Ex Parte XuDownload PDFPatent Trials and Appeals BoardSep 10, 201412102237 - (D) (P.T.A.B. Sep. 10, 2014) 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. 12/102,237 04/14/2008 Bo Xu 21381-00091-US2 9788 10574 7590 09/11/2014 NOVAK DRUCE CONNOLLY BOVE + QUIGG LLP (Southern Research Institute) 1875 EYE STREET, N.W. Suite 1100 WASHINGTON, DC 20006 EXAMINER PAGONAKIS, ANNA ART UNIT PAPER NUMBER 1628 MAIL DATE DELIVERY MODE 09/11/2014 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 Bo Xu1 __________ Appeal 2012–005937 Application 12/102,237 Technology Center 1600 __________ Before DONALD E. ADAMS, LORA M. GREEN, and ROBERT A. POLLOCK, Administrative Patent Judges. POLLOCK, Administrative Patent Judge. DECISION ON APPEAL Appellant appeals under 35 U.S.C. § 134(a) from the Examiner’s rejection of the pending claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. We also enter a new ground of rejection. STATEMENT OF THE CASE Appellant’s invention relates to methods of enhancing the radiosensitivity of cancer cells using the nucleoside analog clofarabine. 1 According to Appellant, the Real Party in Interest is Southern Research Institute. (App. Br. 2). Appeal 2012–005937 Application 12/102,237 2 Representative independent claim 4 reads as follows: 4. A method of potentiating radiotherapy treatment comprising administering to a patient in need thereof a therapeutically effective amount of clofarabine, and subjecting the patient to radiotherapy. The following grounds of rejection are before us for review: Claims 4-8, 12-14, 18-20, and 24-252 are rejected as unpatentable under 35 U.S.C. § 103 over the combination of Cunningham3, USC-CPBD4, and Cheson5. 2 Appellant contends that claims 4-8, 9-11, 15-17, and 21-23 are on appeal. (App. Br. 2, 5.) The Examiner agrees that “the statement of the status of the claims contained in the brief is correct” (Ans. 3), and directs the sole rejection to claims 4-11, 15-17 and 21-23 (id. at 4). Many of these claims were previously cancelled. Claims 1-25 were pending as of the Final Office Action dated July 29, 2010. By Amendment under 37 C.F.R. § 1.31 dated September 17, 2012, Appellant requested cancelation of claims 1-3, 9-11, 15-17, and 21-23 and amendment of claims 4-8, 12-14, 18-20, 24, and 25. The Advisory Action dated October 1, 2010 indicates that these amendments would be entered such that only claims 4-8, 12-14, 18-20, 24, and 25 would be pending. As these are the same claims set forth in Appellant’s Claims Appendix, we consider claims 4-8, 12-14, 18-20, 24, and 25 the subject of both the outstanding rejection and the instant appeal. We recognize that the Examiner’s rejection did not include claims 12-14, 18-20, 24, and 25, but find that this omission represents an inadvertent typographical error. 3 Cunningham et al., “Clofarabine administered weekly to adult patients with advanced solid tumors in a phase I dose-finding study,” 2004 ASCO Proceedings, J. Clin. Oncol. 22:14S (July 15 Suppl.), 3115. 4 University of Southern California, Center for Pancreatic and Biliary Diseases, Treatment of Pancreatic Cancer, 2002. 5 Gregoir and Hittelman, Nucleoside Analogs as Radiosensitizing Agents, in NUCLEOSIDE ANALOGS IN CANCER THERAPY, pp. 318-319 (Cheson et al., eds. 1997). Appeal 2012–005937 Application 12/102,237 3 FINDINGS OF FACT FF. 1 Cunningham reports the administration of clofarabine to 30 adult patients with solid tumors in a phase I dose-finding study. This one- page abstract describes clofarabine as “a next-generation nucleoside analogue that inhibits DNA synthesis.” Cunningham further discloses that clofarabine has shown “potent cytotoxic activity in a wide range of solid tumor cell lines,” “therapeutic activity in murine tumor models,” and “has demonstrated activity in acute leukemia in Phase I and II trials.” (Cunningham, see also Ans. 4–5.) FF. 2 USC—CPBD teaches the treatment of pancreatic cancer with a combination of chemotherapy and radiation. (USC—CPBD 2–3; see also Ans. 5.) The reference states: The common chemotherapy drugs that are utilized for treatment of pancreatic cancer included 5 flouro—uracil, leukovirin and gemcitidine. Radiation therapy is delivered in daily fractions over a six week period to a total dose of approximately 5,000 rads. The chemotherapy may be administered together or sequentially with the radiation therapy. (USC—CPBD 3.) FF. 3 The instant Specification states that “[r]adiation is [a] commonly used treatment for cancer” and is “[o]ften combined with chemotherapy.” (Spec. 2:9–10.) FF. 4 Cheson teaches that “[n]ucleoside analogs are particularly attractive candidates for enhancing radiation response in tumors for several reasons.” (Cheson 318.) First, because of their cytotoxic activity in proliferating cells, they have antitumor activity on their own. . . . Appeal 2012–005937 Application 12/102,237 4 Second, as inhibitors of DNA replication, they also have the potential for inhibiting DNA repair following ionizing radiation treatment. . . . Third, some nucleoside analogs can be incorporated during DNA synthesis and poison subsequent DNA synthesis by either causing chain termination or serving as a poor template in subsequent rounds of DNA synthesis. . . . Finally, nucleoside analogs are potentially attractive as radioenhancers because as inhibitors of DNA synthesis they can serve to slow tumor clonogen regrowth between radiation dose fractions. (Id. 318-19.) FF. 5 Cheson further states that “emphasis will be placed on newly developed nucleoside analogs (e.g. . . . gemcitabine) that have already shown clinical activity on their own and in combination with other chemotherapeutic agents and appear to be promising candidates for combining with radiation.” (Id. 319.) FF. 6 Clofarabine, 5-flourouricil (5-FU), and gemcitabine are nucleoside analogs. (Ans. 9; App. Br. 14–15; Cunningham; Cheson 319.) FF. 7 Example 5 of the Specification “compare[s] clofarabine’s radiosensitizing potential with other proven radiosensitizing anti- metabolites, radiosensitivity is tested in HeLa cells treated with a combination of clofarabine, gemcitabine, or 5-FU with radiation therapy. . . . the results are presented in Figure 4.” (Spec. 18:6-11; Fig. 4.) FF. 8 Example 8 of the Specification describes the in vivo testing of clofarabine and radiation on six different tumor types. (Spec. 20:25-22:18) The Specification states that: Appeal 2012–005937 Application 12/102,237 5 Three out of the six tumor models tested showed marked radiosensitization with clofarabine while another tumor model showed an additive effect. Two out of the six models tested showed no evidence of an interaction between clofarabine and radiation. The data indicates a trend showing clofarabine’s ability to radiosensitize tumor cells. (Id. 22:14–19.) FF. 9 The Specification further states that SR475HN head and neck tumors were radiosensitized by clofarabine with T—C values (based on 2 tumor doublings) of 18.2, 73.2, and> 162 days for clofarabine, radiation, and the combination, respectively. PANC-l pancreatic tumors were radiosensitized by clofarabine with T—C values (based on 2 tumor doublings) of 17.2, 1.7, 5 and 63.8 days for clofarabine, radiation, and the combination, respectively. HCT-116 colon tumors were radiosensitized by clofarabine with T—C values (based on 3 tumor doublings) of 24.2, 29.3, and >78.9 days for clofarabine, radiation, and the combination, respectively. The radiosensitizing capacity of gemcitabine tracked with the clofarabine results. (Id. 22:1-9.) FF. 10 The Examiner cites the ILEX Briefing document6 as evidence that one of ordinary skill in the art “would not expect that 5-FU, gemcitabine and clofarabine would have identical results when each is combined with radiotherapy.” (Ans. 8.) ILEX states that: Based upon its mechanism of action as an inhibitor of both ribonucleotide reductase and DNA polymerase α and ε, clofarabine is a member of a class of nucleoside analogues that includes gemcitabine, fludarabine, and cladribine. 6 ILEX Products, 2004 Oncologic Drug Advisory Committee Briefing Document for Clofarabine NDA 21–673 (27 October 2004) (“ILEX”). Appeal 2012–005937 Application 12/102,237 6 (ILEX 9.) Clofarabine represents a novel oncolytic that has demonstrated activity in patients with advanced-multiply recurrent or refractory—leukemia. Clofarabine is a nucleoside analogue that differs from similar approved agents (ie, fludarabine and cladribine) in the following respects: The efficiency (VmaX/Km) of phosphorylation of clofarabine by deoxycytidine kinase (dCK) is equal to or greater than that of its natural substrate deoxycytidine (dCyd), and significantly greater than that of cladribine (~3- 4 times greater) and fludarabine (~25 times greater). . . . . The inhibitory potency of clofarabine triphosphate on ribonucleotide reductase was similar to that of cladribine triphosphate, 10 times greater than fludarabine triphosphate, and 100 times greater than gemcitabine triphosphate. (Id. xii, 9 (same).) ANALYSIS The relevant dispute in this case is not over whether the prior art discloses all of the claim elements, or over the motivation to combine the prior art references, but the weight that should be accorded Appellant’s evidence of secondary considerations. Obviousness under 35 U.S.C. § 103 is a legal conclusion based on underlying facts. Graham v. John Deere Co., 383 U.S. 1, 17 (1966). Factual considerations that underlie the obviousness inquiry include the scope and content of the prior art, the differences between the prior art and the claimed invention, the level of ordinary skill in the art, and any relevant secondary considerations. See Graham, 383 U.S. at 17–18. Relevant secondary considerations include commercial success, long-felt but unsolved needs, Appeal 2012–005937 Application 12/102,237 7 failure of others, and unexpected results. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406, (2007). Although evidence pertaining to secondary considerations must be taken into account whenever present, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc. 480 F.3d 1348, 1372 (Fed. Cir. 2007). (“Here, the record establishes such a strong case of obviousness that Pfizer’s alleged unexpectedly superior results are ultimately insufficient.”) The Examiner finds that one of ordinary skill in the art would have found it obvious to administer clofarabine in combination with radiotherapy as taught by Cunningham and USC—CPBD “because [] each of the therapeutics have been individually taught in the prior art to be successful for the treatment of pancreatic tumors.” (Ans. 6.) Citing In re Kerkoven, 626 F.2d 846 (CCPA 1980), the Examiner finds that “it is prima facie obvious to combine two agents each of which is taught by the prior art to be useful for the very same purpose” thus, in the present case, one of ordinary skill in the art would have had a reasonable expectation of success that administering clofarabine in combination with radiotherapy would treat pancreatic cancer tumors. (Id.) The Examiner further finds that clofarabine is a nucleoside analog, and because Cheson teaches the use of nucleoside analogs “to enhance radiosensitivity and potentiate radiotherapy of solid tumors, . . . one of skill in the art would have a reasonable expectation of success that by combining clofarabine with radiation therapy, one would achieve a method to enhance radiosensitivity and potentiate radiotherapy of pancreatic cancer tumors.” (Id. 7.) Appeal 2012–005937 Application 12/102,237 8 Appellant argues that the rejection is “improper in view of the unexpected synergistic results achieved by the combination of clorfarabine with radiation therapy.” (App. Br. 5.) In particular, Appellant argues that “a much more profound radiosensitizing effect was observed in clofarabine- treated cells than cells treated with gemcitabine and 5-FU.” (Reply Br. 3.) The survival curves for the treated cells are shown in Figure 4 of the instant application and also illustrated in Figure 2 of Cariveau et al.7” (Id.) If the compound has a strong radiosensitizing effect (strong synergy), it will require less radiation to slow or stop cell growth. In other words, the higher the SER the better the radiosensitizing effect (synergy). The SER was 1.12 for 5- FU, 1.73 for gemcitabine, and 2.71 for clofarabine. In other words, the enhancement ratio for clofarabine was 2.4 fold better than 5-FU and 1.6 fold better than gemcitabine. Thus, clofarabine exhibits an unexpectedly greater synergistic effect with radiotherapy than other nucleoside analogs known to potentiate radiotherapy. (Reply Br. 4 (emphasis in original.)) Although we are mindful of the Examiner’s disagreement over the methodology underlying Appellant’s evidence unexpected results (Ans. 9), for the purpose of this appeal we accept Appellant’s assertion that Figure 4 of the Specification and Figure 2 of Caraiveau et al. show an “enhancement ratio for clofarabine [] 2.4 fold better than 5-FU and 1.6 fold better than gemcitabine” in HeLa cells treated with a combination of clofarabine, gemcitabine, or 5-FU with radiation therapy. (Reply Br. 3-4; Spec. 18:4- 7 Cariveau et al., “Clorfarabine Acts As Radiosensitizer In Vitro and In Vivo by Interfering with DNA Damage Response,” 2007 Int. J. Radiation Oncology Biol. Phys 70(1), 213-220. Appeal 2012–005937 Application 12/102,237 9 15.) Nevertheless, we are not persuaded that this evidence is sufficient to outweigh the Examiner’s strong prima facie showing of obviousness. As an initial matter, we agree with the Examiner that synergistic results “do not appear to be unexpected,” because Cheson teaches that nucleoside analogs (such as gemcitabine) are “particularly attractive candidates for enhancing radiation response in tumors.” (Ans. 7; Cheson 318.) Thus, “the combination of radiation with a nucleoside analog, such as clofarabine, per Cheson exhibits an enhanced radiation response . . . and thus cannot be deemed unexpected.” (Ans. 7.) We are also unpersuaded by Appellant’s argument that “clofarabine exhibits an unexpectedly greater synergistic effect with radiotherapy than other nucleoside analogs known to potentiate radiotherapy.” (Reply 4.) “Unexpected results that are probative of nonobviousness are those that are ‘different in kind and not merely in degree from the results of the prior art.’” Galderma Labs., LP v. Tolmar, Inc., 737 F.3d 731, 739 (Fed Cir. 2013) (quoting Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004). Results which differ by percentages are differences in degree rather than kind, where the modification of the percentage is within the capabilities of one skilled in the art at the time. See In re Harris, 409 F.3d 1339, 1344 (Fed.Cir.2005) (“32–43% increase in stress-rupture life . . . does not represent a ‘difference in kind’ that is required to show unexpected results”). Rather, we agree with the Examiner that one of ordinary skill in the art “would not expect that 5-FU, gemcitabine, and clofarabine would have identical results when each is combined with radiotherapy.” (Ans. 8.) We support this conclusion with the following evidence. Appeal 2012–005937 Application 12/102,237 10 First, to illustrate the compound-to-compound variability among therapeutic agents, the Examiner points to the ILEX Briefing document, which compares the pharmacology of the nucleoside analog clofarabine with “similar8 approved agents.” (Ans. 8; ILEX xii, 9.) As the Examiner points out, ILEX states that “[t]he inhibitory potency of clofarabine triphosphate on ribonuclease reductase was similar to that of cladribine triphosphate, 10 times greater than fludarabine triphosphate, and 100 times greater than gemcitabine triphosphate.” (Ans. 10-11 (citing ILEX xii).) ILEX similarly discloses that “The efficiency (Vmax/Km) of phosphorylation of clofarabine by deoxycytidine kinase (dCK) is . . . significantly greater than that of cladribine (~3-4 times greater) and fludarabine (~25 times greater).” (ILEX xii, 9) Given that these biological activities can vary up to 100 fold between clofarabine and “similar approved agents,” we are not convinced that a 1.6 or 2.4 fold difference in radiation enhancement is anything but an expected compound—to—compound variation. Second, despite Appellant’s assertion that “the enhancement ratio for clofarabine was 2.4 fold better than 5-FU and 1.6 fold better than gemcitabine” (Reply Br. 4 (underlining in original), these results, derived from cultured tumor cells (see Spec. 16:4–15; Fig. 4; Cariveau Fig. 2), are not consistent with other data in the Specification. In particular, Example 8 of the Specification describes the testing of six in vivo tumor models with clofarabine and radiation. (Spec. 20:25–22:19.) Fifty percent of these models produced no evidence of synergy: 8 Page 9 of ILEX teaches that “clorarabine is a member of a class of analogues that includes gemcitabine, fludarabine, and cladribine.” Appeal 2012–005937 Application 12/102,237 11 Three out of the six tumor models tested showed marked radiosensitization with clofarabine while another tumor model showed an additive effect. Two out of the six models tested showed no evidence of an interaction between clofarabine and radiation. (Id. 22:14–17.) In summarizing these results, the Specification merely states that “[t]he data indicates a trend showing clofarabine’s ability to radiosensitize tumor cells.” (Id. 22:17–18.) Further, whereas Example 8 does not present numerical data for any parallel experiments using other nucleoside analogs, the Specification discloses that, for at least HCT-116 colon tumors, “[t]he radiosensitizing capacity of gemcitabine tracked with the clofarabine results.”9 (Id. 22:6–10.) Thus, to the extent Appellant’s demonstrates synergism and potentially improved radiosensitivity as compared to other nucleoside analogs in vitro, the in vivo results are not compelling. In footnote 2, above, we note that the Examiner’s rejection did not include claims 12-14, 18-20, 24, and 25, but find that this omission represents an inadvertent typographical error. Claims 12-14 and 18-20 relate to the radiosensitivity of cell populations, including tumor cells. Representative claim 12 recites: 12. A method for enhancing radiosensitivity of a cell population comprising exposing said cell population to a sensitizing amount of clofarabine, and subjecting the cell population to radiation. Claim 12, thus, essentially parallels representative claim 4, with the caveat that treated cell population is not necessarily within a human patient. As 9 The Specification does not make clear whether gemcitabine “tracking” also applies to the SR475HN and PANC-1 tumor models. (See Spec. 22:1-9.) Appeal 2012–005937 Application 12/102,237 12 claim 12 is broader than claim 1, and Appellants have not provided separate arguments for claims 12-14 and 18-20, we find that these claims fall with claim 4. Claim 24 and its dependent claim 25, similarly parallel claim 1 and its dependent claim 8 but make explicit the “synergistic combination of ionizing radiation and clofarabine.” As we do not find Appellants evidence of synergy compelling, claims 24 and 25 fall with claim 4. SUMMARY We affirm the rejection of claim 4 as unpatentable under 35 U.S.C. § 103 over the combination of Cunningham, USC-CPBD, and Cheson. Claims 5-8 are not separately argued and fall with claim 4. Separate arguments were not provided for claims 12-14, 18-20, 24, and 25, which also fall with claim 4. We recognize that the Examiner’s rejection did not include claims 12-14, 18-20, 24, and 25, but find that this omission represents an inadvertent typographical error.10 Nevertheless, in an excess of caution we designate our affirmance of claims 12-14, 18-20, 24, and 25 a new ground of rejection. TIME PERIOD FOR RESPONSE Regarding the affirmed rejection(s), 37 C.F.R. § 41.52(a)(1) provides “Appellant may file a single request for rehearing within two months from the date of the original decision of the Board.” 10 See footnote 2. Appeal 2012–005937 Application 12/102,237 13 In addition to affirming the Examiner’s rejection(s) of one or more claims, this decision contains a new ground of rejection pursuant to 37 C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” 37 C.F.R. § 41.50(b) also provides that the Appellant, WITHIN TWO MONTHS FROM THE DATE OF THE DECISION, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new evidence relating to the claims so rejected, or both, and have the matter reconsidered by the examiner, in which event the proceeding will be remanded to the examiner…. (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same record…. Should the Appellant elect to prosecute further before the Examiner pursuant to 37 C.F.R. § 41.50(b)(1), in order to preserve the right to seek review under 35 U.S.C. §§ 141 or 145 with respect to the affirmed rejection, the effective date of the affirmance is deferred until conclusion of the prosecution before the Examiner unless, as a mere incident to the limited prosecution, the affirmed rejection is overcome. Appeal 2012–005937 Application 12/102,237 14 If the Appellant elects prosecution before the Examiner and this does not result in allowance of the application, abandonment or a second appeal, this case should be returned to the Patent Trial and Appeal Board for final action on the affirmed rejection, including any timely request for rehearing thereof. AFFIRMED; 37 C.F.R. § 41.50(b) pgc Copy with citationCopy as parenthetical citation