Ex Parte Ashworth et al

Patent Trials and Appeals BoardApr 3, 2019

14125185 - (D) (P.T.A.B. Apr. 3, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 14/125,185 03/19/2014 110 7590 04/04/2019 DANN, DORFMAN, HERRELL & SKILLMAN 1601 MARKET STREET SUITE 2400 PHILADELPHIA, PA 19103-2307 Alan Ashworth 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 0380-P05332US01 3786 EXAMINER STONE, CHRISTOPHER R ART UNIT PAPER NUMBER 1628 MAIL DATE DELIVERY MODE 04/04/2019 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 ALAN ASHWORTH, CHRISTOPHER JAMES LORD, RACHEL BROUGH, and JESSICA FRANKUM Appeal2018-000975 Application 14/125, 185 Technology Center 1600 Before JEFFREY N. FREDMAN, JOHN G. NEW, and DAVID COTTA, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1,2 under 35 U.S.C. Â§ 134 involving claims to a method of treating an individual having a Phosphatase and Tensin Homo log (PTEN) mutated or deficient cancer. The Examiner rejected the claims as indefinite and as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b ). We affirm. 1 Appellants identify the Real Party in Interest as The Institute of Cancer Research: Royal Cancer Hospital (see App. Br. 1 ). 2 We have considered and refer to the Specification of Dec. 10, 2013 ("Spec."); Final Office Action of Aug. 22, 2016 ("Final Action"); Appeal Brief of Apr. 4, 2017 ("Br."); and Examiner's Answer of Aug. 8, 2017 ("Ans."). Appeal2018-000975 Application 14/125, 185 Statement of the Case Background "Central to the design of novel therapeutic strategies for cancer is the identification of genes that are critical to the survival of tumor cells but which are largely redundant in normal cells" (Spec. 1: 10-12). "Correlating molecular changes with tumorigenesis has provided one route to the identification of potential drug targets and provides the rationale behind efforts to characterise genetic variation and gene expression in tumors" (id. at 1: 13-16). "[T]he present invention is based on the experiments described herein in which inhibition of a mitotic kinase, such as TTK protein kinase, is effective for the treatment of PTEN mutated or deficient cancer" (id. at 3: 1- 4 ). The Claims Claims 22, 43--46, 48, and 51 are on appeal. 3 Claim 22 is representative and reads as follows: 22. A method of treating an individual having a Phosphatase and Tensin Homolog (PTEN) mutated or deficient cancer, the method comprising administering to the individual a therapeutically effective amount of a mitotic kinase inhibitor said mitotic kinase inhibitor being an inhibitor of TTK protein kinase. The Rejections A. The Examiner rejected claim 51 under 35 U.S.C. Â§ 112, second 3 While Appellants filed an After-Final response that cancelled claim 51, the Examiner did not indicate that the Amendment was entered in an Advisory Action, so we treat the indefiniteness rejection as still pending consistent with the Examiner's statement in the Answer (see Ans. 2). 2 Appeal2018-000975 Application 14/125, 185 paragraph (Final Act. 3) B. The Examiner rejected claims 22, 43--46, and 48 under 35 U.S.C. Â§ I03(a) as obvious over Song,4 Cui, 5 and Reinhard6 (Final Act. 4--5). A. 35 US.C. Â§ 112, second paragraph Appellants do not argue this rejection in the Appeal Brief. Because the Examiner stated that rejections written in the Final Action are maintained (see Ans. 2), we summarily affirm the rejection. See Manual of Patent Examining ProcedureÂ§ 1205.02 ("If a ground of rejection stated by the examiner is not addressed in the appellant's brief, that ground of rejection will be summarily sustained by the Board."); See also In re Berger, 279 F.3d 975, 984 (Fed. Cir. 2002) (in which the Board affirmed an uncontested rejection of claims under 35 U.S.C. 112, second paragraph, and on appeal the Federal Circuit affirmed the Board's decision and found that the appellant had waived his right to contest the indefiniteness rejection by not presenting arguments as to error in the rejection on appeal to the Board). B. 35 US.C. Â§ 103(a) as obvious over Song, Cui, and Reinhard The Examiner finds that Song teaches "PTEN null cancer cells, including PC3 prostate cancer cells, are highly sensitive to inhibition of mitotic kinase targets of APC-CDHI" (Final Act. 4). The Examiner finds 4 Song et al., Nuclear PTEN Regulates the APC-CDHl Tumor-Suppressive Complex in a Phosphatase-Independent Manner, 144 Cell 187-99 (2011 ). 5 Cui et al., Degradation of the Human Mitotic Checkpoint Kinase Mpsl Is Cell Cycle-regulated by APC-ccdc20 and APC-ccdhI Ubiquitin Ligases, 285 J. Biol. Chem. 32988-98 (2010). 6 Reinhard et al., US 2003/0045491 Al, published Mar. 6, 2003. 3 Appeal2018-000975 Application 14/125, 185 that Song teaches "the combination of such Aurora kinase inhibitors and other anticancer therapies, e.g. PI3K/mTOR inhibitors, may useful in the treatment of such cancers" (id. at 5). The Examiner acknowledges that Song "does not expressly teach TTK as the particular mitotic kinase target of APC-CDHl to be inhibited" (id.). The Examiner finds that Cui teaches "TTK is a mitotic kinase target of APC-CDHl" and that Reinhard teaches "small molecule inhibitors of TTK are useful in the treatment of cancer" (Final Act. 5). The Examiner finds that it would have been obvious to use a small molecule TTK inhibitor as the particular inhibitor of a mitotic kinase target of APC-CDHl in the treatment of PTEN null cancers, since TTK was known to be a mitotic kinase target of APC-CDHl, such inhibitors were known to be useful in the treatment of PTEN null cancers, and small molecule inhibitors of TTK were known to be useful in the treatment of cancer. (Final Act. 5). The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner's conclusion that Song, Cui, and Reinhard suggest treatment of a PTEN type cancer using an inhibitor of TTK protein kinase as required by claim 22? Findings of Fact 1. Song teaches "PTEN (phosphatase and tensin homolog) is among the most frequently lost or mutated tumor suppressors" (Song 187, col. 1 ). Song teaches that: Cell-cycle progression is controlled by ubiquitination-mediated proteolysis of cell-cycle machinery. The two major E3 ubiquitin ligases controlling this process are SCP (Skp 1/Cullin/F-box protein complex) and APC/C (anaphase-promoting complex/ 4 Appeal2018-000975 Application 14/125, 185 cyclosome) ... APC/C contains at least 11 different structural subunits, and its activity is controlled through the binding of CDC20 and CDHl, which recognize and recruit specific substrates. (Song 187, col. 2). 2. Song teaches that "APC-CDHl substrates, such as Cyclin A, PLKl, Aurora A, CDC20, or SKP2, are overexpressed in human tumors and are associated with chromosomal instability and poor prognosis" (Song 188, col. 1 ). 3. Song teaches "we demonstrate that nuclear PTEN directly enhances the activity of APC/C by promoting its association with CDHl. Conversely, PTEN loss impairs the activity of the APC-CDHl tumor- suppressive complex. Critically, PTEN activates APC-CDHl in a phosphatase-independent manner, an observation that has important implications for cancer therapy" (Song 188, col. 2). 4. Song teaches "[i]nhibition of APC-CDHl targets, such as PLKl or Aurora kinases, has been pursued as a therapeutic modality to treat human cancers due to the fact that APC-CDHl activity is reduced in tumors" (Song 195, col. 1 ). 5. Song teaches "PLKl inhibitors as well as Aurora A inhibitors are currently being evaluated as anticancer agents" (Song 195, col. 1). 6. Song teaches "our study indicates that patients with cancers harboring complete PTEN loss may benefit from pharmacological targeting of the APC-CDHl pathway, whereas we predict mutant PTEN tumors to be much less sensitive" (Song 196, col. 2 to 197, col. 1 ). 5 Appeal2018-000975 Application 14/125, 185 7. Song teaches "it is tempting to speculate that combinatorial therapy with PLKI/ Aurora kinases and PI3K/mTOR inhibitors may be an effective approach in PTEN null cancers" (Song. 197, col. 1 ). 8. Cui teaches the "monopolar spindle 1 (Mpsl), also called TTK, is a conserved dual specificity protein kinase" (Cui 32988, col. 2). 9. Cui teaches that "our results suggest that the sequential actions of the APC-ccdc20 and APC-ccdhl ubiquitin ligases regulate the clearance of Mpsl levels and are critical for Mpsl functions during the cell cycle in human cells" (Cui 32988, abstract). 10. Reinhard teaches "methods of inhibiting tumor growth by inhibiting activity of TTK" (Reinhard, abstract). 11. Reinhard teaches that "TTK is a human homologue of the S. cerevesiae kinase mpsl and the S. pombe protein mphl, both of which are involved in cell cycle spindle assembly checkpoint, thus indicating that TTK is a spindle checkpoint gene" (Reinhard ,r 4). 12. Reinhard teaches using "small molecule or other compound[s] identified as modulating activity of TTK, preferably decreasing TTK activity .... Therapeutic effects also include reduction in physical symptoms, such as decreased body temperature, and/ or in the effect upon tumor load in the subject (e.g., decrease in tumor size or inhibition in tumor growth)" (Reinhard ,r 148). Principles of Law "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). Analysis 6 Appeal2018-000975 Application 14/125, 185 We adopt the Examiner's findings regarding the scope and content of the prior art (Final Act. 4--5) and agree with the conclusion that the method of claim 22 would have been obvious in view of Song, Cui, and Reinhard (FF 1-12). We address Appellants arguments below. Appellants contend it was incumbent upon the Examiner to show that the cited prior art would have (a) suggested to one of ordinary skill in the art the treatment of PTEN mutated or deficient cancer using an inhibitor of TTK protein kinase, and (b) provided a reasonable expectation that the administration of such an inhibitor in a therapeutically effective amount to an individual having PTEN mutated or deficient cancer would be successful. The prior art of record fails on both counts. (App. Br. 4). We find this argument unpersuasive because Song teaches that in PTEN cancers, the PTEN tumor suppressor is associated with cellular components termed APC/C or APC-CDHl (FF 1, 3) and that these APC components are themselves associated with tumors and poor cancer prognosis (FF 2-3). Song explains that inhibitors of APC components are under development as cancer treatment agents (FF 4--6) and that these inhibitors "may be an effective approach in PTEN null cancers" (FF 7). Thus, Song demonstrates that inhibitors of APC are desirable as treatment agents for some PTEN based cancers (FF 1-7). Cui teaches that TTK (also called MPS) partners with APC components in the cell cycle process (FF 8-9). Reinhard teaches that inhibiting TTK inhibits tumor growth (FF 10) and is involved in cell cycle (FF 9, 11 ). Reinhard suggests pharmaceutical compositions that inhibit TTK (FF 12). 7 Appeal2018-000975 Application 14/125, 185 Reinhard and Cui therefore provide a linkage between TTK and APC, cell cycle components that were known to interact with one another, where inhibitors of TTK and APC are both identified as treating tumors, and provide support for the Examiner's position that it would have been obvious for "one of ordinary skill to look to the prior art ( e.g. Cui et al) for additional pro-proliferation targets of APC-CDHl, e.g. the mitotic kinase TTK, for inhibition in the treatment of PTEN null cancers" (Ans. 6). That is, Cui demonstrates that TTK is an APC target because APC regulates TTK (FF 9) and because Song teaches inhibitors of APC targets are desirable treatments of PTEN null tumors (FF 4--5), the ordinary artisan would have had reason to select TTK inhibitors, particularly because Reinhard separately teaches the use of such inhibitors to treat cancer (FF 10-12). Appellants contend: Conspicuously missing from the disclosure of Song is any indication of the results of the clinical testing conducted to assess the anticancer efficacy of AURORA/PLKl inhibitors. In the absence of positive results, it cannot reasonably be maintained, as the examiner essentially has, that inhibition of specific APC/C substrates, such as mitotic kinases that mediate cell-cycle progression, would result "in the practice of the instantly claimed invention with a reasonable expectation of success". (App. Br. 5). We find this argument unpersuasive because there would have been a reasonable expectation of success based on Song's guidance to treat PTEN tumors with inhibitors of APC signaling molecules (FF 1, 4, 7), Cui's teaching that TTK is a signaling molecule regulated by APC (FF 9), and Reinhard's teaching that TTK inhibitors treat cancer (FF 10-11). We note that Reinhard teaches pharmaceutical compositions for inhibiting TTK (FF 8 Appeal2018-000975 Application 14/125, 185 12) for treatment of cancer (FF 10) and the Specification acknowledges a variety of TTK inhibitors were known in the prior art (see Spec. 8:25 to 9:6). "Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success." In re Kubin, 561 F.3d 13 51, 13 60 (Fed. Cir. 2009). Moreover, "conducting clinical trials to test for an optimal dose for a drug 'is generally a routine process[']." Eli Lilly and Co. v. Teva Pharmaceuticals USA, Inc., 619 F.3d 1329, 1342 (Fed. Cir. 2010). Appellants have provided no persuasive evidence demonstrating unpredictability in treatment of PTEN tumors with TTK inhibitors, and the "case law is clear that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Appellants contend: "Song fails to expressly teach TTK as the particular mitotic kasine target of APC-CDHl to be inhibited" (App. Br. 5); "Cui makes no reference to the treatment of PTEN mutated or deficient cancer" (App. Br. 6); and "the examiner's proposal to modify Song in view of Cui is simply a matter of hindsight reconstruction of the appellant's method, based essentially on a single sentence from Cui" (App. Br. 6-7). We find these arguments unpersuasive. While we are fully aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), Appellants point to no findings of fact made by the Examiner that relied upon knowledge gleaned only from Appellants' Specification. Consequently, Appellants' argument that the Examiner impermissibly relied upon hindsight analysis is not persuasive. See In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Furthermore, 9 Appeal2018-000975 Application 14/125, 185 we are also mindful that the Supreme Court has clearly stated that the "combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR, 550 U.S. at 416. In the present case, the Examiner provides a specific reason to select TTK as a target, stating that Song teaches PTEN null cancers are highly sensitive to inhibition of mitotic kinase targets of APC-CDHl by small molecule drugs (abstract), thus motivating one of ordinary skill to look to the prior art ( e.g. Cui et al) for additional pro-proliferation targets of APC-CDHl, e.g. the mitotic kinase TTK, for inhibition in the treatment of PTEN null cancers. (Ans. 6). We agree with the Examiner that based on Song's teaching to treat PTEN tumors with kinase inhibitors associated with APC, Cui' s teaching that TTK is a kinase associated with TTK, and Reinhard's teaching that TTK inhibitors treat tumors, the ordinary artisan would have had reason to apply TTK inhibitors to PTEN tumors (FF 1-12). Appellants contend "[a]s for Reinhard, its disclosure plainly fails to compensate for the fundamental deficiencies noted above in the combined teachings of Song and Cui" (App. Br. 7). Appellants also contend that "the Examiner is mistaken in asserting that Appellants are 'attacking references individually where the rejections are based on combinations of references"' (App. Br. 8). We do not find this argument persuasive for every argument. While some of Appellants arguments, addressed above, are detailed (if unpersuasive), there are specific arguments, such as the argument above regarding Reinhard, that fail to address the combined teachings of the references. "Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a 10 Appeal2018-000975 Application 14/125, 185 combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Appellants contend "[n]otably, the subject matter of Reinhard's claims 1-7, drawn to a method of reducing growth of a cancerous cell, was found, upon examination, to be non-enabled" (App. Br. 8). We do not find this argument persuasive for two reasons. First, even if we accepted Appellants' position that Reinhard's claims were not enabled, that does not demonstrate that Reinhard's Specification, as opposed to the specific claims, was not enabled. Appellants have provided no specific evidence of their own demonstrating the nonenablement of Reinhard for the material relied upon by the instant Examiner. See In re Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir. 2012) ("[W]e therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling.") Second, a review of the continuity data of Reinhard's 10/081,119 application shows that four patents, US 7,501,242, US 7,501,243, US 7,501,244, and US 7,867,731 issued as divisionals or as a continuation-in-part, respectively. Conclusion of Law A preponderance of the evidence of record supports the Examiner's conclusion that Song, Cui, and Reinhard suggest treatment of a PTEN type cancer using an inhibitor of TTK protein kinase as required by claim 22. 11 Appeal2018-000975 Application 14/125, 185 SUMMARY We affirm the rejection of claim 51 under 35 U.S.C. Â§ 112, second paragraph. We affirm the rejection of claim 22 under 35 U.S.C. Â§ 103(a) as obvious over Song, Cui, and Reinhard. Claims 43--46 and 48 fall with claim 22. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ 1.136(a). AFFIRMED 12