Ex Parte BRAUGHLER et alDownload PDFPatent Trials and Appeals BoardMay 16, 201912247738 - (D) (P.T.A.B. May. 16, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/247,738 10/08/2008 80011 7590 05/20/2019 Sterne, Kessler, Goldstein & Fox P.L.L.C. 1100 New York Avenue, N.W. Washington, DC 20005 FIRST NAMED INVENTOR J. MARK BRAUGHLER 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. 2584.0070009/RWE/C-K 8553 EXAMINER NGUYEN, QUANG ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 05/20/2019 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): dlucas@intrexon.com e-office@sternekessler.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte J. MARK BRAUGHLER, PRASANNA KUMAR, WALTER J. STORKUS, and HIDEHO OKADA 1 Appeal 2018-001294 Application 12/247,738 Technology Center 1600 Before DEBORAH KATZ, JOHN G. NEW, and DAVID COTTA, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants identify Intrexon Corporation as the real party-in-interest. App. Br. 1. Appeal 2018-001294 Application 12/247,738 SUMMARY Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner's Final Rejection of claims 111-117 as unpatentable under 35 U.S.C. § 103(a) as being obvious over the combination of Tahara et al. (US 6,482,405 Bl, November 19, 2002) ("Tahara"), D. Karzenowski et al., Inducible Control ofTransgene Expression with Ecdysone Receptor: Gene Switches with High Sensitivity, Robust Expression, and Reduced Size, 39 BIOTECHNIQUES 191-200 (2005) ("Karzenowski"), O'Malley et al. (US 2002/0182698 Al, December 5, 2002) ("O'Malley"), Gilman et al. (US 6,306,649 Bl, October 23, 2001) ("Gilman"), and T. Tatsumi et al., lntratumoral Delivery of Dendritic Cells Engineered to Secrete Both Interleukin (IL)-12 and IL-18 Effectively Treats Local and Distant Disease in Association with Broadly Reactive Tel-type Immunity, 63 CANCER RES. 6378-386 (2003) ("Tatsumi"). Claim 112 also stands rejected as unpatentable under 35 U.S.C. § 103(a) over the combination of Tahara, Karzenowski, O'Malley, Gilman, Tatsumi, and Hormann et al. (US 2006/0020146 Al, January 26, 2006) ("Hormann"). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants' invention is directed to methods of generating in vitro engineered dendritic cells conditionally expressing interleukin-12 ("IL-12") under the control of a gene expression modulation system in the presence of 2 Appeal 2018-001294 Application 12/247,738 activating ligand and uses for therapeutic purposes in animals including humans. Abstract. REPRESENTATIVE CLAIM Independent claim 111 is illustrative of the claims on appeal and recites: 111. (Previously Presented) A method of treating a melanoma tumor in a mammal, said method comprising: (a) administering intratumorally to said mammal a population of in vitro engineered dendritic cells comprising a vector comprising a polynucleotide encoding a gene switch compnsmg (1) a polynucleotide sequence compnsmg a first transcription factor sequence and a second transcription factor sequence under the control of a promoter, wherein the proteins encoded by the first transcription factor sequence and second transcription factor sequence interact to form a ligand-dependent transcription factor complex, and (2) an IL-12 polynucleotide sequence that is at least 85% identical to a wild type human IL-12 sequence linked to a promoter which is activated by said ligand-dependent transcription factor complex; and (b) administering an effective amount of said ligand to said mammal less than 48 hours after said in vitro engineered dendritic cells are administered, and for a period of 5 to 28 days, wherein said IL-12 po lynucleotide sequence is expressed in said in vitro engineered dendritic cells, wherein the first transcription factor sequence comprises a nucleic acid encoding a VP-16 transactivation domain and a retinoic acid-X-receptor (RXR) polypeptide, 3 Appeal 2018-001294 Application 12/247,738 wherein the RXR polypeptide is a genetically engineered chimera comprising vertebrate RXR and invertebrate RXR domains, wherein said vertebrate RXR domain is a human RXR ligand binding domain, wherein the second transcription factor sequence comprises a nucleic acid encoding a GAL-4 DNA binding domain and an ecdysone receptor protein, wherein said ecdysone receptor ligand binding domain is obtained from a Choristoneura fumiferna ecdysone receptor ligand binding domain, wherein said Choristoneura fumiferna ecdysone receptor ligand binding domain further comprises a genetically engineered substitution mutation compared to the naturally occurring Choristoneura fumiferna ecdysone receptor ligand binding domain from which it was obtained, wherein said ligand is a diacylhydrazine, wherein said vector is an adenoviral vector, and wherein the size of said melanoma tumor in said mammal is reduced after said population of in vitro engineered dendritic cells and said ligand are administered to said mammal. App. Br. 24-25. ISSUES AND ANALYSES We adopt the Examiner's conclusion that the claims are prima facie obvious over the combined cited prior art. We address the arguments raised by Appellants below. 4 Appeal 2018-001294 Application 12/247,738 A. Rejection of claims 111-117 Issue Appellants argue that the Examiner erred in finding that the combined cited prior art references teach or suggest the limitation of claim 111 reciting: "administering an effective amount of said ligand to said mammal less than 48 hours after said in vitro dendritic cells are administered, and for a period of 5 to 28 days." App. Br. 10. Analysis The Examiner finds that Tahara teaches a method for treating a subject having a tumor comprising injecting, near or at the site of the tumor, an effective amount of autologous or allogeneic professional antigen- presenting cells, preferably dendritic cells which have been genetically modified by transduction with a viral vector encoding an immunostimulatory cytokine ( e.g., IL-12 and IFN-alpha cytokines from human or other mammalian sources), to induce a specific immune response against antigen at the site of injection. Final Act. 3-4 ( citing Tahara col. 5, 11. 1-11; col. 6, 11. 49-55; col. 11, 11. 48-53). The Examiner finds that Tahara also expressly teaches that inducible promoters can be used in a genetic construct to enhance the expression of an immunostimulatory cytokine if the conditions for induction can be met under physiological conditions, with or without additional treatment of the subject, such as administering an inducer. Final Act. 4 ( citing Tahara cols. 8-9, 11. 61-2). The Examiner finds that Tahara further teaches that cancer patients treated by this method may have at least one physically well-defined tumor (i.e., a benign tumor), rather than a diffuse, highly-metastasized 5 Appeal 2018-001294 Application 12/247,738 cancer, but that patients with diffuse, highly metastasized cancers with at least one identified site of a tumor can also be treated. Id. ( citing Tahara cols. 5-6, 11. 57-8). The Examiner finds that Tahara teaches that the number of administered cells is between 104 and 108, and preferably between 105- 107 cells per site per treatment; the number of cells to be introduced depends upon a number of factors such as the number of sites to be injected, the number of injections which are to be administered overtime. Id. ( citing Tahara col. 6, 11. 31-38). However, the Examiner finds, Tahara does not expressly teach a method of treating a melanoma tumor in a mammal comprising administering intratumorally to a mammal a population of in vitro engineered dendritic cells comprising an adenoviral vector comprising a polynucleotide encoding a gene switch having the components recited in independent claim 111, and administering an effective amount of a diacylhydrazine ligand (i.e., the RG-115819 ligand) to the mammal less than 48 hours after the administration of the engineered dendritic cells, and for a period of 5 to 28 days. Final Act. 4-5. The Examiner finds that Karzenowski is directed to an ecdysone receptor (EcR)-based gene regulation system for the inducible control of transgene expression with robust expression and extremely high sensitivity using the RG-115819 ligand in the subnanomolar range, and suitable for gene/cell therapy. Final Act 5 (citing Karzenowski Abstr., 191, Fig. 1). The Examiner notes that Karzenowski teaches precise spatial and temporal modulation and control over levels of trans gene expression via external application of a small molecule as an extremely powerful technology for gene and cell therapy application. Id. The Examiner finds that the EcR- 6 Appeal 2018-001294 Application 12/247,738 based gene regulation system taught by Karzenowski has several advantages: (1) low basal expression; (2) ecdysteroids are not present in mammalian cells, and many safe nonsteroidal inducers are available; (3) EcR mutants can differentially respond to different chemotypes; and (4) EcR mutants can independently and simultaneously regulate two or more genes. Id. ( citing Karzenowski 191 ). The Examiner finds that Karzenowski teaches evaluation of many two hybrid-format synthetic gene constructs in which a GAL4 DNA binding domain was fused to the ligand binding domain of the Choristoneurafumiferana EcR mutant V3901/Y401E, which has increased sensitivity to diacylhydrazine inducers such as RG-115819, and various activation domains CVP 16, p5 3, p65 or E2F 1. Id. The Examiner finds that these latter were fused to the EF domains of chimeric human RXR, including two hybrid-format synthetic gene constructs in which co- expression of both receptor genes with encephalomyocarditis virus (EMCV) or elF4G internal ribosome entry site (IRES) sequences both in vitro and in vivo. Id. ( citing Karzenowski 192, Figs. 1-6). The Examiner finds that O'Malley also teaches a molecular switch for regulating expression of a nucleic acid sequence. Final Act. 6. The Examiner finds that the molecular switch taught by O'Malley is a polynucleotide comprising a coding region encoding a recombinant steroid hormone receptor superfamily protein, in which the protein comprises: a DNA binding domain ( e.g., GAL4 DNA), a transregulatory domain ( e.g., VP 16, T AF-1 ), and a modified steroid hormone receptor superfamily protein ligand binding domain ( e.g., a truncated human progesterone receptor ligand binding domain), and in which the recombinant steroid hormone receptor protein responds to RU486 (mifepristone). Id. (citing O'Malley ,-J,-J 150-160, 7 Appeal 2018-001294 Application 12/247,738 claims 59-86). The Examiner further finds that O'Malley expressly teaches that the molecular switch is attached to a nucleic acid cassette, comprising the desired heterologous nucleic acid sequence to be expressed and which is under the control of the molecular switch and a ligand that binds to the modified ligand binding domain. Id. ( citing O'Malley ,-J,-J 157-159). The Examiner also finds that Gilman teaches an ex vivo method in which, approximately 1 hour following intramuscular injection of transfected cells comprising DNA constructs encoding regulable transcriptional factor components into mice, rapamycin was administered into the mice to induce hGH expression. Final Act. 6-7 ( citing Gilman cols. 3-4, col. 38, 11. 61 et seq., Fig. 1). Finally, the Examiner finds that Tatsumi teaches intratumoral delivery of adenoviral transduced dendritic cells ("DCs") engineered to secrete IL-12 in the form ofIL-12p70 and/or IL-18, to treat local and distant disease in association with broadly reactive Tel-type immunity. Final Act. 7. The Examiner finds Tatsumi teaches that these cytokine gene-engineered DCs have a survival advantage in situ when injected into tumor lesions. Id. (citing Tatsumi Abstr., 6380-381). The Examiner finds that Tatsumi also teaches that DCs are required for the observed efficacy of intratumoral therapy via the rapid rejection of CMS4 tumors after intratumoral administration of AdiL12/lL18 DCs, but not for the combined adenoviruses ("Ads") at 7, 14, 21 and 28 days post-tumor inoculation. Id. (citing Tatsumi 6382, Fig. 5). The Examiner concludes that it would have been obvious for an artisan of ordinary skill to modify the method of Tahara by adapting the disclosed EcR-based gene switch system taught by Karzenowski, in the form 8 Appeal 2018-001294 Application 12/247,738 of a recombinant adenoviral vector for inducing human lL-2 expression in genetically-modified dendritic cells administered to treat a subject having a melanoma tumor, and in which the EcR-based gene switch can be attached to a nucleic acid cassette comprising a human IL-12 polynucleotide, the expression of which is under control of the gene switch, as taught by O'Malley. Final Act. 7-8. The Examiner concludes that it would also have been obvious to a person of ordinary skill in the art to administer a bioavailable, non-steroidal diacylhydrazine ligand approximately 1 hour following the injection of the genetically-modified dendritic cells to induce the expression of IL-12, as taught by Gilman, and to administer the ligand for an ensuing period of 5 to 28 days, as taught by Tatsumi. Id. at 8. The Examiner also concludes that a skilled artisan would have been motivated to combine the references because of the advantages offered by the EcR-based gene regulation system taught by Karzenowski, particularly the robust transgene expression and extremely high sensitivity, combined with the use of the nonsteroidal RG-115819 ligand in the subnanomolar range. Final Act. 9. The Examiner further notes that Karzenowski teaches that precise spatial and temporal modulation and control over levels of transgene expression by external application of a small molecule is an extremely powerful technology for gene and cell therapy application. Id. The Examiner also finds that O'Malley teaches a molecular switch that can be attached to a nucleic acid cassette, comprising the desired heterologous nucleic acid sequence to be expressed which is under the control of the molecular switch and the presence of a ligand that binds the modified ligand binding domain. Id. The Examiner points out that was recognized by those of skill in the art that unless and until the RG-115830 9 Appeal 2018-001294 Application 12/247,738 ligand is administered into the patient, substantially no expression of exogenous IL-12 would be expressed by the transplanted genetically modified dendritic cells; and that an inducer or an activator could be effectively administered approximately one hour after the transplantation, and at 7, 14, 21, or 28 days, to induce the expression of the desired gene product, as taught Gilman and Tatsumi, respectively. Id. at 8-9. Appellants argue that the administration schedule recited in claim 111 is described in paragraph [0238] of Appellants' Specification, and discloses that in: "another embodiment, the ligand is administered daily for a period of 5 to 28 days." App. Br. 11. According to Appellants, the Examples disclosed by the Specification also refer to daily dosing for various time periods, starting at 5 consecutive days. Id. ( citing Spec. ,i 262). Therefore, Appellants contend, a person of ordinary skill in the art would interpret the ligand administration schedule as including daily dosing of ligand for a period of 5 to 28 days. Id. It is Appellants' position that a person of ordinary skill in the art would have had no reason to combine the prior art cited by the Examiner to arrive at the claimed invention, particularly with respect to administering the ligand according to the recited schedule. App. Br. 11. Appellants argue that Tahara teaches the use of commercially available vectors, and discusses only the withdrawal of tetracycline or exposure to IPTG as an external stimulus for protein expression. Id. ( citing Tahara col. 9, 11. 28-34). Appellants assert that the experimental results provided in Tahara demonstrate that tumor-specific immune responses were obtained using vectors that constitutively expressed protein. Id. ( citing Tahara, e.g., col. 12, 11. 21-24, Fig. 5) (Appellants' emphasis). Therefore, argue Appellants, Tahara would 10 Appeal 2018-001294 Application 12/247,738 have led a person of ordinary skill away from the use of inducible promoters or, at most, Tahara would have led a skilled artisan to a tet or lac promoter type system, and not an ecdysone receptor-based gene switch system as recited. Id. at 11-12. Appellants next argue that Karzenowski teaches an ecdysone gene switch system, and does not teach expression of cytokines. App. Br. 12 (citing Karzenowski, Abstr., 192-193). Appellants contend that, although Karzenowski discloses certain advantages of an ecdysone gene switch system, the Examiner has provided no reason why a person of ordinary skill would have found the advantages of an ecdysone gene switch system to be useful in the methods of Tahara. Id. According to Appellants, Tahara teaches advantageous results when IL-12 is constitutively expressed, but the Examiner has provided no reason why a person of ordinary skill would have used an ecdysone receptor-based gene switch system, when constitutive expression is taught by Tahara as providing successful results. Id. Appellants argue further that O'Malley, although teaching an ecdysone receptor, provides no teaching or suggestion of any advantage to using an ecdysone receptor-based gene switch. App. Br. 12. Appellants contend that O'Malley, like Karzenowski, provides no teaching of the expression of a cytokine. Id. Therefore, argue Appellants, a person of ordinary skill would have been less likely to look to the teachings of O'Malley than the teachings of Karzenowski if seeking to modify the methods of Tahara. Id. Appellants assert that neither Karzenowski nor O'Malley teaches or suggests anything related to a ligand administration schedule. Id. 11 Appeal 2018-001294 Application 12/247,738 Appellants also argue that they have discovered that administering ligand within 48 hours provides the unexpected result of greatly improved efficacy when compared ligand administration at 48 hours. App. Br. 13. For example, Appellants argue, animals administered ligand 24 hours following dendritic cell administration showed effective regression of melanoma tumors while animals in which ligand was administered 48 hours following dendritic cell administration demonstrated melanoma tumor progression, requiring euthanasia. Id. ( citing Spec. ,i,i 267-268, Figs. 3A- B). Therefore, Appellants assert, administration of activating ligand within 48 hours provided unexpected efficacy against melanoma tumors. Id. Appellants assert that Gilman teaches administration of a rapamycin ligand at 1, 16, 32, 48 and 64 hours (but not after 64 hours) following administration of cells expressing human growth hormone (hGH) under control of a rapamycin gene switch. App. Br. 13 ( citing Gilman col. 39, 11. 45-65). Appellants point out that Gilman does not teach or suggest the treatment of a tumor, including a melanoma tumor, or even the treatment of any type of disease in the tested animals. Id. Rather, Appellants assert, Gilman teaches only administration of hGH to determine if hGH is then subsequently present in the blood of the tested mice. By contrast, Appellants argue, the time points of administration taught by Gilman appear to be arbitrary times for achieving steady blood concentrations of hGH. Id. Appellants assert that no teaching or suggestion of Gilman would lead a person of ordinary skill to administer a diacylhydrazine ligand less than 48 hours following the administration of in vitro dendritic cells conditionally expressing IL-12 to achieve improved treatment of melanoma. Id. at 13-14. 12 Appeal 2018-001294 Application 12/247,738 With respect to the references, Appellants argue, Tatsumi teaches the administration of dendritic cells, not ligand, at 7 and 14 days following the first administration of cells. App. Br. 14 ( citing Tatsumi Fig. 5, see fn.3). Appellants contend that Tatsumi does not teach a ligand-inducible administration schedule but, rather, teaches only the use of constitutive promoters and, as such, does not disclose administration of ligand at all. Id. ( citing Tatsumi 6379). According to Appellants, a person of ordinary skill in the art would not have looked to Tatsumi' s teaching of the administration of dendritic cells to modify Tahara with the recited administration schedule. Id. Appellants also argue that Tatsumi would not have provided any reason for a skilled artisan to extend the short time period of ligand administration disclosed in Gilman. Id. Furthermore Appellants assert, the Examiner provides no reasoning as to why a person of ordinary skill in the art would have modified Tahara with the teachings of the secondary references to arrive at Appellants' claimed invention. App. Br. 15. Appellants assert that, arguendo, even if one of the cited references provided some type of ecdysone or diacylhydrazine ligand administration schedule, the Examiner's recognizing of certain disclosures in the cited prior art is not a sufficient basis to support a prima facie conclusion of obviousness. Id. Finally, Appellants argue, because the Examiner has not provided an adequate reason to combine the cited references, the Examiner has improperly relied upon hindsight analysis to work backwards from the claimed method and combine the teachings of the prior art to arrive at the limitations of Appellants' claimed invention. Id. at 19-20. 13 Appeal 2018-001294 Application 12/247,738 We are not persuaded by Appellants' arguments. As an initial matter, we remind Appellants that: "one cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of references." In re Keller, 642 F.2d 413,426 (C.C.P.A. 1981). Rather, the test for obviousness is: "what the combined teachings of the references would have suggested to those of ordinary skill in the art." Id. at 425. Appellants essentially make three arguments, concerning the combination of the cited references, that the Examiner erred: ( 1) that the combined references do not teach the ligand administration schedule recited in the claims; (2) that a person of ordinary skill in the art would not have had a reason to combine the references; and (3) that the Examiner employed impermissible hindsight reasoning. We address each argument in tum. 1. The ligand administration schedule With respect to the ligand administration schedule, Gilman teaches that rapamycin is well-known in the art as being capable of being an inducer of expression in transfected genes in implanted cells. Gilman col. 4, 11. 5- 17, cols. 11-12, 11. 55-7. Furthermore, Gilman also teaches that: "Approximately one hour following injection of the cells, mice received the first of five intravenous 10.0 mg/kg doses ofrapamycin. The four remaining doses were given under anesthesia, immediately subsequent to blood collection, at 16, 32, 48, and 64 hours." Id. at col. 39, 11. 59-64. Consequently, Gilman expressly teaches the administration of an inducer to transplanted, genetically-transformed dendritic cells: "less than 48 hours after said in vitro engineered dendritic cells are administered," as recited in claim 111. 14 Appeal 2018-001294 Application 12/247,738 Furthermore, Gilman teaches administration of the inducer after 48 hours, at 64 hours. Gilman does not teach administration of the inducer "for a period of 5 to 28 days," as recited in claim 111. Gilman does, however, teach the efficacy of repeated dosages of ligand: Interestingly, administration of a second dose of rapamycin to these animals at 42 hr resulted in a second peak of serum hGH, which decayed with similar kinetics indicating that the engineered cells retained the ability to respond to rapamycin for at least two days. Therefore, to ascertain the ability of this system to elevate and maintain circulating hGH concentrations, we performed an experiment in which animals received multiple doses of rapamycin at 16-hour intervals. This interval corresponds to the time required for hGH levels to peak and then decline approximately halfway. According to this regimen, rapamycin concentration is predicted to approach a steady-state trough concentration of 1. 7 µg/ml after two doses. hGH levels should also approach a steady state trough concentration following the second dose. Indeed, treated animals held relatively stable levels of circulating hGH in response to repeated doses of rapamycin. After the final dose, hGH levels remained constant for 16 hours and then declined with a similar half-life as rapamycin (6.8 hours for hGH versus 4.6 hours for rapamycin). These data suggest that upon multiple dosing, circulating rapamycin imparts tight control over the secretion of hGH from transfected cells in vivo. In particular, it is apparent that protein production is rapidly terminated upon withdrawal of drug. Gilman col. 40-41, 11. 47-5 (emphases added). Gilman thus teaches that repeated administration of the inducer is necessary to maintain production of the polypeptide expressed by the transformed cells and suggests, to a person of ordinary skill in the art, that repeated injections administered over a prolonged period are necessary for, and efficacious in, promoting expression of the transfected gene in the transformed cells in situ. As such, the rate and 15 Appeal 2018-001294 Application 12/247,738 duration of ligand administration is a result effective variable, i.e., without repeated administration of ligand, protein production is rapidly terminated. We consequently conclude that it would have been obvious to a person of ordinary skill in the art, based upon the teachings of Gilman, to optimize the administration schedule of ligand, recited in claim 111, "for a period of 5 to 28 days." See In re Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980) ("[D]iscovery of an optimum value of a result effective variable ... is ordinarily within the skill of the art"). We acknowledge that Gilman does not teach the use of an ecdysone receptor ligand-binding domain and its corresponding ligand, but rather uses rapamycin as an inducer of human growth hormone ("hGH") expression in genetically transformed and transplanted dendritic cells. Nevertheless, the basic principle of operation of the method taught by Gilman and by Appellants' claimed method is essentially the same, and we conclude that a person of ordinary skill in the art would understand from the teachings of Gilman that regular, periodic administration of the ligand would produce a steady-state expression of cytokines. Nor are we persuaded by Appellants' claims of unexpected results. "[W]hen 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). Appellants contend that it was unexpected that administration of the ligand within 48 hours produced superior cytokine expression in their claimed method. See App. Br. 13. However, and as we have explained supra, Gilman teaches administration of an inducer ligand approximately 1 hour after injection of the transformed dendritic cells, as well as at 16 and 32 hours, all of which 16 Appeal 2018-001294 Application 12/247,738 fall within Appellants' claimed 48 hour post-injection interval. See Gilman col. 39, 11. 62-64. Appellants provide no evidence as to why, in view of these express teachings of Gilman, their results would not have been expected by a person of ordinary skill in the art. We agree with Appellants that the Examiner's reliance upon Tatsumi as teaching the recited ligand administration schedule of "for a period of 5 to 28 days," is inapposite because Tatsumi teaches administration of the transformed cells at 14 days after the original administration. See Tatsumi 6379. However, this does not alter our analysis supra explaining why the ligand administration would have been obvious over the teachings of Gilman. We therefore agree with the Examiner that a person of ordinary skill in the art understanding the principles of Gilman, and in combination with the teachings of the remainder of the cited prior art, would have had a reasonable expectation of success in administering the inducer to the transformed and transplanted cells at the administration schedule recited in the claims. 2. No reason to combine Appellants argue that, given the allegedly disparate teachings of the cited prior art, the Examiner has failed to provide reasoning as to why a person of ordinary skill in the art would have reason to combine the teachings of the references to arrive at their claimed invention. We disagree. In the Final Office Action, the Examiner concludes: An ordinary skilled artisan would have been motivated to carry out the above modifications [ of Tahara] because of several advantages offered by the EcR-based gene regulation system 17 Appeal 2018-001294 Application 12/247,738 taught by Karzenowski et al[.], particularly the robust transgene expression and extremely high sensitivity with the use of at least the nonsteroidal RG-115819 ligand in the subnanomolar range. Karzenowski et al also taught that precise spatial and temporal modulation and control over levels of transgene expression by external application of a small molecule is an extremely powerful technology for gene and cell therapy application. Additionally, O'Malley et al[.] already taught that a molecular switch can be attached to a nucleic acid cassette comprising the desired heterologous nucleic acid sequence to be expressed which expression is under the control of the molecular switch and the presence of a ligand that binds the modified ligand binding domain. It is readily recognized by those of skill in the art that unless and until the RG-115830 ligand is administered into the patient, substantially no expression of exogenous IL-12 will be expressed by the transplanted genetically modified dendritic cells; and that an inducer or an activator has been administered into a mammal approximately 1 hour after the transplantation of genetically modified cells to induce the expression of a desired gene product as taught at least by Gilman et al. Final Act. 8-9. Appellants argue that Tahara teaches that successful tumor-specific immune responses were obtained using different vectors that constitutively (i.e., continuously and unregulated) expressed protein, and argues that there would have been no reason why a person of ordinary skill would have combined its method with the teachings of Karzenowski when Tahara' s method was reported to work successfully without any type of gene regulation. See App. Br. 15-16. However, the Examiner expressly states that the method of Karzenowski features: [P]articularly [ ] robust transgene expression and extremely high sensitivity with the use of at least the nonsteroidal RG-115819 ligand in the subnanomolar range. Karzenowski et al also taught that precise spatial and temporal modulation and control over 18 Appeal 2018-001294 Application 12/247,738 levels of trans gene expression by external application of a small molecule is an extremely powerful technology for gene and cell therapy application. Final Act. 8. Appellants offer no evidence of record disputing the Examiner's conclusion in this regard, and we find that the Examiner has thus articulated a persuasive reason why a person of ordinary skill in the art would have been motivated to combine the teachings of the references. Appellants argue further that, even if a person of ordinary skill would have combined Tahara and Karzenowski, the Examiner does not provide a reason to combine those teachings with any of the other cited references. App. Br. 16. We disagree. The passage from the Final Action at pages 8-9 quoted supra articulates a rational reason why a person of ordinary skill in the art would have combined the teachings of Tahara, Karzenowski, O'Malley and Gilman. 3. Impermissible hindsight analysis Appellants reason from the preceding arguments that the Examiner could only have reached Appellants' claimed invention by the use of impermissible hindsight analysis. See App. Br. 19-20. We have explained supra why we are not persuaded by Appellants' arguments 1 and 2. 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 point to no evidence of record that the Examiner in any way relied on knowledge 19 Appeal 2018-001294 Application 12/247,738 gleaned only from the disclosures of Appellants' Specification. Rather, Appellants arguments are entirely conclusory and unsupported by evidence. We accord such attorney argument no probative value. See In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997) (Attorney arguments and conclusory statements that are unsupported by factual evidence are entitled to little probative value). We consequently affirm the Examiner's rejection of claims 111-11 7. B. Rejection of claims 112 Appellants additionally make a separate argument with respect to claim 112. App. Br. 22. Appellants contend that Hormann does not overcome the alleged deficiencies in the Examiner's reasoning for modifying Tahara with the combination of Karzenowski, O'Malley, Gilman and Tatsumi. Id. We have explained our reasoning as to why we are not persuaded by Appellants' arguments with respect to claims 111-11 7. Because Appellants rely upon these same arguments with respect to claim 112, we affirm the Examiner's rejection of the claim. DECISION The Examiner's rejection of claims 111-117 under 35 U.S.C. § 103(a) is affirmed. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § l .136(a)(l )(iv). AFFIRMED 20 Copy with citationCopy as parenthetical citation