Ex Parte Ben-Neriah et alDownload PDFPatent Trial and Appeal BoardDec 14, 201612994856 (P.T.A.B. Dec. 14, 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. 12/994,856 11/28/2010 Yinon Ben-Neriah 50016 6399 67801 7590 12/16/2016 MARTIN D. MOYNIHAN d/b/a PRTSI, INC. P.O. BOX 16446 ARLINGTON, VA 22215 EXAMINER MCDONALD, JENNIFER SUE PITRAK ART UNIT PAPER NUMBER 1674 NOTIFICATION DATE DELIVERY MODE 12/16/2016 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): usptomail@ipatent.co.il PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte YINON BEN-NERIAH, ELA ELYADA and ARIEL PRIBLUDA Appeal 2015-008199 Application 12/994,856 Technology Center 1600 Before DEMETRA J. MILLS, TIMOTHY G. MAJORS, and RACHEL H. TOWNSEND, Administrative Patent Judges. MILLS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35U.S.C. § 134. The Examiner has rejected the claims for anticipation and obviousness. We have jurisdiction under 35 U.S.C. § 6(b). Appeal 2015-008199 Application 12/994,856 STATEMENT OF CASE According to the Specification, the present invention provides a method of treating or preventing a cancer associated with a mutation in APC [Adenomatous polyposis coli] for onset and/or progression, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of CKI, said CKI being selected from the group consisting of CKIa and CKI8, thereby treating or preventing the cancer associated with a mutation in APC. Spec. 4. “The present inventors conclude that the APC+/mm mutation is incompatible with CKIa deficiency and the double mutation is synthetically lethal in intestinal epithelial cells.” Spec. 13. On the basis of these observations the present inventors suggest that CKIa inhibition may eradicate intestinal epithelial cells harboring APC mutations, particularly APC-mutated tumors, without significantly compromising the normal gut epithelium and as such the present inventors propose that CKIa inhibitors may be used for the treatment of cancers associated with same. Id. CLAIM The following claim is representative. 1. A method of preventing colorectal cancer in a subject having a mutation in an Adenomatous polyposis coli (APC) gene, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of Casein kinase I (CKI), said CKI being selected from the group consisting of CKIa and CKI8, thereby preventing the colorectal cancer. 2 Appeal 2015-008199 Application 12/994,856 Grounds of Rejection Claims 1, 6, 7, and 9-11 are rejected under 35 U.S.C. § 102(b) as being anticipated by Ben-Neriah.1 Claims 1, 6, 7, and 9-11 are rejected under 35 U.S.C. § 103(a) as being unpatentable over Ben-Neriah and Zhao.2 FINDINGS OF FACT The Examiner’s findings of fact are set forth in the Final Action at pages 2—7. The following facts are highlighted. 1. According to the Specification, Examples of APC mutations are for instance those which cause truncation of the APC product. Typically mutations occur in the first half of the coding sequence, and somatic mutations in colorectal tumors are further clustered in a particular region, called MCR (mutation cluster region). List of APC mutations involved in human disease are provided in OMIM, ww.ncbi.nlm.nih.gov/omim/. Spec. 13-14. 2. According to the Specification, Deregulation of the canonical Wnt signal leads to various cancers, among which is colorectal carcinoma (CRC), hepatocellular carcinoma (HCC) and melanoma. In such cancers, one or more Wnt component is often mutated, resulting in aberrant accumulation of nuclear P-catenin. This explains the requirement for tight regulation on P-catenin levels in the cell. 1 Ben-Neriah et al., US 2005/0171005 Al, published Aug. 4, 2005. 2 Zhao et al., WO 2005/046726 Al, published May 26, 2005. 3 Appeal 2015-008199 Application 12/994,856 The mechanism by which P-catenin is phosphorylated and degraded has been revealed only recently, emphasizing significant players in the Wnt signaling pathway. The P-catenin degradation complex consists of the Adenomatous polyposis coli (APC) tumor suppressor, Axinl or Axin2 ..., and of two Serine/Threonine kinases: Casein kinase I (CKI) and Glycogen synthase kinase-3 (GSK3), which phosphorylate P-catenin on four N-terminal Ser/Thr residues. This event marks P-catenin for ubiquitination by the SCF(vl r( P E3 ubiquitin ligase and subsequent proteasomal degradation. It has been shown lately that the first phosphorylation event is mediated by CKI, which phosphorylates Ser45 of P-catenin. This creates a priming site for GSK3, which subsequently phosphorylates Thr41, Ser37 and Ser33. The last two residues, when phosphorylated, serve as a docking site for the E3 ligase P-TrCP, which marks P- catenin for degradation. Spec. 1—2 (emphasis added). 3. APC is a colon-specific tumor suppressor gene. The APC protein is a key regulator of the Wnt pathway. APC tumor suppressor has been shown to participate in several cellular processes including cell cycle regulation, apoptosis, cell adhesion, cell migration, signal transduction, microtubule assembly and chromosomal segregation. However, despite the fact that each of these roles are potentially linked to cancer, it appears that the tumor suppressing function of APC resides primarily in its capacity to properly regulate P-catenin. This effect takes place in two major posttranslational levels, enhancing P-catenin degradation and exporting it from the nucleus. In the absence of functional APC, P-catenin is stabilized and accumulates in the nucleus where it associates with members of the TCF/LEF family transcriptional activators, thus modulating transcription of Wnt target genes. Recent evidence also implicates APC in a nuclear role, suppressing P- catenin-mediated transcription by forming a repression complex on the DNA, thus giving it a third aspect of Wnt regulation. 4 Appeal 2015-008199 Application 12/994,856 Spec. 3. 4. The P-catenin degradation complex consists of the Adenomatous polyposis coli (APC) tumor suppressor, Axinl or Axin2 ..., and of two Serine/threonine kinases: Casein kinase I (CKI) and Glycogen synthase kinase-3 (GSK3), which phosphorylate P-catenin on four N-terminal Ser/Thr residues. Both CKIa and APC are noted to play a role in Wnt signaling and mitotic spindle regulation. Spec. 12. 5. [MJutant APC locus results in deregulation of the Wnt/p-catenin pathway, with excessive proliferation and tumorigenesis, heterozygous expression of both wild-type and truncated APC protein is compatible with normal life span, differentiation and function of the epithelial cells. Spec. 48. 6. The inventors hypothesized that, “[i]f CKIa deficiency sensitizes APC+/mm cells to apoptosis and p53-mediated cell growth arrest, then adenoma formation should be reduced in double mutants.” Spec. 49. 7. The inventors concluded that, “de novo APC+/mm microadenomas do not tend to appear on a CKIa negative [inhibited] background and suggest a synthetic lethality between CKIa deletion and APC+/mm mutation.” Id. PRINCIPLES OF LAW In making our determination, we apply the preponderance of the evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427 5 Appeal 2015-008199 Application 12/994,856 (Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings before the Office). In order for a prior art reference to serve as an anticipatory reference, it must disclose every limitation of the claimed invention, either explicitly or inherently. See In re Schreiber, 128 F.3d 1473 (Fed. Cir. 1997). Anticipation Rejection We do not find that the Examiner has provided evidence to support a prima facie case of anticipation. Ben-Neriah discloses modulators of P-catenin phosphorylation. More specifically, Ben-Neriah provides inhibitors and enhancers of P-catenin Serine 45 (S45) phosphorylation. Abstract. The Examiner finds that Ben- Neriah discloses and/or claims 1. A modulator of .beta.-catenin Serine 45 (S45) phosphorylation. 2. The modulator of claim 1, wherein said modulator is an inhibitor of .beta.-catenin S45 phosphorylation. 3. The modulator of claim 2, wherein said inhibitor is selected from any one of the proteins Dishevelled (Dvl), a Wnt protein and phosphatase PP2A. 4. The modulator of claim 2, wherein said inhibitor is a CKI inhibitor. 5. The modulator of claim 4, wherein said inhibitor is CKI7. 20. A pharmaceutical composition comprising a modulator of .beta.-catenin as defined in claim 1, for use in the treatment of cancerous cells wherein .beta.-catenin is stabilized and its phosphorylation is impaired. 21. The pharmaceutical composition of claim 20, wherein said cancerous cells are derived from any one of colorectal adenoma and colorectal carcinoma. 6 Appeal 2015-008199 Application 12/994,856 As is evident from the above claims, CKI7, a small molecule inhibitor, is a modulator of P-catenin that is claimed as useful for treating colorectal cancer. CKI7 is a species of the genus of compounds claimed in the instant claim 1. Ans. 4—5. Appellants contend that Ben-Neriah does not disclose CKI inhibitors for the treatment or prevention of colorectal cancer. Despite the fact that Ben-Neriah broadly claims any agent which modulates P-catenin phosphorylation for the treatment of cancer, there is no unambiguous delineation of treating colorectal carcinoma with an inhibitor of Casein kinase la. Furthermore, the specification of Ben-Neriah (paragraph 117) clearly teaches that for the treatment of colorectal carcinoma, P-catenin should be destabilized. Since phosphorylation of P-catenin directly leads to its degradation, Ben-Neriah teaches enhancement of phosphorylation of f- catenin for the treatment of colorectal carcinoma. Since CKI inhibitors act to reduce phosphorylation off-catenin, clearly Ben-Neriah did not conceive of CKI inhibitors for the treatment of colorectal carcinoma. Reply Br. 2 (emphasis added); see also App. Br. 5—6. We are persuaded by Appellants’ arguments. The pending method claims require that the subject have a mutation in an Adenomatous polyposis coli (APC) gene and a method step of administering to the subject a therapeutically effective amount of an inhibitor of Casein kinase I (CKI). 7 Appeal 2015-008199 Application 12/994,856 (Claim 1.) Inhibition of CKIa3 or CKIS reduces phosphorylation of P-catenin. Ben-Neriah 144. Ben-Neriah particularly discloses that The vast majority of colorectal tumors contain mutations in the APC gene, whose product has been shown to be involved in P-catenin phosphorylation. Colorectal tumors lacking an APC mutation are very likely to have a mutation in the P-catenin gene, affecting phosphorylation sites. Interestingly, most of P-catenin mutations found in human cancers are located between serine 29 (S29) and lysine 49 (K49), a region rich in phosphorylation sites and which is also involved in P-catenin degradation. 1121 (emphasis added). Ben Neriah discloses that The strong correlation between a defective P-catenin phosphorylation pathway and tumor formation (and progression), has made this pathway a focal point for therapy. Restoring P-catenin phosphorylation should halt the cancerous process. There are indications that induced destabilization of P-catenin triggers the death of cancerous cells 1122 (emphasis added). Ben-Neriah further discloses that By inhibiting the PP2A phosphatase, okadaic acid or a similar agent can be useful in inducing the axin-CKI phosphorylation activity, resulting in enhanced P-catenin degradation in APC- mutated colon cancer and possibly in other tumors. This is because overexpression of axin in APC- or axin mutated cells can drive P-catenin degradation . . . and tumor apoptosis .... 3 Zhao teaches that CKI7 and polynucleotide inhibitors of CKIa are equivalent means by which to inhibit CKIa. Zhao, p. 10; Ans. 6. 8 Appeal 2015-008199 Application 12/994,856 By augmenting the activity of endogenous axin, okadaic acid would induce the apoptosis of the tumor. Therefore, compounds that facilitate [f-catenin] S45 phosphorylation will be useful as anti-cancer agents. 197 (emphasis added), see also Abstract, 113. Thus, Ben-Neriah principally addresses colorectal tumors lacking an APC mutation (with a mutation in the P-catenin gene), and suggests to facilitate or enhance phosphorylation of P-catenin. 11121, 129. Ben-Neriah, in multiple locations, suggests that, in APC mutated colon cancers, one of ordinary skill in the art should look to compounds that facilitate phosphorylation of P-catenin. See, e.g., 1129. Conspicuously absent is any mention in the Ben-Neriah Specification of inhibiting phosphorylation of P- catenin in order to treat colon cancers. When the Ben-Neriah Specification discusses inhibiting phosphorylation of P-catenin it is with reference to malignant melanoma: “in malignant melanomas for example, it is desirable to inhibit its phosphorylation in order to block the transcriptional activation of downstream targets that are potential oncogenes.” 1129. On the other hand, the claimed invention deals particulary with APC mutated subjects and seeks to inhibit CKIa or CKI8 and therefore to reduce phosphorylation of P-catenin. Reply Br. 2. We find no specific, anticipatory disclosure in Ben Neriah of treating or preventing cancer in APC subjects by administering CKIa or CKIS inhibitors, and therefore to reduce phosphorylation of P-catenin. On balance, we do not find that the evidence of record supports the Examiner’s prima facie case of anticipation and the anticipation rejection is reversed. 9 Appeal 2015-008199 Application 12/994,856 Obviousness Rejection The Examiner finds that Ben-Neriah does not teach that the CKI inhibitors useful in the methods of treating or preventing colorectal cancer include polynucleotide inhibitors. Zhao teaches methods of treating or preventing cancer comprising administering a CKIa inhibitor, wherein the inhibitors include CKI-7 and polynucleotide inhibitors (claims 16, 18; page 14, line 10 to page 22, line 34; page 22, lines 11- 15). It would have been obvious to one of ordinary skill in the art at the time the invention was made to inhibit CKIa for the treatment or prevention of cancer because both the Ben-Neriah and Zhao references teach such methods. Final Act. 6. In view of the discussion with respect to rejection 1, we do not find that Zhao overcomes the deficiencies of Ben-Neriah. The obviousness rejection is reversed. CONCLUSION OF LAW The preponderance of the evidence does not support the Examiner’s anticipation and obviousness rejections, which are reversed. REVERSED 10 Copy with citationCopy as parenthetical citation