Ex Parte LI et alDownload PDFPatent Trial and Appeal BoardDec 28, 201613757262 (P.T.A.B. Dec. 28, 2016) 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. 13/757,262 02/01/2013 Hui Li 06-950-E-CON3 7097 84067 7590 12/29/2016 McDonnell Boehnen Hulbert & Berghoff LLP 300 South Wacker Drive Chicago, IL 60606 EXAMINER RAO, DEEPAK R ART UNIT PAPER NUMBER 1624 MAIL DATE DELIVERY MODE 12/29/2016 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 HUI LI, ANKUSH ARGADE, RAJINDER SINGH, SAMBAIAH THOTA, DAVID CARROLL, KIN TSO, VANESSA TAYLOR, JOHN MCLAUGHLIN, and VADIM MARKOVTSOV1 Appeal 2015-001190 Application 13/757,262 Technology Center 1600 Before ULRIKE W. JENKS, TAWEN CHANG, and KRISTI L. R. SAWERT, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of inhibiting Aurora kinase. The Examiner rejects the claims as lacking enablement. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM-IN-PART. 1 According to Appellants, the real party in interest is Rigel Pharmaceuticals, Inc. (App. Br. 2.) Appeal 2015-001190 Application 13/757,262 STATEMENT OF THE CASE According to the Specification ‘“Aurora kinase’ refers to a member of the family of serine/threonine protein kinases that are generally referred to as ‘Aurora’ kinases. The Aurora family of serine/threonine protein kinases are essential for cell proliferation” (Spec. 18). “[T]he Aurora kinase family is expressed at a low level[] in the majority of normal tissues, the exceptions being tissues with a high proportion of dividing cells such[] as the thymus and testis” {id.at 19—20). “Presently, there are three known mammalian family members: Aurora-A (‘2’), Aurora-B (T) and Aurora-C (‘3’)” {id.at 18). Claims 49-53 are on appeal, and can be found in the Claims Appendix of the Appeal Brief. Appellants request review of the Examiner’s rejection of claims 49— 53 under 35 U.S.C. § 112, first paragraph as lacking enablement for the recited methods (App. Br. 3). The issue is: Does the evidence of record support the Examiner’s conclusion that the disclosure in the Specification is insufficient to enable one of ordinary skill in the art to practice the full scope of the claimed invention? Findings of Fact Breadth of Claims FF1. Claim 49 is directed to “[a] method of inhibiting an Aurora kinase in a cell, the method comprising contacting the cell with an effective amount of a compound according to structural formula (I)” (shown below {see FF3)). 2 Appeal 2015-001190 Application 13/757,262 FF2. Claim 52 is directed to “[a] method of treating an Aurora kinase- mediated disease or disorder in a[n] animal or human subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to structural formula (I): (shown below (see FF3)). Presence of Working Examples FF3. Table 1 of the Specification discloses 188 substituted 2,4-pyrimidinediamine compounds having a structure corresponding to formula (I) (see Spec. 1, 2, and 80—144). These 188 compounds “were tested against A549 and HI299 cells for their ability to inhibit [cell] proliferation using standard in vitro antiproliferation assays” (Spec. 79). FF4. The Specification further discloses: Certain compounds [from table 1] were tested against other cell types for their ability to inhibit proliferation in standard antiproliferation assays. The various cells lines tested included: A549 (lung carcinoma); ASPC-1 (pancreatic adenocarcinoma); BXPC-3 (pabcreatic adenocarcinoma); CaOV-3 (ovarian adenocarcinoma); COLO 205 (colorectal adenocarcinoma); DU145 (prostate carcinoma); ES-2 (ovarian clear cell carcinoma); H1299 (non-small cell lung carcinoma); HI 155 (non-small cell lung carcinoma); H460 (large cell lung carcinoma); HELA (cervical adenocarcinoma); HL160 (promyeloblast promyelocytic leukemia); K562 (bone marrow chronic myelogenous 3 Appeal 2015-001190 Application 13/757,262 leukemia); L1210 (mouse lymphocytic leukemia); MiaPaCa-2 (pancreatice [sic] carcinoma); MOLT4 (T lymphoblast acute lymphoblastic leukemia); OVCAR-3 (ovarian adenocarcinoma); MOLT3 (T lymphoblast acute lymphoblastic leukemia); OVCAR-8 (ovarian carcinoma); PC3 (prostate adenocarcinoma); SK-OV-3 (ovarian adenocarcinoma); SU86.86 (pancreatic carcinoma); SW620 (colorectal adenocarcinoma); THP-1 (monocyte acute monocytic leukemia); TOV-21G (ovarian clear cell carcinoma); U20S (bone osteosarcoma); and U937 (histiocytic lymphoma). (Spec. 145, see also 145—146, Table 2). FF5. The Specification discloses that “the bisHCl salt of Compound 60a (enantiomer E3; Compound 234) was tested for its ability to shrink A549 and Colo205 tumors in a standard xenograft therapeutic model in SCID mice, and Colo205 and MiaPaCa tumors in a standard xenograph regression model in SCID mice” (Spec. 148, see also 148— 149, Tables 3 and 4). Amount of Direction and Guidance Presented FF6. The Specification discloses “Aurora kinases are a family of enzymes known to be key regulators of cell division” (Spec. 10). “Aurora kinase family is expressed at a low levels in the majority of normal tissues, the exceptions being tissues with a high proportion of dividing cells such, as the thymus and testis” (Spec. 19-20). FF7. The Specification discloses that “Aurora kinase-mediated diseases and disorders include any disease, disorder, or other deleterious condition in which a member of the Aurora kinase family of enzymes plays a role” (Spec. 11). 4 Appeal 2015-001190 Application 13/757,262 FF8. The Specification discloses that “[t]he Aurora kinases have been reported to be over-expressed in a wide range of human tumors,” including: colorectal, ovarian, gastric tumors, invasive duct adenocarcinomas of the breast, renal, cervical, neuroblastoma, melanoma, lymphoma, pancreatic and prostate tumor cell lines (Spec. 19). State of Prior Art and Unpredictability of the Art FF9. Lu2 teaches that “Aurora A null mice were embryonic lethal” (Lu 13787), while “Aurora A+/' mice developed tumors at a higher frequency of 25.5% compared with 8.8% in Aurora A+/+ mice” (id.). FF10. Lu teaches that “Aurora A also has a direct role in spindle assembly and microtubule organization” (id. at 31789). “Aurora A may act as a haploinsufficient tumor suppressor. Combined with the overwhelming evidence that supports Aurora A as an oncogene, we propose that a balanced level of Aurora A is required for maintaining genomic stability” (id. at 31790). FF11. Lu acknowledges that Because of the frequent Aurora A overexpression observed in human tumors, several Aurora kinase inhibitors are currently in clinical trials for cancer treatment. ... It appears that short-term treatment with these inhibitors does not cause any major side effects and are beneficial to the patients. However, the potential long term effects of these inhibitors remain unknown. In this study, we used an Aurora inhibitor and showed that whereas they have great potency in inhibiting tumor cell growth, they also generate aneuploidy in normal cells, 2 Lu et al., Aurora A Is Essential for Early Embryonic Development and Tumor Suppression, 283 J. Biological Chem. 31785—790 (2008). 5 Appeal 2015-001190 Application 13/757,262 which has been previously reported in normal mammary epithelial cells []. The data from our Aurora A+/' mouse model would hint that chromosomal instability generated by Aurora inhibition may potentially cause secondary tumor formation later in life. (Id.) FF12. Harrington3 teaches Aurora-A has a crucial role in mitotic spindle formation and centra some maturation, ensuring faithful segregation of chromosomes into daughter cells. . . . Aurora-B is a ‘chromosomal passenger’ protein that is essential for chromosomal congression and cytokinesis. . . . Overexpression of kinase-inactive Aurora-B disrupts kinetochore-microtubule interactions, cleavage furrow formation and cytokinesis, leading to polyploidy.... The function of Aurora-C remains unclear. (Harrington 262.) FF 13. Harrington teaches VX-680 is a potent inhibitor of all three Aurora kinases (id. at 263). Targeting of the Aurora kinases is a new approach to cancer therapy, and therefore holds the potential to inhibit the growth of tumors that are refractory to conventional therapies. Encouragingly, we have shown that VX-680 can completely ablate colony formation of primary AML cells taken from patients who were refractory to the standard treatments. (id. at 266.) 3 Harrington et al., VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo, 10 Nature Medicine 262-267 (2004). 6 Appeal 2015-001190 Application 13/757,262 FF14.Carvajal4 teaches that “[t]he evidence linking Aurora overexpression and malignancy has stimulated interest in developing Aurora inhibitors for cancer therapy” (Carvajal 6874). “Preclinical data for Aurora kinase inhibition is promising and preliminary clinical data reveals disease stability with treatment in an otherwise treatment- refractory patient population. Whether targeting Aurora-A, Aurora-B, or both will result in optimal antitumor activity is unknown” (id. at 6874). FF15. Pearce5 teaches that more is required to develop a cancer-treating drug than merely identifying a good target. Choosing targets that are abundantly expressed in normal tissues requires special care. The pursuit of over expressed targets in tumor tissue often leads to an inescapable reality: the target is more highly expressed in diseased tissue than in normal tissue, but biochemical stoichiometry suggests that it will be more difficult to inhibit the target in diseased tissues than in normal tissues. Hence, normal biology may be more affected by a drug than disease biology leading to adverse events (normal tissue dose-limiting toxicities) (Pearce 427.) FF 16. Pearce teaches In cancer drug discovery, these are usually rodent models bearing a transplantable tumor. Yet the vast majority of these investigational drugs fail to meet their pre-specified clinical benefit or efficacy endpoints. . . . The predictive 4 Carvajal et al. Aurora Kinases: New Targets for Cancer Therapy, 12 Clin. Cancer Res. 6869-75 (2006). 5 Pearce et al., Failure modes in anticancer drug discovery and development, in Cancer Drug Design and Discovery 424-A35 (Stephen Neidle ed., 2008). 7 Appeal 2015-001190 Application 13/757,262 quality of standard animal models has been assessed in a retrospective analysis, with the conclusion that tumor specificity does not translate from laboratory to clinic. (Pearce 424.) FF17. Pearce teaches that “[tjransgenic and knock-out mice develop diseases that present a cancer phenotype; however, they often lack clinical reality. A thymoma or pituitary tumor that never metastasizes or locally invades, but kills by normal organ compression, is unlikely to provide many useful cancer targets for drug discovery” (Pearce 428). FF18. Pearce teaches that “the animal model is less important in the predication of efficacy, but rather in the demonstration that the drug candidate is capable of partitioning across pharmacologic compartments, and interacting with its target in a pharmacologically meaningful way” (Pearce 428). Quantity of Experimentation FF19.The Examiner finds that “the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity” (Ans. 14). Skill in the Art FF20. The Examiner finds, and Appellants do not contest, that “Applicants must teach the skilled practitioner, in this case a physician, how to treat a given subject. The physician clearly must know what diseases and what symptoms are to be treated” (Final Act. 4; see also Reply Br. 8 (“But whether one characterizes the level of skill in the art Tow’ or ‘high’ is not relevant. What is relevant is the actual level of skill, which the applicants submit is that of one having an MD or PhD in 8 Appeal 2015-001190 Application 13/757,262 medicinal chemistry or biology with several years of research experience.”)). Principle of Law When rejecting a claim under the enablement requirement of section 112, the PTO bears an initial burden of setting forth a reasonable explanation as to why it believes that the scope of protection provided by that claim is not adequately enabled by the description of the invention provided in the specification of the application. In re Wright, 999 F.2d 1557, 1561—62 (Fed. Cir. 1993). “[T]he question of undue experimentation is a matter of degree. The fact that some experimentation is necessary does not preclude enablement; what is required is that the amount of experimentation ‘must not be unduly extensive.’” PPG Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558, 1564 (Fed. Cir. 1996). Factors to be considered in determining whether a disclosure would require undue experimentation ... include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Analysis Claims 49—51 The Examiner finds that “the specification, while being enabling for a method of inhibiting Aurora kinase in a cell wherein the cell is a colon, lung or pancreatic cancer cell. . . does not reasonably provide enablement for a method of inhibiting an Aurora kinase in a cell generally” (Final Act. 2 (emphasis added); Ans. 13; see FF1). 9 Appeal 2015-001190 Application 13/757,262 Appellants contend that “the examiner improperly conflates (i) methods of inhibiting Aurora kinase in a cell with (ii) methods of treating proliferative disorders (particularly cancer)” (Reply Br. 2; see App. Br. 4). “[CJlaims 49-51 do not recite methods of treatment, and, so, these claims need not be enabled for treatment” (Reply Br. 3). Appellants direct us to “Table 1 demonstrating numerous compounds according to the claims and structurally similar compounds that all have antiproliferative activity” (Reply Br. 3). After considering the evidence and the arguments, we conclude the weight of the evidence favors Appellants with respect to the limitation of “inhibiting an Aurora kinase in a cell” as claimed. The Specification established that Aurora kinases belong to a family of kinases and provides numerous examples of structurally related compounds that are effective at inhibiting Aurora kinase (FF3 and FF4). All 188 compounds made were initially tested for their inhibition of kinase activity and inhibition of cell growth in two different cell lines (FF3). The Specification also tested a smaller group of the disclosed inhibitors against a more diverse group of cell lines (FF4). We recognize, but do not agree with the Examiner’s position, that evidence in the Specification is such that it could only reasonably be extended to the specific cell types tested. Accordingly, we find that Appellants have sufficiently enabled a method of inhibiting Aurora kinase in cells by contacting the cell with inhibitors within the bounds represented by formula (I) (see claim 49, FF3). We also do not agree with the Examiner’s position that “‘a method of inhibiting Aurora kinase in a celF [means that it] is also associated with a method of treatment of diseases associated with Aurora kinase activity” 10 Appeal 2015-001190 Application 13/757,262 (Ans. 13). In other words, the Examiner’s position is that cells are part of a body and thereby “inhibiting Aurora kinase in a cell” necessarily extends to treating disease. We do not agree with this interpretation because the claim encompasses inhibition of the kinase activity: All that is required to meet the claim is that the kinase is inhibited to some degree; there is no requirement with respect to the extent of inhibition. As pointed out by Appellants, the evidence in the Specification is such that at least one compound falling within the structure of claimed formula (I) was tested in an animal model. Specifically, the Specification used a standard xenograft regression model to first establish tumors in SCID mice using A549 and Colo205 cells (FF5). These mice were then treated with compound 60a and showed tumor regression (FF5). In other words, the model established that a sufficient amount of inhibitor may be administered to an animal and this inhibitor is able to reach the location of the transplanted cells. This is consistent with the art that recognizes that animal models, such as the xenograph regression model, demonstrate that drugs can reach its target in sufficient quantity (FF18). Thus, the Specification provides sufficient evidence to establish that Aurora kinase can be inhibited in a cell. Accordingly, we agree with Appellants’ position that the Specification provides sufficient guidance with respect to “inhibiting Aurora kinase in a cell” as claimed. We reverse the Examiner’s rejection of claims 49—51 because the Specification provides sufficient support to enable inhibition of Aurora kinase in a cell using a compound falling within the bounds of formula (I) as claimed. 11 Appeal 2015-001190 Application 13/757,262 Claims 52 and 53 The Examiner finds that the specification, while being enabling for “a method of treating an Aurora kinase-mediated disease or disorder wherein the disease or disorder is colon, lung or pancreatic cancer, does not reasonably provide enablement for ... a method of treating an Aurora kinase-mediated disease or disorder generally” (Ans. 2 (emphasis added); see FF2). According to the Examiner, the Specification does not provide a “model that correlates the ability of the compounds recited in instant claims . . . to treat the many different types of diseases/disorders encompassed by the instant claims . . . [and therefore,] the specification is not commensurate in scope with the instant claims” (Ans. 7). According to Appellants, “the claims are directed to treatment of Aurora kinase-mediated diseases, not to any diseases or any cancers” (App. Br. 5). Appellants contend that “[t]he scientific literature cited in the present specification establishes that Aurora kinase is (i) involved at the fundamental level of cellular mitosis” (Reply Br. 7). After considering the evidence and the arguments, we conclude the weight of the evidence favors the Examiner’s conclusion that the Specification does not provide sufficient support for the full scope of enablement with respect to the aspect of “treating an[y] Aurora kinase- mediated disease” other than colon, lung or pancreatic cancer identified by the Examiner as being enabled (Ans. 2). We adopt the Examiner’s reasoning as set out in the Answer and Final Office Action mailed January 14, 2014, and agree that the Examiner properly found Appellants’ arguments unpersuasive (see Response to Argument, Ans. 12—21). We provide the following points for emphasis. 12 Appeal 2015-001190 Application 13/757,262 We begin with claim interpretation “treating an Aurora kinase- mediated disease or disorder.” The Specification provides that Aurora- kinase mediated diseases can include any disease or disorder in which one of the kinases are involved (FF7). We, therefore, agree with the Examiner’s position that the claims are broadly drawn to generally treating any Aurora kinase disease or disorder, i.e. a disorder that has Aurora kinase as the mechanism of disease, but the Specification does not support methods of treating diseases other than colon, lung or pancreatic cancer (see Ans. 4 (characterizing Appellant’s claims as reach through claims that “thereby reach through any or all diseases, disorders or medical conditions, for which they lack written description and enabling disclosure in the specification thereby requiring undue experimentation for one of skill in the art to practice the invention”)). As we balance the Wands factors, we find that the Specification is not enabling for the full scope of the claims. The claims are broadly directed to “treating an Aurora kinase-mediated disease or disorder” generally (FF2), but the working examples only demonstrate that Aurora kinase can be inhibited in cell lines and a xenograft model (FF3—FF5). There is no guidance for treating any disease associated with Aurora kinase, other than colon, lung, or pancreatic cancer (FF6—FF8). Furthermore, the state of the prior art is speculative (FF8—FF14), and the cited references provide persuasive evidence with respect to the unpredictability of the art (FF11, FF17, and FF18) and the significant quantity of experimentation needed to practice the invention (FF15—FF19), even when one takes into account the high level of skill of the practitioners in the relevant art (FF20). Balancing 13 Appeal 2015-001190 Application 13/757,262 all these factors supports a finding of lack of enablement with respect to claims 52 and 53. The Specification provides that Aurora kinase belongs to a family of enzymes (FF6), and so far three Aurora kinase enzymes have been discovered (FF12). Aurora kinases are shown to be important regulators of cell division (FF6 and FF9—FF12). However, the Specification only establishes their association with specific types of cancer (FF8; see Ans. 2 (the Examiner finds specifically that methods of treatment are enabled where the “disease or disorder is colon, lung, or pancreatic cancer”)), and this is consistent with what is known in the art that shows Aurora kinase to be involved with cancers (see FF11—FF14). We agree with the Examiner’s position that the working examples provided in the Specification (FF4—FF6) do not provide sufficient guidance for “treating Aurora kinase mediated disease” generally (see Ans. 5 (“the therapeutic role of Aurora kinase inhibitors is very speculative”). The Examiner’s position is that “successful animal tests with human tumor xenografts with cancer X do not predict success in humans with cancer X” (Ans. 7). This is supported by the art that recognizes the benefit of animal models is to establish that the drug can be given to the animal in sufficient quantity that it can reach the target tissue (FF18). Merely reaching the target tissue, however, is not sufficient to establish that the drug will actually treat disease (FF16). The involvement of Aurora kinase A in tumor development has been shown in mice (FF9). Aurora A has also been shown to be overexpressed in human tumors (FF11) and one mechanism of the role in tumor formation is the involvement in the spindle assembly and microtubule organization (see 14 Appeal 2015-001190 Application 13/757,262 FF10—FF12). The art discloses that Aurora kinase is a promising target to develop cancer treatments, and even establishes that some other inhibitors are in clinical trials, however, identifying a promising target is not sufficient to establish that this target will prove successful in practice (FF13 and FF14). The art explains that a reason for the lack of therapeutic success when inhibiting targets, even those that are overexpressed in tumor tissue, is that the “biochemical stoichiometry suggests that it will be more difficult to inhibit the target in diseased tissues than in normal tissues. Hence, normal biology may be more affected by a drug than disease biology leading to adverse events (normal tissue dose-limiting toxicities)” (FF15). The art also recognizes that long term effects of the inhibitors are not known, but can “potentially cause secondary tumor formation” based on the Aurora mouse model (FF11). In other words, there is a potential that the drug can be active against one type of cancer but then actually cause another type of cancer. We agree that the art with respect to Aurora kinases supports the Examiner’s finding that “the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity” (Ans. 9). Thus, when balancing the totality of the evidence based on the Wands factors we find that the weight of the evidence supports the Examiner’s conclusion that the claims are not enabled for the full scope “of treating an Aurora kinase-mediated disease or disorder” as claimed. Accordingly, we affirm the rejection of claims 52 and 53 as not being enabled by the Specification for the full scope as claimed. 15 Appeal 2015-001190 Application 13/757,262 SUMMARY We reverse the rejection of claims 49-51 under 35 U.S.C. § 112, first paragraph as lacking enablement for inhibiting Aurora kinase in a cell. We affirm the rejection of claims 52 and 53 under 35 U.S.C. § 112, first paragraph as lacking enablement treating an Aurora kinase mediated disease or disorder generally. 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-IN-PART 16 Copy with citationCopy as parenthetical citation