Ex Parte YAMANAKA et alDownload PDFPatent Trial and Appeal BoardSep 17, 201813942208 (P.T.A.B. Sep. 17, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/942,208 07/15/2013 23460 7590 09/19/2018 LEYDIG VOIT & MA YER, LTD TWO PRUDENTIAL PLAZA, SUITE 4900 180 NORTH STETSON A VENUE CHICAGO, IL 60601-6731 FIRST NAMED INVENTOR Shin ya YAMANAKA 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. 713544 3588 EXAMINER WILSON, MICHAEL C ART UNIT PAPER NUMBER 1632 NOTIFICATION DATE DELIVERY MODE 09/19/2018 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): Chgpatent@leydig.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SHINY A YAMANAKA, KAZUTOSHI TAKAHASHI, and KEISUKE OKITA1 Appeal2017-009825 Application 13/942,208 Technology Center 1600 Before ULRIKE W. JENKS, JOHN G. NEW, and TIMOTHY G. MAJORS, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants identify Kyoto University as the real party-in-interest. App. Br. 1. Appeal2017-009825 Application 13/942,208 SUMMARY Appellants file this appeal under 35 U.S.C. § I34(a) from the Examiner's Final Rejection of claims 1-11, 13, and 14 as unpatentable under 35 U.S.C. § I03(a) as being obvious over the combination of P. Mali et al., Improved Efficiency and Pace of Generating Induced Pluripotent Stem Cells from Human Adult and Fetal Fibroblasts, 26(8) STEM CELLS, 1998-2005 (2008) ("Mali"), M. Dobbelstein et al., The Large T Antigen of Simian Virus 40 Binds and Inactivates p53 but not p73J, 79 J. GENERAL VIROL., 3079-83 (1998) ("Dobbelstein"), T. Bowman et al., Tissue-Specific Inactivation of P53 Tumor Suppression in the Mouse, IO GENES DEV. 826-35 (1996) ("Bowman"), A. Willis et al., Mutant p53 Exerts a Dominant Negative Effect by Preventing Wild-Type P53 from Binding to the Promoter of its Target Genes, 23 ONCOGENE, 2330-38 (2004) ("Willis"), O'Neill (US 2007 /0006332 Al, January 4, 2007) ("O'Neill '332"), and O'Neill (US 2007/0254309 Al, November 1, 2007) ("O'Neill '309"). Claims 1-11, 13, and 14 also stand rejected as unpatentable under the nonstatutory doctrine of obviousness-type double patenting over claims 1-9 of Yamanaka et al. (US 8,530,238 B2, September 10, 2013) ("the '238 patent"). 2 We have jurisdiction under 35 U.S.C. § 6(b ). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants' invention is directed to an in vitro method of improving the efficiency of establishment of induced pluripotent stem ("iPS") cells. The method 2 The Examiner also rejected the claims under 35 U.S.C. § 112, first paragraph as lacking enablement. Final Act. 4. The Examiner has withdrawn this rejection. Ans. 2. 2 Appeal2017-009825 Application 13/942,208 comprises contacting an isolated somatic cell being reprogrammed into an iPS cell with an inhibitor of p53 function. Abstract. REPRESENTATIVE CLAIM Claim 1 is representative of the claims on appeal and recites: 1. An in vitro method of improving the efficiency of establishment of an induced pluripotent stem (iPS) cell, comprising contacting an isolated somatic cell being reprogrammed into an iPS cell with an inhibitor of p53 function selected from the group consisting of: (a) a dominant negative mutant of p53 or a nucleic acid that encodes the same, and (b) murine double minute 2 (MDM2) or a nucleic acid that encodes the same, wherein the somatic cell is reprogrammed by contacting the somatic cell with nuclear reprogramming substances or nucleic acids encoding the nuclear reprogramming substances comprising the substances selected from the group consisting of: (i) Oct3/4 and Sox2, (ii) Oct3/4, Klf4 and Sox2, (iii) Oct3/4, Klf4, Sox2 and c-Myc, (iv) Oct3/4, Sox2 and Lin28, (v) Oct3/4, Sox2, Lin28 and Nanog, (vi) Oct3/4, Sox2 and Nanog, and (vii) nucleic acids encoding the nuclear reprogrammmg substances (i), (ii), (iii), (iv), (v), and (vi). 3 Appeal2017-009825 Application 13/942,208 App. Br. 13. ISSUES AND ANALYSES We adopt the Examiner's findings of fact, reasoning, and conclusions that the appealed claims are obvious over the combined cited prior art. We address the arguments raised by Appellants below. A. Rejection of claims 1-11, 13, and 14 under 35 U.S.C. § 103(a) Issue 1 Appellants argue that the Examiner erred because the combination of references relied upon by the Examiner to support the obviousness rejection does not teach or suggest the present invention. App. Br. 6. Analysis The Examiner finds that Mali teaches improving the production of induced pluripotent stem ("iPS") cells by adding SV40 large T antigen to either set of four known reprogramming factors, specifically Oct4, Klf4, Sox2, and cMyc, SV40. Final Act. 16. The Examiner finds that Mali teaches that it was known in the art that SV 40 large T antigen inhibits p53 function. Id. ( citing Mali 2003) ("T simultaneously disables the retinoblastoma and p53 tumor suppressor pathways"); see also Dobbelstein Abstr. ). The Examiner finds that Mali does not teach inhibiting p53 using (i) a dominant negative mutant of p53 or a nucleic acid that encodes the same, (ii) PFT- a, PFT-13, or analogs thereof; or (iii) MDM2 or a nucleic acid that encodes the same, into contact with a somatic cell. Final Act. 16. However, the Examiner finds that Willis teaches that dominant negative mutants of p53 were known to 4 Appeal2017-009825 Application 13/942,208 inhibit p53 function; specifically, the p53DD dominant negative p53 mutant described by Bowman. Id. The Examiner also finds that it was well known in the art to specifically target p53 to maintain pluripotency, as taught by O'Neill '332, O'Neill '309, and also by O'Neill (US 7,695,426 B2, April 13 2010) ("O'Neill '426"). The Examiner finds, by way of example, that O'Neill '426, expressly teaches using p53 inhibitors for making embryonic stem cell lines. Id. ( citing O'Neill '426 col. 11, 11. 9, 37, 60). The Examiner concludes that it would have been obvious to those of ordinary skill in the art to improve iPS production by inhibiting p53, as described by Mali, and especially by an inhibitor of p53 that is a dominant negative p53 mutant, as described by Willis, and specifically the p53DD mutant, as described by Bowman. Final Act. 16-17. The Examiner further concludes that a person of ordinary skill in the art would have been motivated to replace SV 40 large T antigen of Mali with the p53DD dominant negative p53 mutant of Bowman, because Bowman teaches that p53DD was specific to inactivating p53 while simultaneously keeping active the Rb-family proteins, and because overexpression of p53DD did not result in abnormalities. Id. at 17 (citing Bowman 828, 832, Figs. 2A-B). Appellants argue that Mali teaches the use of the SV40 large T antigen, which inhibits p53 function as well as other targets, but which is not a p53 inhibitor as required by the claims [i.e., a dominant negative mutant of p53, murine double minute 2 ("MDM2") or their corresponding nucleic acids]. App. Br. 6. Appellants contend that, although Willis and Bowman disclose the specific p53 inhibitors required by the claims on appeal, a person of ordinary skill in the art would not have had reason to replace the SV 40 large T antigen of Mali, with the p53 inhibitors taught by Willis or Brown. Id. Appellants dispute the Examiner's 5 Appeal2017-009825 Application 13/942,208 finding that a person of ordinary skill would reason that another p53 inhibitor, regardless of other characteristics, could be substituted for the SV 40 large T antigen to improve iPS cell induction. Id. Appellants enlarge upon this argument, contending that, although SV40 large T antigen inhibits p53, there are other targets of the SV40 large T antigen. App. Br. 6. In support of that argument, Appellants assert that Mali teaches that the SV40 large T antigen "simultaneously disables the retinoblastoma and p53 tumor suppressor pathways and alters other cellular targets." Id. (quoting Mali 2003). Furthermore, argue Appellants, the SV40 large T antigen also targets in addition to p53, HSC70, retinoblastoma (Rb)-family proteins such as pRB, pl 07, and p 130, p300, and Bub 1. Id. Therefore, Appellants assert, SV 40 large T antigen is not a p53- specific inhibitor and exerts pleiotropic effects within a cell. Id. Appellants argue further that Mali neither teaches nor suggests which, if any, of the multiple phenotypic effects of the SV 40 large T antigen are important to improve the efficiency of establishing iPS cells, let alone the effect on p53 function. App. Br. 7. Appellants contend that Dobbelstein, which is relied upon by the Examiner as disclosing that the SV 40 large T antigen is known to inhibit p53 as opposed to p75, merely teaches that p75 is not a target of the SV40 large T antigen. Id. Appellants assert that, even ifDobbelstein teaches that the SV40 large T antigen was known to inhibit p53, such a teaching does not change the fact that the SV 40 large T antigen has other characteristics, including, but not limited to the inhibition of p53 function, and that Mali does not teach or suggest which of the characteristics is important for carrying out the method disclosed in Mali. Id. Therefore, Appellants argue, a person of ordinary skill in the art-even if that person were interested for some reason in substituting another substance for SV40 6 Appeal2017-009825 Application 13/942,208 large T antigen-would not know to select a substance that inhibits p53 function, let alone one of the particular p53 inhibitors specified in the appealed claims, as opposed to a substance with one or more of the other characteristics of the SV 40 large T antigen. Id. at 8. With respect to the O'Neill references, Appellants argue that references are directed to means to enhance the viability of embryos. App. Br. 8. In particular, assert Appellants, O'Neill '426 describes the enhancement of viability of an embryo having a p53 loss-of-function, the enhancement of viability of an embryo by a chemical inhibitor of p5 3 (PFT-a ), and the enhancement of viability of an embryo using p53 siRNA. Id. (citing O'Neill '426 Examples 4(A), 4(B), 8, Fig. 3, 5). According to Appellants, O'Neill '309 teach methods to assess embryo viability including measuring levels of a marker that is indicative of the viability of the embryo; the marker can be p53, Cavl.2, or catalase. Id. at 8-9 (citing O'Neill '309 ,r,r 9-18). Therefore, Appellants assert, the teachings of the O'Neill references are not relevant to the method of Mali. Id. at 9. Specifically, Appellants argue that, first, the O'Neill references do not demonstrate or suggest the effects of p53 inhibition on (a) embryonic stem cells ("ES" cells) or (b) ES cell induction from blastocysts. App. Br. 9. Appellants contend that the O'Neill references only mention ES cells as an indirect effect of enhancing the viability of embryos. Id. By way of example, Appellants argue that O'Neill '426 teaches that "the method and compositions of the present invention ... find application in all circumstances in which it is beneficial to improve embryo viability, for example in the production of embryonic stem cells ... " Id. (citing O'Neill '426 col. 11, 11. 32- 40; see also O'Neill '309 ,r 67). 7 Appeal2017-009825 Application 13/942,208 Secondly, Appellants argue, an ES cell is induced by isolating one or more cells from the undifferentiated inner cell mass ("ICM") of a blastocyst (which is a later-stage embryo), and culturing the cells from the ICM. App. Br. 9. In other words, Appellants argue, ES cell induction is achieved by maintaining the pluripotency and the undifferentiated state of an early embryo and, therefore, the production of ES cells does not require reprogramming to pluripotency ( as with somatic cells reprogrammed to iPS cells). Id. According to Appellants, iPS cells, which are the subject of Mali and the claims on appeal, are induced by reprogramming somatic cells, such that iPS cell induction does not include an embryo or blastocyst as in the O'Neill references. Id. at 10. We are not persuaded by Appellants' arguments. Mali teaches that administration of the SV 40 large T antigen is effective at increasing the efficiency of the process by which fibroblasts are reprogrammed into iPS cells. Mali Abstr. Furthermore, Mali specifically teaches that: "In addition to being an essential protein for SV40 DNA replication, [the SV40 large antigen] simultaneously disables the retinoblastoma and p53 tumor suppressor pathways and alters other cellular targets." Mali 2003. The O'Neill references severally teach that inhibition of the p53 tumor suppressor pathway increases the viability of embryonic cells. See O'Neill '309 ,r 57, 67; O'Neill '332, 98, 100; O'Neill '426 cols. 2-3, 11. 66-4. In particular, O'Neill '332 teaches that: p53 forms part of an interconnected network of pathways that allow cells, including gametes, and the embryo to sense and respond to inappropriate stresses. As disclosed herein, embodiments of the present invention demonstrate that disruption of key components of this network has the capacity to enhance the viability of gametes and embryos. 8 Appeal2017-009825 Application 13/942,208 O'Neill '332 ,r 100. Furthermore, all three O'Neill references expressly teach that inhibition of the p53 pathway is likely to be useful in a number of other applications, including increasing the viability of embryonic stem cells. For example: The present invention is of particular benefit in increasing embryo viability following ART, and in particular NF. Other suitable ART techniques to which the present invention is applicable include, but are not limited to, gamete intrafallopian transfer (GIFT), ... other forms of embryo micromanipulation including formation of embryos by nuclear transfer and production [ of] transgenic lines and genetically modified lines. It is also applicable to production of embryonic stem cell lines. O'Neill '332 ,r 102 (emphasis added); see also O'Neill '309 ,r 66; O'Neill '426 cols. 10-11, 11. 65-9. We agree with the Examiner that a person of ordinary skill in the art would have understood that the combined references support Mali's teaching that SV40 large antigen functions as, inter alia, a p53 inhibitor, that significantly increases the induction and viability of iPS stem cells from fibroblasts, and that combined with the O'Neill references teach that p53 inhibition can increase the viability of many types of embryonic cells, including stem cells. We further agree that a person of ordinary skill in the art would have recognized from these teachings that inhibition of the p53 pathway is therefore a likely factor in why the SV 40 large antigen is successful in increasing the successful induction and viability of iPS cells, and would have sought a more selective and effective p53 inhibitor, such as those taught by Bowman and Willis, like recited in Appellants' claims. See Bowman Abstr., 832; Willis Abstr. We conclude, therefore, that a person of ordinary skill in the art would have been motivated to combine the teachings of the cited prior art to arrive at 9 Appeal2017-009825 Application 13/942,208 Appellants' claims on appeal. See KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,420 (2007) ("A person of ordinary skill is also a person of ordinary creativity, not an automaton"). Issue 2 Appellants argue that a person of ordinary skill would not have expected the large enhancement of iPS cell induction from somatic cells by p53 inhibition using dominant negative mutants of p53. App. Br. 11. Analysis Appellants argue that, even if a person of ordinary skill in the art would have predicted that p53 inhibition enhanced the viability of iPS cells, based on the teachings of the O'Neill references, such an enhancing effect of p53 inhibition would be expected to be at most 2-fold, compared to Appellants' 10- to 44-fold increase in human cells. App. Br. 10 (citing, e.g., O'Neill '332). According to Appellants, the "remarkable enhancement" of iPS cell induction from somatic cells by p53 inhibition using dominant negative mutants of p53 in accordance with the present invention cannot be solely explained by the enhancement of viability of iPS cells, and would have not been expected by a person of ordinary skill. Id. We disagree. "When unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art." In re Baxter Travenol Labs., 952 F.2d 388,392 (Fed. Cir. 1991). We find that Mali is the closest prior art to Appellants' claims cited by the Examiner because it teaches the effect of a known p53 inhibitor on the induction of iPS cells from somatic cells. 10 Appeal2017-009825 Application 13/942,208 Mali teaches that treatment of fibroblasts with SV 40 large antigen, which is, inter alia, a known p53 pathway inhibitor: "enhanced the efficiency by 23- to 70- fold from both human adult and fetal fibroblasts." Mali Abstr. These results overlap, and exceed, the Appellants' claimed effect of 10- to 44-fold in human cells. App. Br. 10 (citing Spec. 3, Ex. 7, Figs. 17a-b). We are therefore not persuaded by Appellants' assertion that the method recited in their claims on appeal produce unexpected results that outweighs the evidence of obviousness on this record. Issue 3 Appellants' argue the Examiner impermissibly relied upon hindsight analysis in arriving at the conclusion that the claims are prima facie obvious over the prior art. App. Br. 11. Analysis Appellants argue that the connections made by the Examiner between the SV 40 large T antigen taught by Mali and the particular p53 inhibitors taught by Willis and Bowman, as well as between the iPS cells of Mali and the embryos/blastocysts and ES cells of the O'Neill references, are the result of the Examiner's reading more into the limited disclosures of Mali and the O'Neill references than is truly there, apparently as a result of knowledge of the present invention. App. Br. 11. We are not persuaded. Appellants' conclusory argument that the Examiner relied upon hindsight analysis is without evidentiary support and constitutes attorney argument, to which we accord little probative weight. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). Moreover: 11 Appeal2017-009825 Application 13/942,208 Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from applicant's disclosure, such a reconstruction is proper. In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Appellants have adduced no evidence of record that the Examiner relied upon knowledge that could have been gleaned only from Appellants' Specification in concluding that the claims were prima facie obvious over the combined teachings of the cited prior art. We consequently affirm the Examiner's rejection of claims 1-11, 13, and 14. B. Rejection of claims 1-11, 13, and 14 under the nonstatutory doctrine of obviousness-type double patenting The Examiner entered this rejection as a New Ground of Rejection in the Answer to Appellants' Appeal Brief. Ans. 3. In their Reply Brief, Appellants argue, inter alia, that the Examiner cannot properly reject the present application for obviousness-type double patenting over the '23 8 patent because the present application is a divisional application from the application that issued as the '238 patent. Reply Br. 3. Appellants contend that the pending claims of the present application are directed to subject matter that was not elected in response to the restriction requirement issued by the Examiner during the prosecution of the '23 8 patent. Reply Br. 3. We agree. 35 U.S.C. § 121 states that: If two or more independent and distinct inventions are claimed in one application, the Director may require the application to be restricted to one of the inventions. If the other invention is made the subject of a divisional application which complies with the requirements of section 120 it shall be entitled to the benefit of the filing date of the original application. A patent issuing on an application with respect to which a 12 Appeal2017-009825 Application 13/942,208 requirement for restriction under this section has been made, or on an application filed as a result of such a requirement, shall not be used as a reference either in the Patent and Trademark Office or in the courts against a divisional application or against the original application or any patent issued on either of them, if the divisional application is filed before the issuance of the patent on the other application. The validity of a patent shall not be questioned for failure of the Director to require the application to be restricted to one invention. (Emphasis added). The instant application is a divisional application of US Ser. No. 12/672,042 (the "'042 application"), which issued as the '238 patent. Specifically, Group I of the '042 application encompassed methods employing chemical inhibitors of p53 and Group II encompassed methods employing dominant negative mutants of p53. Id. Neither of these was elected by Appellants, who instead elected Group III, which was directed to methods employing siRNAs and shRNAs against p53. Id. Because the subject matter of the claims on appeal was excluded from the '238 patent by the Examiner's division of the '042 application, the '238 patent cannot be used as a reference against Appellants' instant application. We consequently reverse the Examiner's rejection of the claims on this ground. DECISION The Examiner's rejection of claims 1-11, 13, and 14 as unpatentable under 35 U.S.C. § 103(a) is affirmed. The Examiner's rejection of claims 1-11, 13, and 14 as unpatentable under the nonstatutory doctrine of obviousness-type double patenting is reversed. AFFIRMED 13 Copy with citationCopy as parenthetical citation