non- Final Act. 4.) Alternatively, the Examiner finds Chong teaches administering PBMAPCI for treating colorectal, breast, and platinum-resistant ovarian cancer, as well as lymphomas, leukemias, rhabdomyosarcoma, and neuroblastoma. (Chong ¶¶ 10, 251–255; see Non-Final Act. 6.) Chong teaches “the dosage of an irinotecan-conjugate will typically range from about 50 mg/m2 to about 350 mg/m2.” (Chong ¶ 260; see Non-Final Act. 6.) Appeal 2019-004329 Application 14/354,080 6 The Examiner determines a person of ordinary skill in the art would have been motivated by Chong’s teachings to substitute PBMAPCI for Morgensztern’s unmodified irinotecan, thus arriving at the method of claims 1 and 5–14. (See Non-Final Act. 6.) Appellant argues that the Examiner fails to present a prima facie case of obviousness for several reasons. First, Appellant argues that Morgensztern does not suggest combining a long-acting topoisomerase II inhibitor with a long-acting topoisomerase I as taught by Zhao or Chong. (Appeal Br. 8.) Appellant argues that Morgensztern teaches bimodal therapy of a long-acting topoisomerase II inhibitor combined with non-long acting topoisomerase I inhibitor. (Reply Br. 2.) Appellant argues “Morgensztern is concerned with investigating combination therapy to define the [maximum tolerated dose] MTD of the combination, but does not require ‘simultaneous’ targeting.” (Id. at 3.) We are not persuaded by Appellant’s arguments characterizing Morgensztern. Rather, we agree with the Examiner that Morgensztern teaches simultaneous administration of PLD and irinotecan to “take advantage of combined topoisomerase targeting.” (Morgensztern 442.) Moreover, we are not persuaded by Appellant’s arguments that Morgensztern alone does not provide a reason to combine the references. The Examiner determines that one of ordinary skill in the art would modify Morgensztern’s combination therapy with a long-acting irinotecan based on Zhao or Chong, and not Morgensztern alone. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Appeal 2019-004329 Application 14/354,080 7 Second, Appellant argues there was no reason to modify Morgensztern’s irinotecan with the claimed PBMAPCI because the prior art teaches numerous long-acting forms of irinotecan. (Appeal Br. 8–9.) Appellant argues that a different long-acting irinotecan liposome injection (ONIVYDETM) was already approved for use. (Id.) Appellant argues that Zhao teaches many different drugs and “large numbers of organic core molecules and polymer arms,” in addition to modified-irinotecan. (Id. at 9.) Appellant repeats the same argument as to Chong, arguing that one of skill in the art would not have combined the references absent hindsight. (Id. at 13.) We are not persuaded by Appellant’s argument that there is no reason to combine the references. Zhao teaches multiple benefits of PBMAPCI as compared to unmodified-irinotecan, including greater tumor suppression, longer activity, and reduced adverse side effects. (See Zhao 7:1–12.) Likewise, Chong teaches Zhao’s polymer conjugates can improve the water- solubility of an active agent. (See Chong ¶ 4, citing U.S. Patent No. 7,744,861.) Chong also teaches conjugated versions of active agents often exhibit clinically beneficial properties as to safety and efficacy. (See Chong ¶ 6.) That PBMAPCI was not approved at the time and was one of many options does not negate the Examiner’s reason to combine the references. “The motivation to combine inquiry is not limited to what products are forthcoming or currently available on the market . . . Any motivation, whether articulated in the references themselves or supported by evidence of the knowledge of a skilled artisan, is sufficient.” Bayer Pharma AG v. Watson Labs., Inc., 874 F.3d 1316, 1324 (Fed. Cir. 2017). As to Appellant’s hindsight argument, the Examiner takes into account only knowledge which Appeal 2019-004329 Application 14/354,080 8 was within the level of ordinary skill at the time the claimed invention was made, and, therefore, properly reconstructs the prior art. See In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Third, Appellant argues that there was no reason to administer greater than 100 mg/m2 irinotecan equivalents. (Appeal Br. 10.) Appellant contends Morgensztern teaches that 100 mg/m2 is the maximum tolerated dose of irinotecan because a higher dose of 125 mg/m2 resulted in significant and undesirable side effects. (Id.) Appellant contends that Zhao’s doses higher than 100 mg/m2 “relate to administration solely of a long-acting irinotecan.” (Id.) Appellant does not address Chong’s dose range. (See id. at 13.) We are not persuaded by Appellant’s argument. Morgensztern teaches that for the specific trial, the maximum tolerated dose of unmodified irinotecan was 100 mg/m2. (Morgensztern 443.) However, Morgensztern also teaches that other studies determined a maximum tolerated dose of “300 mg/m2 of irinotecan when given every 21 days with growth factor support.” (Id. at 442.) Accordingly, Morgensztern suggests that the dose amount of irinotecan may vary depending on the dosing schedule, dosing regimen, and other treatment parameters. Moreover, as previously discussed, the Examiner rejected the claims based on the combination of Morgensztern with Zhao or Chong, not Morgensztern alone. Both Zhao and Chong expressly describe the beneficial properties of polymer-active conjugates, e.g., PBMAPCI, as including greater tumor suppression and reduced adverse effects. (Zhao 7:1–12; see Chong ¶ 6.) Both references teach dose amounts greater than 100 mg/m2. (See Zhao 44:1–7; see Chong ¶ 260.) Chong expressly teaches that the dose Appeal 2019-004329 Application 14/354,080 9 range for an irinotecan-polymer conjugate may be adjusted “[w]hen administered conjointly with other pharmaceutically active agents.” (Chong ¶ 260.) Accordingly, one of ordinary skill in the art would have applied Zhao’s or Chong’s dose ranges when modifying Morgensztern’s combined therapy with a long-acting irinotecan. Because the prior art ranges overlap the claimed amount of greater than 100 mg/m2, we agree with the Examiner’s determination that the claims are prima facie obvious over the prior art. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). Appellant argues that the claimed method “provides an unexpected treatment benefit that is nowhere suggested by the cited art.” (Appeal Br. 10.) Particularly, Appellant argues that Example 2 of the Specification demonstrates a significant difference in overall survival between the claimed combination therapy and corresponding PBMAPCI and DLI monotherapies. (Id. at 10–11, citing Spec. ¶ 75.) Appellant argues the combination therapy “showed marked synergism demonstrated by complete response in all animals . . . without additive toxicity.” (Id. at 11, citing ¶¶ 75–77.) We are not persuaded by Appellant’s evidence of unexpected results. “To be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). As explained by the Examiner, Appellant’s test results do not compare the claimed invention to the closest prior art. (See Ans. 8–9.) The test results Appeal 2019-004329 Application 14/354,080 10 compare combination therapy to monotherapies in a xenograft mouse model. (See Spec. ¶¶ 50–51.) In contrast, Morgensztern is the closest prior art as it teaches combination therapy for cancer patients suffering from the claimed cancers. (See Morgensztern 441.) Appellant’s results do not compare the claimed combination of two long-acting topoisomerase inhibitors to a similar combination therapy, albeit with a short-acting type I inhibitor and a long-acting type II inhibitor. Morgensztern further explains that a person of ordinary skill in the art would have expected “synergism between topoisomerase I and II inhibitors.” (Id.) Morgensztern expressly teaches that preclinical studies have shown synergism due to combined topoisomerase targeting. (Id. at 442.) Morgensztern explains that the absence of synergism was unexpected, and provided a number of potential factors for that unexpected absence. (See Morgensztern 444.) Morgensztern recommends further evaluation of the combination, particularly for patients with ovarian cancer. (Id.) In view of the recommendation for further evaluation, combined with the benefits of PBMAPCI taught by Zhao and Chong, a person of ordinary skill in the art would have expected the combination therapy of long-acting topoisomerase I and II inhibitors to provide a synergistic effect. Therefore, Appellant’s results are not unexpected and we agree with the Examiner’s conclusion that the claims would have been obvious over Morgensztern combined with Zhao or Chong. Appellant argues the rejections of claims 6 and 9 separately. As to claim 6, Appellant argues Wilailak fails to suggest administering a combination of PEGylated liposomal doxorubicin with a long-acting form of irinotecan. (Appeal Br. 11.) As to claim 9, Appellant argues “Gatti is not Appeal 2019-004329 Application 14/354,080 11 concerned with liposomal forms of doxorubicin, nor PEGylated liposomal forms of doxorubicin, nor coadministration with a second anticancer drug of any type.” (Id. at 12.) Appellant argues that Wilailak and Gatti individually “fail[] to make up for the deficiencies of the combination of Morgensztern in view of Zhao as set forth above.” (Id. at 11–12.) We are not persuaded by Appellant’s arguments against Wilailak and Gatti alone. The Examiner cites Wilailak for teaching administering PEGylated liposomal doxorubicin to treating platinum-resistant ovarian cancer. (See Wilailak 183, see Non-Final Act. 4.) The Examiner cites Gatti for administering doxorubicin to treat leukemia and neuroblastoma. (See Gatti 4:57–68, see Non-Final Act. 5.) The Examiner does not rely on either reference for teaching combination therapy. (See Non-Final Act. 4–5.) Rather, the Examiner relies on the references to teach a reasonable expectation of success in administering the combination to treat the recited cancers of claims 6 and 9. (Id.) Appellant has not addressed the Examiner’s combination. Accordingly, we agree with the Examiner that it would have been obvious to administer the combination therapy taught by Morgensztern and Zhao to treat the cancers taught by Wilailak or Gatti. Because we are not persuaded by Appellant’s arguments that the Examiner erred, we affirm the rejection of claims 1 and 5–14. CONCLUSION Upon consideration of the record and for the reasons given, we AFFIRM the Examiner’s rejection. In summary: Appeal 2019-004329 Application 14/354,080 12 Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 5, 7, 8, 10–14 103(a) Morgensztern, Zhao 1, 5, 7, 8, 10–14 6 103(a) Morgensztern, Zhao, Wilailak 6 9 103(a) Morgensztern, Zhao, Gatti 9 1, 5–14 103(a) Morgensztern, Chong 1, 5–14 Overall Outcome 1, 5–14 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136. AFFIRMED Copy with citationCopy as parenthetical citation