Ex Parte Huang et alDownload PDFPatent Trial and Appeal BoardApr 20, 201713989016 (P.T.A.B. Apr. 20, 2017) 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. 13/989,016 10/11/2013 Peng Huang UTSC.P1056US 3042 108197 7590 04/24/2017 Parker Highlander PLLC 1120 South Capital of Texas Highway Bldg. 1, Suite 200 Austin, TX 78746 EXAMINER MATOS NEGRON, TAINA DEL MAR ART UNIT PAPER NUMBER 1621 NOTIFICATION DATE DELIVERY MODE 04/24/2017 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket @ phiplaw .com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PENG HUANG, WAN ZHANG, and MICHAEL J. KEATING Appeal 2016-004023 Application 13/989,0161 Technology Center 1600 Before DONALD E. ADAMS, FRANCISCO C. PRATS, and RACHEL H. TOWNSEND, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134(a) involves claims 1, 3, 8-10, 12, and 13 (Final Act.2 2).3 Examiner entered rejections under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellants identify the real party in interest as the “Board of Regents, The University of Texas System” (Br. 3). 2 Examiner’s November 19, 2014 Final Office Action. 3 Pending claims 5-7 and 11 stand withdraw from consideration (Final Act. 2). Appeal 2016-004023 Application 13/989,016 STATEMENT OF THE CASE Appellants disclose “cancer therapy of hematologic malignant cells, including chronic lymphocytic leukemia cells, using selenium-containing compositions” (Spec. ^ 2). Claim 1 is representative and reproduced below: 1. A method of treating chronic lymphocytic leukemia (CLL) in a human individual having CLL in a stromal tissue microenvironment, comprising the step of administering to the individual an amount of a selecticine[4] that is effective to kill CLL cells in said stromal tissue microenvironment, wherein the selecticine is selected from the group consisting of selenocystine, a combination of selenocystine and 2- mercaptoethanol, a combination of selenocystine and dithiothreitol, and a combination of selenocystine and hydrochloric acid. (Br. 17.) 4 According to Appellants “[t]he term ‘selecticine’ [] refers to chemical compositions comprising selenocystine or selenocysteine and agents that make these selenium-containing compounds soluble and stable, thereby suitable for therapeutic applications. Examples of such agents include hydrochloric acid, 2-mercaptoethanol, and dithiothreitol” (Spec. ^ 54). 2 Appeal 2016-004023 Application 13/989,016 The claims stand rejected as follows: Claims 1, 3, and 13 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Milner,5 Last,6 and Caligaris-Cappio.7’8 Claims 1, 3, 8-10, 12, and 13 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Milner, Last, Caligaris-Cappio, and Stiefel.9’10 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? 5 J.A. Milner and C. Y. Hsu, Inhibitory Effects of Selenium on the Growth of LI210 Leukemic Cells, 41 Cancer Res. 1652-1656 (1981). 6 K. Last et al., The activity of methylated and non-methylated selenium species in lymphoma cell lines and primary tumours, 17 Annals of Oncology 773-779 (2006). 7 Caligaris-Cappio, Role of the Microenvironment in Chronic Lymphocytic Leukaemia, 123 British Journal of Haematology 380-388 (2003). 8 Appellants included cancelled claim 2 in their discussion of the rejection over Milner, Last, and Caligaris-Cappio (see, e.g., Br. 4; cf Final Act. 2). We did not include cancelled claim 2 in our deliberations. 9 Stiefel et al., US 6,656,509 Bl, issued Dec. 2, 2003. 10 Appellants included cancelled claims 2 and 4 in their discussion of the rejection over Milner, Last, Caligaris-Cappio, and Stiefel (see, e.g., Br. 15; cf. Final Act. 2). We did not include cancelled claims 2 and 4 in our deliberations. 3 Appeal 2016-004023 Application 13/989,016 FACTUAL FINDINGS (FF) FF 1. Etet11 discloses: In the ongoing efforts to develop therapies against chronic lymphocytic leukemia (CLL), stromal factors allowing malignant cells to escape spontaneous and chemotherapy- mediated apoptosis, giving way to relapses, have been abundantly investigated. Bone marrow [(BM)] adherent cell types, collectively referred to as stromal cells, appear to be key players in such escape, mainly because CLL malignant cells, which rapidly undergo spontaneous apoptosis when cultured in vitro, survive, migrate, and resist cytotoxic agents in co-culture with bone marrow stromal cells. (Etet, Abstract.) FF 2. Etet discloses that “BM stroma derives from mesenchymal stromal cells (MSCs)” and “[c]o-culture studies have revealed that BM MSCs and other stromal cell types confer CLL cells the ability to resist both spontaneous and anticancer drug-induced apoptosis, as well as maintenance and proliferation abilities” (Etet 24: col. 1,11. 13-14 and 29: col. 2,11. 7-11; see also Niedermeier12 5555: col. 1,11. 8-14 (“[interactions between CLL cells and the microenvironment are critical for maintenance and expansion of the neoplastic B-cell clone. These interactions occur in tissue compartments, such as the marrow and secondary lymphatic tissues, where CLL cells interact with a variety of nonmalignant accessory cells collectively referred to as stromal cells,” wherein “[tjhese interactions provide growth and survival signals and also confer drug resistance”)). 11 Etet et al., Stromal control of chronic lymphocytic leukemia cells, 4 Research and Reports in Biology 23-32 (2013). 12 Niedermeier et al., Isoform-selective phosphoinositide 3 ’-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach, 113 Blood 5549-5557 (2009). 4 Appeal 2016-004023 Application 13/989,016 FF 3. Caligaris-Cappio discloses “that [] direct physical contact between BM stromal cells and leukaemic cells extends the survival of CLL cell[s]” and that “[i]n vitro, it has been shown that malignant CLL cells interact with BM stromal cells via [31 and [32 integrins,” wherein “[t]his binding rescues CLL cells from apoptosis and extends their lifespan, suggesting a potential mechanism for the preferential in vivo accumulation and survival of CLL cells within the BM” (Caligaris-Cappio 384: col. 2,11. 28-42; Ans. 4). FF 4. Milner discloses that “[sjelenium has been shown to inhibit [growth of] L1210 [Leukemic] cells both in vitro and in vivo,” wherein “[s]elenium administration as sodium selenite was shown to be more effective in increasing the longevity of L1210-inoculated mice than was treatment with sodium selen[i]te, selenocystine, or selenomethionine” (Milner Abstract; Ans. 3). FF 5. Milner discloses that “L1210 cells incubated [in vitro] with selenium (0.5 pg.ml) in various forms were [] found to have decreased viability,” wherein “[t]he order of relative toxicity of the selenium compounds after 3 hr of incubation [with L1210 cells in vitro] was selenium dioxide > sodium selenite > selenocystine > sodium selen[i]te, based on trypan blue exclusion” (Milner 1653: col. 2,11. 1-6; Ans. 3). FF 6. Milner found that “[s]elenium administration [to mice inoculated with varying quantities of L1210 tumor cells] significantly increased the longevity of the mice, regardless of the initial cell number” used to inoculate the mice (Milner 1654: col. 1,11. 22-27; see also id. at 1653: col. 1,11. 3-12 (Milner discloses the use of “i.p. injection[]” to administer selenium compounds to mice); Ans. 3). 5 Appeal 2016-004023 Application 13/989,016 FF 7. Milner discloses that “[t]he order of efficacy for the forms of selenium tested was sodium selenite » selenocystine > selenomethionine = sodium selenate” (Milner 1654: col. 1,11. 36-39; Ans. 3). FF 8. Milner discloses that “selenium can alter the growth of L1210 leukemic cells,” wherein “sodium selenite is one of the most efficient compounds both in vitro and in vivo against L1210 cells,” while “[sjodium selenate and selenocystine are less effective in altering the growth of this tumor cell line” (Milner 1655: col. 1,11. 1-14; Ans. 3). FF 9. Milner discloses that the “[t]ypes of tumors as well as [the] form of selenium administered may [] be important factors in the efficacy of selenium therapy” (Milner 1655: col. 1,11. 16-18; see generally Ans. 3). FF 10. Milner discloses that “[t]he response to selenium was at least additive when given in conjunction with the chemotherapeutic agent, methotrexate” (Milner 1655: col. 2,11. 2—4; Ans. 3—4). FF 11. Examiner finds that Milner fails to disclose the treatment of “chronic lymphocytic leukemia [(CLL)] in a human [] having CLL in a stromal tissue microenvironment [], administering to the individual an amount effective to kill CLL cells[, or] the step of diagnosing chronic lymphocytic leukemia” (Ans. 4). FF 12. Last discloses “a study of the effects of methylseleninic acid (MSA) and selenodiglutathione (SDG), representing methylated and non-methylated selenium species, respectively, in a lymphoma cell line panel and in a primary lymphoma culture system,” which included “CHO cells transfected to express CD40 ligand” that were “irradiated to prevent further proliferation,” and, thereby, “provide[d] a stromal layer supporting B-cell proliferation” (Last 773: col. 2,11. 19-23; id. at 774: col. 1,11. 31-33; see 6 Appeal 2016-004023 Application 13/989,016 generally Ans. 4). The selenium species used in the in vitro studies were “activated selenium species,” which would mimic dietary forms of selenium, such as L-selenomethionine, a selenium compound which is activated in vivo and has little in vitro activity. (Last 776: col. 1,11. 17-24.) FF 13. Last discloses that “[t]he activity of a 48-h exposure to SDG or MSA was [] investigated in primary B-cell malignancy samples from patients with mantle cell lymphoma [], follicular lymphoma [], chronic lymphocytic leukemia [] and a normal B-cell sample from a healthy blood donor” and Last’s results demonstrated that “[a]ll samples showed a concentration- dependent decrease in percentage viability with MSA and SDG” (Last 775- 776, bridging paragraph (emphasis added); see also id. at 777: col. 2,11. 10- 13 (Last’s “studies were conducted to determine the activity of different selenium species as single agents, prior to examining the role of selenium in mediating chemosensitivity in vitro and in vivo in the lymphoma setting”); Ans. 4). FF 14. Last found that “[b]oth MSA and SDG induced cytostasis and cytotoxicity in the lymphoma cell line panel studied, in a concentration and time-dependent manner,” wherein “cells appeared more sensitive to SDG [] than MSA” (Last 776: col. 2,11. 3-6; id. at col. 1,11. 6-7). Last further suggests that other selenium compounds may be appropriate for clinical use. (Last 777: col. 2,11. 17-21.) FF 15. Last discloses that “[djiffuse large B-cell lymphoma patients with low serum selenium concentration at presentation have a lower response rate and overall survival than patients with higher serum selenium. The co administration of selenium with conventional chemotherapy may be useful in these patients” (Last, Abstract). 7 Appeal 2016-004023 Application 13/989,016 FF 16. Examiner finds that the combination of Milner, Last, and Caligaris- Cappio fails to disclose the administration of a selenium compound with “an additional anticancer therapy []; anticancer therapy that comprises chemotherapy []; chemotherapy comprising] [] cyclophosphamide”; or the oral or intravenous delivery of a selenium compound, such as a selecticine (Ans. 7). FF 17. Stiefel “relates to the use of selenium and/or a derivative thereof in combination with a cytostatic or a mixture of cytostatics” (Stiefel 1: 3-5; see generally Ans. 7). FF 18. Stiefel discloses “[t]he use of organic selenium compounds [] to reduce toxicity in comparison with inorganic selenium compounds with simultaneous or improved antitumor efficiency,” wherein “[particularly preferred are the selenium amino acids selenomethionine and selenocysteine as well as the compound phenylenebis(methylene)selenocyanate as well as derivatives thereof’ (Stiefel 5: 1-7; Ans. 7). FF 19. Stiefel discloses the use of selenium or a selenium compound together with, inter alia, “a mitosis-inhibiting cytostatic . . ., a cytostatic inhibiting nucleic acid synthesis, for example methotrexate and fluorouracil, which belong to the group of antimetabolites, or the topisomerase [sic] inhibitor topotecan, mRNA synthesis inhibitors such as doxorubicin, or alkylating agents such as cyclophosphamide and chlorambucil” (Stiefel 6: 3- 13; Ans. 7). FF 20. Stiefel discloses the administration “of a selenium compound and a cytostatic or several cytostatics ... in [a] solid or liquid form” for, inter alia, oral or intravenous administration (Stiefel 9: 29-34; Ans. 7). 8 Appeal 2016-004023 Application 13/989,016 ANALYSIS The combination of Milner, Last, and Caligaris-Cappio: Based on the combination of Milner, Last, and Caligaris-Cappio, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious to develop a method of treating chronic lymphocytic leukemia in an individual by administering selenocystine with [a] reasonable expectation of success because Milner [] demonstrates that selenocystine inhibits L1210 leukemic cells in vitro and in vivo and Last [] demonstrates that selenium compounds induced cytostasis and cytotoxicity in B-cell malignancy samples from patients with chronic lymphocytic leukemia, wherein the B-cell malignancy samples were co-cultured in the presence of a stromal cell surrogate (i.e., “CHO cells transfected to express CD40 ligand” that were “irradiated to prevent further proliferation,” and, thereby, “provide[d] a stromal layer supporting B-cell proliferation”) (Ans. 4-5; FF 12; see generally FF 3-15). The prior art relied upon by Examiner makes clear that the serum selenium concentration of patients with diffuse large B-cell lymphoma, i.e., CFF, affects the patient’s response rate and overall survival (FF 15). The prior art of record establishes that a selenium compound is capable of treating, inter alia, CFF in a concentration dependent manner, when the CFF cells are in a stromal tissue microenvironment (FF 12-13; see also FF 1-3). The prior art relied upon by the Examiner also suggests that selenium concentration can be provided by other selenium species besides MSA or SDG for treating CFF cells in a stromal microenvironment (FF 14). The prior art relied upon by Examiner expressly suggests “[t]he co administration of selenium with conventional chemotherapy” to patients 9 Appeal 2016-004023 Application 13/989,016 with diffuse large B-cell lymphoma, such as CLL (id.; see also FF 10). The prior art of record discloses a number of selenium based compounds that are suitable for administration to a mammal, including selenocystine (FF 4-8 and 12-14). For the foregoing reasons, we are not persuaded by Appellants’ contention that Appellants have “surprisingly shown that selenocystine, can preferentially kill primary chronic leukemia cells isolated from CLL patients, but only [] efficiently in the presence of stromal cells as now required by [Appellants’] claims” (Br. 5; cf. FF 1-8, 10, and 12-15). Last established that selenium based compounds were capable of killing primary CLL cells in the presence of stromal cells and suggested that selenium based compounds be used in the treatment of patients with CLL (FF 12-15), not just the selenium species tested in the specific in vitro tests performed. Milner established that a person of ordinary skill in this art was aware of a number of different selenium based compounds, including selenocystine (FF 4-8). Thus, notwithstanding Appellants’ contention to the contrary, Appellants appear to have, at best, performed the method suggested by the prior art relied upon by Examiner and observed the result. “Scientific confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention.” Pharmastem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir. 2007). See KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1732 (2007) (“Granting patent protection to advances that would occur in the ordinary course without real innovation retards progress”). Further, Appellants failed to establish that their evidence of surprising or unexpected results were compared against the closest prior art. 10 Appeal 2016-004023 Application 13/989,016 For the same reasons we are not persuaded by Appellants’ contentions that their Specification established unexpected results for the use of a selenium compound, i.e., selenocysteine, to provide an anti-CLL effect when administered to CLL cells in a stromal tissue microenvironment (see Br. 6- 8; cf. FF 13). That is, Appellants’ Specification does not account for the teaching of treating CLL with a selenium species already taught by Last. Selenocysteine was known and used in the art prior to Appellants’ claimed invention (FF 4-8). Therefore, we are not persuaded by Appellants’ contentions regarding the stability and manufacture of selenocysteine, or their use of the term “selecticines” (Br. 5-6; see also Spec. ^ 54). For the reasons discussed above, it was known in the art prior to Appellants’ claimed invention that serum selenium concentration of patients with diffuse large B-cell lymphoma, i.e., CLL, affects the patient’s response rate and overall survival (FF 15). The prior art of record also establishes that a selenium compound is capable of treating, inter alia, CLL in a concentration dependent manner, when the CLL cells are in a stromal tissue microenvironment (FF 12-13). Therefore, we are not persuaded by Appellants’ contentions regarding Milner’s failure to “know[] the mechanism of action” for the use of selenium or selenium based compounds in the treatment of cancer (Br. 8). In addition, Milner establishes that selenium based compounds exhibit differences in relative toxicity and efficacy, suggesting that a person of ordinary skill in this art would have found it prima facie obvious to optimize the selenium source and dosage for administration to CLL patients, where, as here, the prior art teaches that CLL cells in a stromal cell microenvironment can be effectively treated with a selenium compound and 11 Appeal 2016-004023 Application 13/989,016 the “[t]ypes of tumors as well as [the] form of selenium administered may [] be important factors in the efficacy of selenium therapy” (see FF 5, 7, 9, and 12-15). See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007) (“[T]he discovery of an optimum value of a variable in a known process is usually obvious”). Therefore, we are not persuaded by Appellants’ contention that “Milner [] teaches away from therapy with selenoamino acids, teaching instead to use inorganic selenium, not the organic selenium found in selenoamino acids” (Br. 9). For the same reasons we are not persuaded by Appellants’ contention that Last “is [of] little relevance [] to the present invention,” because Last used SDG and MSA to “represent[] methylated and non-methylated selenium species” instead of selenocystine (Br. 12; see also id. at 13 (Last’s use of compounds representative of methylated and non-methylated selenium species “teaches away from selenocystine and instead directs [an artisan] in quite another direction, Se-Methylselenocysteine”); id. at 14 (“As for Last [], it is entirely unclear why it is even being cited since it says nothing about selenocystine”); FF 12). We are not persuaded by Appellants’ contentions regarding Milner’s use of “murine L1210 cells without stromal cell co-culture,” which fails to account for the contribution of Last and Caligaris-Cappio to the combination of references relied upon by Examiner (Br. 9; see generally id. at 9-11 and 14, citing Kessel13 and Bichi;14 cf. FF 3 and 12-15). 13 David Kessel and H. Bruce Bosmann, Studies on a Cell Line Derived from the LI210 Murine Leukemia with Altered Surface Properties and Decreased Capacity for Tumor Production, 34 Cancer Research 603-608 (1974). 14 Bichi et al., Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression, 99 PNAS 6955-6960 (2002). 12 Appeal 2016-004023 Application 13/989,016 Last established that selenium compounds, representative of selenium species were effective to treat CLL cells in a stromal microenvironment (FF 12-15). We recognize, but are not persuaded by, Appellants’ contention that “CHO cells are ovary cells unrelated to bone marrow stromal cells” and assertion that Last’s “studies were [] not carried out in the presence of bone marrow stromal cells” (Br. 12). Notwithstanding Appellants’ contention to the contrary, Last modifies CHO cells in such a way that Last expressly characterizes the modified CHO cells as “providing] a stromal layer supporting B-cell proliferation” (FF 12). Appellants failed to establish an evidentiary basis on this record to support a conclusion that Last’s modified CHO cells, which Last characterizes as “providing] a stromal layer supporting B-cell proliferation,” represent a materially different stromal tissue microenvironment than is required by Appellants’ claimed invention (FF 12; cf Br. 17). Appellants do not appear to dispute that Caligaris-Cappio discloses “that [] direct physical contact between BM stromal cells and leukaemic cells extends the survival of CLL cell[s]” and that “[/]/? vitro, it has been shown that malignant CLL cells interact with BM stromal cells via [31 and [32 integrins,” wherein “[t]his binding rescues CLL cells from apoptosis and extends their lifespan, suggesting a potential mechanism for the preferential in vivo accumulation and survival of CLL cells within the BM” (FF 3; cf. Br. 13). The combination of Milner, Last, Caligaris-Cappio, and StiefeT. Based on the combination of Milner, Last, Caligaris-Cappio, and Stiefel, Examiner concludes that, at the time Appellants’ invention was 13 Appeal 2016-004023 Application 13/989,016 made, it would have been prima facie obvious to treat CLL patients with a combination of selenocystine and an additional anti-cancer therapy, such as cyclophosphamide (Ans. 8-9; FF 3-20). Having found no error in the combination of Milner, Last, and Caligaris-Cappio, as it relates to Appellants’ claim 1, we are not persuaded by Appellants’ contention “that Stiefel adds nothing of relevance to the teachings of Milner,” Last, and Caligaris-Cappio (Br. 16). CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable over the combination of Milner, Last, and Caligaris-Cappio is affirmed. Claims 3 and 13 are not separately argued and fall with claim 1. The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable over the combination of Milner, Last, Caligaris-Cappio, and Stiefel is affirmed. Claims 3, 8-10, 12, and 13 are not separately argued and fall with claim 1. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 14 Copy with citationCopy as parenthetical citation