Ex Parte HaddenDownload PDFPatent Trial and Appeal BoardFeb 5, 201813653152 (P.T.A.B. Feb. 5, 2018) 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. 13/653,152 10/16/2012 John W. Hadden U0157.70014US03 6545 23628 7590 02/07/2018 WOLF GREENFIELD & SACKS, P.C. 600 ATLANTIC AVENUE BOSTON, MA 02210-2206 EXAMINER JUEDES, AMY E ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 02/07/2018 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): Patents_eOfficeAction@WolfGreenfield.com W GS_eOffice Action @ W olfGreenfield .com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JOHN W. HADDEN (APPLICANTS: IRX Therapeutics, Inc.) Appeal 2016-0033401 Application 13/653,1522 Technology Center 1600 Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and JOHN G. NEW, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This Appeal3 under 35 U.S.C. § 134(a) involves claims 33—38 and 40-50 (App. Br. 5). Examiner entered a rejection under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Oral hearing held January 30, 2018. 2 Appellant identifies the real party in interest as “IRX Therapeutics, Inc.” (App. Br. 3). 3 This Appeal is related to Appeal 2016-008344, Application 13/940,558 (see App. Br. 4). Appeal 2016-003340 Application 13/653,152 STATEMENT OF THE CASE Appellant’s disclosure “relates to vaccine therapy for cancer patients . . . . More specifically, [Appellant’s disclosure] . . . relates to a vaccine immunotherapy that immunizes patients, having immune suppression, to both endogenous and exogenous tumor peptides or proteins” (Spec.4 1). 33. A method for inducing an immune response to an exogenous antigen in a subject, the method comprising: administering an effective amount of a natural cytokine mixture (NCM) to the subject, wherein the NCM comprises Interleukin-I (IL-1), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-12 (IL-12), Interferon-y (IFN- y), Tumor necrosis factor-a (TNF-a), Granulocyte colony- stimulating factor (G-CSF), and Granulocyte macrophage colony-stimulating factor (GM-CSP); administering an effective amount of a thymic peptide selected from the group consisting of thymosin al, thymosin all, and prothymosin to the subject; and administering at least one exogenous antigen to the subject, wherein an immune response to the at least one exogenous antigen is induced in the subject; and wherein the NCM and the at least one exogenous antigen are administered on the same day to the subject. (App. Br. 30.) The claims stand rejected as follows: Claims 33—38 and 46—50 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’9835 and Eisenbach.6 4 Appellant’s November 3, 2013 Substitute Specification. 5 Hadden, US 5,632,983, issued May 27, 1997. 6 Eisenbach, et al., WO 00/06723, published Feb. 10, 2000. 2 Appeal 2016-003340 Application 13/653,152 Claims 40-45 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’983, Eisenbach, and Hadden ’94(a).7 Claims 33—38, 40-48, and 50 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’983, Hadden ’99,8 and Hadden ’94(b).9 Claims 33—38 and 40-50 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’07210 in view of Hadden ’983, Hadden ’94(a), and Eisenbach. Claims 33—38 and 40-50 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’517* 11 in view of Hadden ’983 and Eisenbach.12 Claims 33—38 and 40-50 stand provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’77913 in view of Hadden ’983 and Hadden ’94(a). 7 John W. Hadden et al., Interleukins and Contrasuppression Induce Immune Regression of Head and Neck Cancer, 120 Arch Otolaryngol Head Neck Surg. 395^103 (1994). 8 J.W. Hadden, The immunology and immunotherapy of breast cancer: an update, 21 International Journal of Immunopharmacology 79-101 (1999). 9 John W. Hadden, T-Cell Adjuvants, 16 Int. J. Immunopharmac. 703—710 (1994). 10 Hadden, US 6,977,072 B2, issued Dec. 20, 2005. 11 Hadden et al., US 9,492,517 B2, issued Nov. 15, 2016. Examiner refers to this reference as Application No. 12/274,732 (see Ans. 8). 12 Application 12/274,732 issued as Hadden ’517. Therefore, this rejection is no longer provisional (cf Ans. 8). 13 Hadden, US 2014/0010779 Al, published Jan. 9, 2014. Examiner refers to this reference as Application No. 13/940,558 (see Ans. 9). 3 Appeal 2016-003340 Application 13/653,152 Claims 33—38 and 40-50 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’79614 in view of Hadden ’983, Hadden ’94(a), and Eisenbach. Claims 33—38 and 40-50 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’51915 in view of Hadden ’983.16 Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Appellant discloses that the art prior to Appellant’s filing date recognized that a fundamental problem in the effort to immunize cancer patients is that the tumor-bearing state is associated with immunosuppressive mechanisms derived from both the tumor and the host’s disturbed immune system . . . thereby making immunization difficult. . . . Immune suppression or depletion involves a reduced capacity of the immune system to respond. Such suppression can be drug or disease induced. The condition can be drug induced by treatment, virus induced as in 14 Hadden, US 8,784,796 B2, issued July 22, 2014. Examiner refers to this reference as Application No. 13/940,579 (see Ans. 9—10). 15 Hadden et al., US 9,492,519 B2, issued Nov. 15, 2016. Examiner refers to this reference as Application No. 13/940,635 (see Ans. 10-11). 16 Application 13/940,635 issued as Hadden ’519. Therefore, this rejection is no longer provisional (cf Ans. 11). 4 Appeal 2016-003340 Application 13/653,152 AIDS, or induced by a disease state such as cancer. The immune system in this condition is effectively turned off. (Spec.17 2 (citations omitted).) See Hadden ’983 2: 22—30: The limited efficacy and significant toxicity associated with high doses of rIL-2, rIFN-y, rTNF-a, and other monotherapies, suggests reconsideration of natural combinations of cytokines in therapeutic strategies. Furthermore, more than one-hundred different cytokine activities have been identified, which raises significant doubt as to whether immunotherapy, based upon combining recombinant cytokines, has a reasonable probability of success in the cancer clinic in the near future. See also Hadden ’983 14: 10-12 (exemplifying “chemotherapeutic agents” as a class of agents that “can damage cells, including T lymphocytes, involved in the immune response”); cf. Hadden ’983 1: 5—6 (Hadden ’983 “relates to an improved method of treating cellular immune deficiencies”); Hadden ’983 14: 4—10 (Hadden ’983’s “composition [] potently promotes T lymphocyte function . . . and development. . ., which is therapeutically relevant in any therapeutic measures requiring stimulation of the immune system or restoring even partial functioning of a damaged or defective immune system”). FF 2. Appellant discloses a method for overcoming immune depression by inducing production of naive T cells and restoring T-cell immunity. That is, the present invention provides an immune restoration. [Appellant’s disclosure]. . . further provides a method of vaccine immunotherapy including the steps of inducing production of naive T cells and exposing the naive T cells to endogenous or exogenous antigens at an appropriate site ...[;] a method for unblocking immunization at a regional lymph node by promoting differentiation and maturation of immature dendritic cells at a regional lymph node and allowing 17 Appellant’s November 3, 2013 Substitute Specification. 5 Appeal 2016-003340 Application 13/653,152 presentation of processed peptides by resulting mature dendritic cells, thus exposing tumor peptides to T cells to gain immunization of the T cells [; and] a method of treating cancer and other persistent lesions by administering an effective amount of a natural cytokine mixture as an adjuvant to endogenous or exogenously administered antigen of the cancer or other persistent lesions. (Spec. 4; cf. Hadden ’983 4: 3—8 (disclosing “a method to treat cellular immune deficiency in ... a patient by the steps of determining the presence of a cellular immune deficiency and coadministering to the patient an effective amount of a thymic peptide such as Thymosin ai combined with an effective amount of a natural cytokine preparation [(NCM)])”; see Hadden ’983 3: 20-21; see also Hadden ’983 16: 39—52 (disclosing “[a] method of improving cellular immune response in a patient comprising coadministering to [a] patient an effective amount of,” i.e., “Thymosin af’ and NCM); Hadden ’983 1: 8—11 (disclosing that “in recent years it has become possible to modulate the immune system to improve its response and, where components of the system are non-functioning, to either partially or completely restore the function of the component”); Hadden ’983 1: 27—31 (disclosing that “[t]he use of immunomodulators in clinical medicine includes the reconstitution of immune function (or the correction of immunodeficiency) and the suppression of normal or excessive immune function. A major class of immunomodulators is cytokines”); see generally Ans. 2-3). FF 3. Appellant’s disclosure provides for unblocking immunization at a regional lymph node by promoting differentiation and activation of dendritic cells in a regional lymph node and thus allowing presentation by resulting mature dendritic cells of small peptides. . . . Additionally, induction of mature dendritic cells is required. 6 Appeal 2016-003340 Application 13/653,152 Finally, mobilization of peripheral blood T-lymphocytes in T- lymphocytopoenic patients in the presence of induction of naive T cells capable of responding to dendritic cells presenting endogenous tumor peptides is desired. . . . [Thus,] the key mechanistic features of [Appellant’s disclosure] are the in vivo maturation of dendritic cells resulting in effective peptide antigen presentation. . . . This this leads to T and B cell clonal expansion, creating immunity in the patient. The resulting infiltration into tumors by hematogenous spread leads to robust tumor destruction. The result... is increased survival due to immunologic memory. . . . [D]endritic cell activation and maturation are considered key factors in cancer immunodeficiency as well as the well-known defects in T cells such as a decreased number and function with anergy and presumed apoptosis. (Spec. 8—9 (citations omitted); cf. Hadden ’983 1: 5—6, 1: 8—11, 1: 27—31, 3: 20-21, 4: 3—8, 14: 4—10, and 16: 39-52; see generally Ans. 2—3.) FF 4. Appellant “predicts] logically that exogenously provided synthetic or extracted tumor peptides . . . can be delivered into the pre-primed or co primed regional or distal lymph node and yield tumor antigen specific T cells, with or without B cells” (Spec. 9; see Ans. 3 (“it would have been obvious to administer the NCM cytokine along with the antigen in the same composition, or on the same day, as a matter of convenience. Furthermore, the ordinary artisan would have a reasonable expectation of success,” because Eisenbach “teaches that the tumor antigen peptides are suitable for use in conjunction with many of the same cytokines in the NCM administered in the method of [Hadden ’983]”). FF 5. Appellant discloses a method of enhancing the immune response of cancer patients to a cancer by administering an effective amount of a composition containing therein [a natural cytokine mixture (NCM)] plus thymosin al and a tumor associated antigen, the NCM plus 7 Appeal 2016-003340 Application 13/653,152 thymosin al acting as an adjuvant to produce the immune response. (Spec. 9; cf Hadden ’983 1: 5-6, 1: 8-11, 1: 27-31, 3: 20-21, 4: 3-8, 14: 4— 10, and 16: 39-52.) FF 6. Appellant defines the term “adjuvant” as “a composition with the ability to enhance the immune response to a particular antigen. To be effective, an adjuvant must be delivered at or near the site of antigen. Such ability is manifested by a significant increase in immune mediated protection” (Spec. 10; cf Hadden ’983 6: 38-49 (disclosing that the combination of NCM and Thymosin al “can be administered in various ways,” including “[sjite specific administration i.e., regional to a cancer is preferred if possible so that adjuvant effects are realized”); see also Hadden ’983 8: 14—15; Ans. 2—3). FF 7. Appellant defines the term “NCM” as “a non-recombinant cytokine mixture ... as set forth in[, inter alia,] Hadden ’983” (Spec. 10; see generally Hadden ’983 1: 38-45, 7: 5—19, and 16: 39-52). FF 8. Appellant discloses that [ujpon administration of [the] NCM to immunosuppressed patients with head and neck cancer, it is demonstrated in this application for the first time that the mobilization of T lymphocytes in the blood of cancer patients treated with the NCM produces an increase in immature, naive T cells bearing both CD2 and CD45 RA. (Spec. 14 (emphasis added); cf Co-pending Application 13/940,558, September 20, 2013 Substitute Specification, 11; Hadden ’983 6: 36—37 (an “[ejxample of the clinical use [of NCM] is exemplified by [Hadden ’94(a)]); see Hadden ’983 15: 24—26.) 8 Appeal 2016-003340 Application 13/653,152 FF 9. Appellant defines the term “pharmaceutically ‘effective amount’” as “determined by such considerations as are known in the art,” wherein “[t]he amount must be effective to achieve immunization, including but not limited to, tumor reduction, fragmentation and infiltration, survival rate or more rapid recover, or improvement or elimination of symptoms” (Spec. 17; cf Hadden ’983 6: 27—37 (disclosing that the term “effective amount,” as used in Hadden ’983’s disclosure, is thus determined by such considerations as are known in the art. The amount must be effective to show improvement in immune function in 25% of patients treated including, but not limited to, improved responses in vitro measurements of cellular immune function, increased T lymphocyte levels in vivo, improved skin test response to recall antigens or NCM, improved survival rate, more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass. {See also Hadden ’983 5: 60—67; see generally Ans. 2—3.)) FF 10. Hadden ’983 discloses that “NCM may be used with other treatments to improve immune function and treat cancer” (Hadden ’983 6: 34—36; see Ans. 7 (citing Hadden ’983 6 and 8) (Hadden ’983 discloses “that the NCM is administered in an amount sufficient to increase T cells and improve T lymphocyte responses to antigens (i.e. induce an immune response in the subject)”). FF 11. Hadden ’983 discloses that “IL-2,” inter alia, “induces and supports proliferation of antigen or mitogen stimulated T-cells” (Hadden ’983 1: 47— 49). FF 12. Hadden ’983 does not disclose administering an exogenous antigen together with a composition comprising a combination of NCM and thymosin al (Ans. 3 and 5). 9 Appeal 2016-003340 Application 13/653,152 FF 13. Eisenbach “relates to tumor associated antigen (TAA) peptides and to the use of same, of polynucleotides encoding same and of cells presenting same as anti-tumor vaccines” (Eisenbach 1: 5—7; see id. at 8: 4—7 (Eisenbach “provides] novel tumor associated antigen peptides effective in eliciting CTL response which may [] be effective therapeutic agents to combat cancer”); id. at 23: 1—3; Ans. 3 (Eisenach discloses “administration of exogenous tumor antigen peptides to treat subjects with cancer”)). Eisenbach discloses that “the phrase ‘anti-tumor vaccines’ refers to vaccines effective in preventing the development of, or curing, cancer, including primary tumor and/or metasteses” (Eisenbach 20: 36—38; see Ans. 3). FF 14. Eisenbach discloses the use of a peptide derived from, inter alia, “Prostate specific membrane antigen (PSMA)” (Eisenbach 4: 13—15; see also Ans. 3). FF 15. Eisenbach discloses that “the tumor associated antigen peptide[s] are presented in [the] context of [a] carrier,” which includes an adjuvant and “cytokines, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, interferon alpha, interferon beta, interferon gamma and others” (Eisenbach 21: 14—26; see Ans. 3). FF 16. Examiner finds that the combination of Hadden ’983 and Eisenbach fail to disclose the administration of “cyclophosphamide, a nonsteroidal anti inflammatory drug (NSID), or zinc” (Ans. 4). FF 17. Hadden ’94(a) discloses the treatment of [mjetastatic squamous cell head and neck cancer . . . with low- dose cyclophosphamide (to reduce suppressor T-cell activity), indomethacin (to reduce prostaglandins that mediate macrophage-induced immune suppression), zinc (to augment T- 10 Appeal 2016-003340 Application 13/653,152 cell function via thymulin), and mixed natural interleukins perilymphatically in the neck (as adjuvant for tumor antigen in the region). (Hadden ’94(a), Abstract; see Ans. 4.) FF 18. Examiner finds that Hadden ’99 discloses “NCM . . . vaccine therapy comprising administration of exogenous tumor antigens” and “that combined use of therapies including vaccines, interleukins, cyclophosphamide, and indomethacin have complementary immunopharmacologies and should be compatible” (Ans. 5 (citing Hadden ’99 92); see also Hadden ’99, Abstract). FF 19. Examiner finds that Hadden ’99 discloses “that zinc can [] be used in combination with indomethacin and cyclophosphamide for treating cancer” (Ans. 5 (citing Hadden ’99 90)). FF 20. Examiner finds that Hadden ’94(b) discloses “that interleukins and thymic hormones act to promote TH cell responses and that coupling such agents with antigens is useful in efforts to produce T cell adjuvenicity” (Ans. 6 (citing Hadden ’94(b) 707)). ANALYSIS The rejection over the combination of Hadden ’983 and Eisenbach: Appellant recognized that it was known in the art, prior to the filing date of Appellant’s claimed invention, that a “fundamental problem in the effort to immunize cancer patients is that the tumor-bearing state is associated with immunosuppressive mechanisms derived from both the tumor and the host’s disturbed immune system” that makes “immunization difficult” (FF 1). Thus, Appellant sought to overcome, or unblock, this immunosuppression and, thereby, restore immunological function so that an 11 Appeal 2016-003340 Application 13/653,152 immune response to at least one exogenous tumor antigen can be stimulated by administering, to the cancer patient, an effective amount of NCM together with a thymic peptide, such as thymosin al, and at least one exogenous antigen, on the same day, so as to induce an immune response in the patient (see FF 1—9; see also Appellant’s claim 33). Methods of inducing an immune response in a patient comprising administering an exogenous antigen and an adjuvant were not new to Appellant’s disclosure. To the contrary, such methods were well known in this art at the time of Appellant’s claimed invention (see FF 13—15). The use of a cytokine or cytokine mixture, as an adjuvant, in a method of inducing an immune response to an exogenous antigen was also not new to Appellant’s disclosure, but was instead routine in this art prior to the filing date of Appellant’s claimed invention (see FF 15 (Eisenbach discloses administering “tumor associated antigen peptide[s]... in [the] context of [a] carrier,” which includes an adjuvant and/or cytokines)); FF 2 (“A major class of immunomodulators is cytokines”); FF 6 (Hadden ’983 discloses a preferred site for NCM administration to realize NCM’s “adjuvant effects”). Thus, while Eisenbach does not expressly disclose that cytokines are adjuvants, we find that identical language between the prior art and claims is not required to sustain a prior-art rejection. In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Any other result would permit the allowance of claims drawn to unpatentable subject matter merely through the employment of descriptive language not chosen by the prior art”). In addition, we note that Appellant’s claim 33 does not require the NCM and/or thymosin peptide to directly induce an immune response to an exogenous antigen in a subject (see Appellant’s claim 33). Nevertheless, given that Hadden ’983 discloses 12 Appeal 2016-003340 Application 13/653,152 that a cytokine mixture, NCM, which may be administered in conjunction with a thymosin peptide, exhibits adjuvant activity and an ability to improve a cellular immune response in a patient, we find no error in Examiner’s conclusion that it would have been prima facie obvious to use the NCM disclosed by Hadden ’983 in Eisenbach’s method or, in the alternative, to add an exogenous antigen to the method disclosed by Hadden ’983 (see Ans. 3; see also id. at 11—12; FF 1—10). Therefore, we are not persuaded by Appellant’s contention that Eisenbach “does not provide any data showing that a single cytokine, let alone a mixture of cytokines, enhances an antigen- specific T cell response to an exogenous antigen,” which fails to account for Hadden ’983’s contribution to the combination of Hadden ’983 and Eisenbach (App. Br. 11). See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (Each reference “must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole”). In addition, we note that the method of Appellant’s claim 33 does not require NCM or a thymosin peptide, alone or in combination, to directly induce an immune response to an exogenous antigen in a subject (see App. Br. 30). In this regard, Eisenbach makes clear that the administration of an exogenous antigen to a patient will induce an immune response to the exogenous antigen (see FF 13—15). Hadden ’983 recognized the “limited efficacy” of prior cytokine therapies, potential “toxicity” associated with the use of cytokines, and the number of potential cytokine combinations (see FF 1). Hadden ’983, therefore, set out to overcome these prior art hurdles in the use of cytokine mixtures as, inter alia, adjuvants, in a method of improving cellular immune response in a patient and successfully developed a specific mixture of 13 Appeal 2016-003340 Application 13/653,152 cytokines, NCM, that may be combined with thymosin al and overcomes the prior art problems with cytokine therapy, overcomes the immunosuppressive state of cancer patients, exhibits adjuvant effects, and improves cellular immune response in a patient (see FF 1—3 and 5—9). There is no dispute on this record that Hadden ’983 ’s NCM is the natural cytokine mixture and is prepared by the same process and that Hadden ’983 discloses the combination of NCM with thymosin al as is required by Appellant’s claim 33 (see FF 6—7). Although Hadden ’983 discloses an effective mixture of cytokines for use in, inter alia, the treatment of cancer, Hadden ’983 does not disclose a vaccine composition that comprises NCM and an exogenous antigen (FF 1— 12). Hadden ’983, however, discloses that its “treatment methods can be performed [in combination] with other cancer treatment regimens” such as those disclosed by Eisenbach, which includes administration of an exogenous antigen, such as the PSMA tumor associated antigen in a carrier that comprises cytokines, such as those disclosed by Hadden ’983 (see FF 1— 15). There is no dispute on this record that the prior art suggests amounts of antigen, thymosin al, and NCM that are effective for administration to a subject to stimulate an immune response to the antigen as is required by Appellant’s claim 33 or that such amounts could not have been “determined by such considerations as are known in the art” (see e.g., FF 9; see generally 1-15). In re Geisler, 116 F.3d 1465, 1470, (Fed. Cir. 1997) (“‘[I]t is not inventive to discover the optimum or workable ranges by routine experimentation.’”) (quoting In re Aller, 220 F.2d 454, 456 (CCPA 1955)). Therefore, we are not persuaded by Appellant’s contention that Hadden ’983 fails to suggest “eliciting an antigen-specific immune response to an 14 Appeal 2016-003340 Application 13/653,152 exogenous antigen by administering the exogenous antigen in combination with a cytokine mixture and a thymic peptide,” which fails to account for Eisenbach’s contribution to the combination of Hadden ’983 and Eisenbach (see App. Br. 10; cf. FF 1—15). See In re Merck & Co., 800 F.2d at 1097. Therefore, as discussed above, we find no error in Examiner’s conclusion that, at the time of Appellant’s claimed invention, a person of ordinary skill in this art would have found it prima facie obvious, to use the NCM disclosed by Hadden ’983 in Eisenbach’s method or, in the alternative, to add an exogenous antigen to the method disclosed by Hadden ’983 (see Ans. 3; see also id. at 11—12; FF 1—15). Although a person of ordinary skill in this art would have reasonably and logically expected that a restored immune system would have facilitated a response to an exogenous antigen,18 Hadden ’983 provides a reason to combine its composition comprising NCM and thymosin al with other cancer treatment regimens, which include the administration of an exogenous tumor associated antigen, such as PSMA, in combination with cytokines as disclosed by Eisenbach, to elicit a response to the exogenously supplied tumor associated antigen (see FF 1—15; see also Ans. 12 (Hadden ’983 and Eisenbach “both [] teach that the compositions (either the NCM or the peptide antigen) are effective for the same purpose, i.e. improving the immune response to treat cancer”)). Thus, on this record, Hadden ’983 suggests its combination with Eisenbach and Eisenbach suggests its combination with Hadden ’983. Therefore, we are not persuaded by Appellant’s contention that “[hjaving a ‘restored’ 18 See In re O’Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success”). 15 Appeal 2016-003340 Application 13/653,152 immune system[, as disclosed by Hadden ’983] is not predictive of whether a subject will respond to an exogenous antigen” (App. Br. 10; cf. FF 1—15). To the contrary, the evidence relied upon by Examiner supports a conclusion that a person of ordinary skill in this art would have combined Hadden ’983’s NCM with Eisenbach’s exogenous antigen in order to induce an immune response to the exogenous antigen in a subject, with a reasonable expectation of success (see FF 1—10). In sum, the combination of Hadden ’983 and Eisenbach suggest the combination of familiar elements according to known methods to yield a predictable result. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”). In this regard, we note that “[ojbviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success.” See In re O'Farrell, 853 F.2d at 903—904; cf. Naylor19110 (“the literature at the time [of Appellant’s claimed invention] and . . . [Eisenbach] does not provide certainty” and “Cavallion20 specifically calls into question the concept of pro- and anti-inflammatory cytokines and teaches that it is not possible to predict with certainty how any individual cytokine or combination of cytokines will act when administered in vivo both with respect to immune activation or suppression”) (emphasis added). Notwithstanding Naylor’s statements to the contrary, “certainty” is not 19 Declaration of Paul H. Naylor, Ph.D., signed July 5, 2014. 20 Jean-Marc Cavaillon, Pro-versus Anti-Inflammatory Cytokines: Myth or Reality, 47 Cellular and Molecular Biology 695—702 (2001). 16 Appeal 2016-003340 Application 13/653,152 required to achieve a reasonable expectation of success. To the contrary, where, as here, a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. KSR, 550 U.S. at 417. On this record, Appellant failed to provide persuasive argument or evidence to support a conclusion that by performing the method suggested by the combination of Hadden ’983 and Eisenbach, an antigen- specific response to an exogenous antigen would not have been induced as required by Appellant’s claim 33 (cf. App. Br. 11). Therefore, we are also not persuaded by Appellant’s contention that: Examiner has not established a prima facie case because she has not met her burden in establishing that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous antigen to a subject. (App. Br. 12 (citing Naylor).) As discussed above, there is no dispute on this record that Hadden ’983’s NCM is the same natural cytokine mixture as is required by Appellant’s claim 33. Appellant appears to be the inventor of the subject matter of Hadden ’983. Appellant and Hadden ’983 both disclose similar features and/or benefits associated with NCM (see FF 1—10). Nevertheless, Appellant contends that “the mechanism of action of the NCM was not known at the time of the filing [of] the present application, and any statements in the art at the time of the filing of the instant application regarding the mechanism of action were ‘inferential and speculative’” (App. 17 Appeal 2016-003340 Application 13/653,152 Br. 16 (citing Naylor 112). Stated differently, subsequent to Appellant’s earlier Hadden ’983 Patent, Appellant discovered new properties and/or benefits associated with the combination of NCM and a thymosin peptide with other cancer therapies. Hadden ’983, however, discloses a composition comprising NCM, together with thymosin al, for use in combination with other cancer therapies that were known in the art, such as those disclosed by Eisenbach (see FF 1—15). Thus, Hadden ’983 disclosed, what was at the time of Appellant’s filing date, an old process. See King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275—76 (Fed. Cir. 2010) (“[Mjerely discovering and claiming a new benefit of an old process cannot render the process again patentable.”); In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). Therefore, we are not persuaded by Appellant’s contention that the observation and further characterization of a composition comprising NCM and thymosin al alone or in combination with other therapies, as disclosed by Hadden ’983, renders Appellant’s old method newly patentable. Further, we recognize Appellant’s contentions and Naylor’s statements regarding NCM’s mechanism of action and citation to a number of supplemental documents, which allegedly support a conclusion that cytokines exhibit different activities (see App. Br. 12—18; Naylor || 8—15). Hadden ’983, however, recognized these concerns in the art and set out to overcome these prior art hurdles in the use of cytokine mixtures as adjuvants and successfully developed a specific mixture of cytokines, NCM, that can be combined with thymosin al, which overcomes the prior art problems with cytokine therapy, overcomes the immunosuppressive state of cancer patients, exhibits adjuvant effects, and facilitates an immune response (see 18 Appeal 2016-003340 Application 13/653,152 FF 1—10). There is no dispute on this record that Hadden ’983 ’s NCM is the natural cytokine mixture required by Appellant’s claim 33 (see FF 7). As this record makes clear, Hadden ’983’s disclosure of an effective cytokine mixture in combination with thymosin al ‘“puts the key in the lock of the door of success’. All that remains for a person having ordinary skill is to turn the key and, in so doing, open the lock. That, in our judgment, does not give rise to a patentable invention.” See Ex parte Goldgaber, 41 USPQ2d 1172, 1175 (Bd. Pat. App. & Int. 1995). Therefore, we are not persuaded by Appellant’s contentions and Naylor’s statements regarding the complexity of the cytokine network or the prior art’s concerns relating to cytokines, which were recognized and overcome by Hadden ’983 (see App. Br. 12-18; Naylor H 8-15; cf. FF 1-15). For the foregoing reasons, we are not persuaded by Naylor or Appellant’s reliance thereon (see Naylor || 8—15; App. Br. 12—18). As discussed above, we are not persuaded by Appellant’s contention and Naylor’s statement that “[wjithout the knowledge of the mechanism of action of NCM, one of ordinary skill in the art would not have predicted that an antigen specific response to an exogenous antigen would be the result of administering the antigen with a NCM and a thymic peptide” (App. Br. 17 (citing Naylor 112); see generally id. at 12—18). Notwithstanding Appellant’s contention to the contrary, Hadden ’983 discloses the same NCM required by Appellant’s claim 33, in combination with a thymic peptide and its use as an adjuvant in combination with other cancer therapies, such as those disclosed by the combination of Eisenbach (FF 1— 15). The observation and further understanding of a composition comprising NCM and thymosin al and its mechanism of action, which are properties of 19 Appeal 2016-003340 Application 13/653,152 the composition itself, does not support a conclusion of non-obviousness on this record. See In re Papesch, 315 315 F.2d 381, 391 (CCPA 1963) (“From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing”). Further, on this record, Appellant failed to provide persuasive evidence or argument to support a conclusion that the administration of an exogenous antigen together with NCM and thymosin al, as suggested by the combination of Hadden ’983 and Eisenbach, to a patient in need thereof would not have achieved the same result as obtained by performing the method of Appellant’s claim 33 (see FF 1-15). For the foregoing reasons, we are not persuaded by Appellant’s contention that Naylor “provides sufficient factual evidence to rebut the Examiner’s allegation that a person of ordinary skill in the art would have had a reasonable expectation of success based on the cited art” (App. Br. 12). For the same reasons, we are not persuaded by Appellant’s contention that “Examiner has not taken into account all of the art and evidence of record and has made an erroneous rejection of the claims” (Reply Br. 4). The rejection over the combination of Hadden ’983, Eisenbach, and Hadden ’94(a): Based on the combination of Hadden ’983, Eisenbach, and Hadden ’94(a), Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to “administer cyclophosphamide, indomethacin, and zinc, as taught by [Hadden ’94(a)], in the method of treating cancer, as taught by the [combination of Hadden ’983 and Eisenbach]” (Ans. 4). We find no error in Examiner’s prima facie case of obviousness (see FF 1—17). 20 Appeal 2016-003340 Application 13/653,152 We are not persuaded by Appellant’s contention that Hadden ’94(a) “does not each or suggest that administering a NCM, a thymic peptide, and an exogenous antigen would result in an immune response to an exogenous antigen in a subject,” which, as discussed above, is suggested by the combination of Hadden ’983 and Eisenbach (App. Br. 18). The rejection over the combination of Hadden ’983, Hadden ’99, and Hadden ’94(b): Based on the combination of Hadden ’983, Hadden ’99, and Hadden ’94(b), Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to “administer a tumor antigen and indomethacin and cyclophosphamide, as taught by [Hadden ’99], in the method of treating a cancer, as taught by the [combination of Hadden ’983 and Hadden ’94(b)]” (Ans. 6; see also id. at 16—17). We find no error in Examiner’s prima facie case of obviousness (see FF 1—12 and 18-20). Hadden ’983 discloses the administering a composition comprising NCM and thymosin al to patients in an amount “effective to show improvement in immune function . . . including, but not limited to, . . . cancer reduction of tumor mass” (FF 9; see also FF 1—8 and 10—12). In this regard, Hadden ’983 discloses that its “treatment methods can be performed [in combination] with other cancer treatment regimens” such as those disclosed by Hadden ’99, which includes administration of a NCM vaccine comprising exogenous tumor antigens (see FF 18; see also FF 1—12). Therefore, we are not persuaded by Appellant’s contention that the combination of Hadden ’983, Hadden ’99, and Hadden ’94(b) “would not have led one of ordinary skill in the art to have a reasonable expectation of 21 Appeal 2016-003340 Application 13/653,152 success that the claimed administration of NCM, a thymic peptide, and an exogenous antigen would stimulate an immune response to the exogenous antigen” (see App. Br. 20; cf. FF 1—12 and 18—20). For the foregoing reasons, we are not persuaded by Appellant’s reliance on their arguments above, and the Naylor Decl., regarding a mechanism of action (App. Br. 20). CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 33 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’983 and Eisenbach is affirmed. Claims 34—38 and 46—50 are not separately argued and fall with claim 33. The rejection of claim 40 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’983, Eisenbach, and Hadden ’94(a) is affirmed. Claims 41—45 are not separately argued and fall with claim 40. The rejection of claim 33 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hadden ’983, Hadden ’99, and Hadden ’94(b) is affirmed. Claims 34—38, 40-48, and 50 are not separately argued and fall with claim 33. Obviousness-type Double Patenting'. Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness-type double patenting? 22 Appeal 2016-003340 Application 13/653,152 FACTUAL FINDINGS (FF) FF 21. Hadden ’072’s claim 1 is reproduced below: 1. A method for unblocking immunization at a regional lymph node of a patient comprising: (i) perilymphatically administering a natural cytokine mixture [(NCM)] to a patient having an accumulation of dendritic cells, which have ingested or processed an antigen but are unable to mature, whereby said perilymphatic administration promotes the differentiation and maturation of the said dendritic cells; and (ii) administering to the patient cyclophosamide and an NS AID, whereby said administration decreases T-cell suppression. (Hadden ’072 24: 26—37 (emphasis added).) FF 22. Hadden ’072’s claim 6 defines the antigen of Hadden ’072’s claim 1 as “an exogenous antigen” (Hadden ’072 24: 48-49). FF 23. Hadden ’072’s claim 2 depends from and further defines step (i) of Hadden ’072’s claim 1 “as administering a . . . [NCM] perilymphatically into lymphatics that drain into lymph nodes regional to a lesion to be treated” (Hadden ’072 24: 38^11). FF 24. Hadden ’072’s claim 7 defines the NCM of Hadden ’072’s claim 1 as “including IL-1, IL-2, IL-6, IL-8, 8IFN and TNFa” (Hadden ’072’s 24: 50-52). FF 25. Hadden ’517’s claim 1 is reproduced below: 1. A method of immunotherapy to treat cancer in a patient comprising: administering an effective amount of a cytokine mixture comprising IL-1, IL-2, IL-6, IL-8, IFN-y, and TNF-a to the patient; and administering an effective amount of at least one exogenous tumor peptide antigen to the patient, 23 Appeal 2016-003340 Application 13/653,152 wherein the cytokine mixture acts as an adjuvant and stimulates in the patient an enhanced antigen-specific immune response to the at least one exogenous tumor peptide antigen. (Hadden ’517 42: 33—43.) FF 26. Hadden ’517’s claim 7 defines the cytokine mixture of Hadden ’517’s claim 1 as a “natural cytokine” mixture (NCM) (Hadden ’517 42: 59- 60). FF 27. Hadden ’517’s claim 5 ultimately depends from and further limits Hadden ’517’s claim 1 to require that the “cytokine mixture and the at least one exogenous tumor peptide antigen are administered at the same time” (Hadden ’517 42: 53-55). FF 28. Hadden ’779’s claim 30 is reproduced below: 30. A method for inducing an immune response to at least one exogenous antigen in a patient, the method comprising: administering to the patient an effective amount of a natural cytokine mixture [(NCM)] comprising the cytokines IL-1 beta, IL-2, IL-6, IL-8, IFN-gamma, and TNF-alpha; and administering to the patient an effective amount of at least one exogenous antigen, wherein the . . . [NCM] acts as an adjuvant with the at least one exogenous antigen and stimulates an immune response to the at least one exogenous antigen in the patient. (Hadden ’779 13: claim 30.) FF 29. Hadden ’779’s claim 35 depends from and further defines the NCM of Hadden ’779’s claim 30 to “further comprise^ GM-CSF and G-CSF” (Hadden ’779 14: claim 35). FF 30. Hadden ’796’s claim 1 is reproduced below: 1. A method for treating hepatocellular cancer in a patient, the method comprising: administering to the patient having hepatocellular cancer an effective amount of a natural 24 Appeal 2016-003340 Application 13/653,152 cytokine mixture [(NCM)] comprising the cytokines IL- lbeta, IL-2, IL-6, IL-8, IFN-gamma, and TNF-alpha. (Hadden ’796 24: 58-62.) FF 31. Hadden ’796’s claim 6 depends from and further defines the NCM of Hadden ’796’s claim 1 to further comprise GM-CSF and G-CSF (Hadden ’796 25: 13-14). FF 32. Hadden ’796’s claim 5 depends from and further limits Hadden ’796’s claim 1 to “further comprises: administering to the patient an effective amount of at least one exogenous tumor antigen” (Hadden ’796 25: 9-12). FF 33. Hadden ’519’s claim 1 is reproduced below: 1. A method for treating a patient having advanced prostate cancer, the method comprises: (a) administering to the patient having advanced prostate cancer an effective amount of a composition comprising a natural cytokine mixture (NCM), the NCM comprising IL-1, IL-2, IL-6, IL-8, IFN-gamma, and TNF-alpha; and (b) administering to the patient an effective amount of at least one exogenous tumor antigen, wherein the cytokines act as an adjuvant with the at least one exogenous tumor antigen and stimulate an immune response to the at least one exogenous tumor antigen in the patient; wherein the immune response is effective to alleviate or eliminate symptoms and effects of the advanced prostate cancer in the patient; wherein the patient has previously received surgery, radiotherapy, chemotherapy, or combinations thereof; and wherein after surgery, radiotherapy, chemotherapy, or combinations thereof the patient has tumor recurrence, a rise in PSA antigen levels, or a combination thereof. (Hadden’519 43: 59-44: 13.) 25 Appeal 2016-003340 Application 13/653,152 FF 34. Hadden ’519’s claim 2 depends from and further limits Hadden ’519’s claim 1 to comprise “administering the composition and the at least one exogenous tumor antigen at the same time” (Hadden ’519 44: 13—15). ANALYSIS The rejection over the claims of Hadden ’072 in view of Hadden ’983, Hadden ’94(a), andEisenbach: Based on the combination of Hadden ’072 in view of Hadden ’983, Hadden ’94(a), and Eisenbach, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to substitute Hadden ’072’s NCM composition with a composition comprising thymosin-al and NCM, which falls within the scope of the NCM of Appellant’s claim 33, for the benefits suggested by Hadden ’983 (Ans. 7 and 17 ; see FF 21—24 and 1—12; see also FF 13—15 (Eisenbach discloses the administration of an exogenous antigen together with a carrier comprising cytokines)). In addition, Examiner reasons that “it would [have been] obvious to administer the various treatments on the same day as a matter of convenience” (Ans. 8). We find no error in Examiner’s prima facie case. Appellant contends that Examiner failed to “establish[] that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous antigen to a subject” (App. Br. 21; see also id. at 21—22 (citing Naylor Deck)). We are not persuaded. Eisenbach suggests the administration of a composition comprising an exogenous antigen and cytokines to induce an immune response to the exogenous antigen in a subject (see FF 13—15). Hadden ’072’s claimed 26 Appeal 2016-003340 Application 13/653,152 method comprises the administration of NCM and an exogenous antigen to decrease T-cell suppression, and, thereby, enhance the immune response (FF 21—24). Hadden ’983 discloses the administration of a composition comprising NCM and thymosin-al to, inter alia, “increase^ T lymphocyte levels in vivo, . . . improved survival rate, [provide] more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass” and further discloses that the composition “may be used with other treatments to improve immune function and treat cancer” (FF 9; cf Spec. 17: 19—23). Thus, notwithstanding Appellant’s contention to the contrary, when taken as a whole, Hadden ’072 in combination with Hadden ’983, Hadden ’94(a), and Eisenbach provides a person of ordinary skill in this art with a reasonable expectation of success in inducing an immune response to an exogenous antigen in a subject. See In re O'Farrell, 853 F.2d at 903-904 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success”). The rejection over the claims of Hadden ’517 in view of Hadden ’983 and Eisenbach'. Based on the combination of Hadden ’517 in view of Hadden ’983 and Eisenbach, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to substitute Hadden ’517’s NCM composition with a composition comprising thymosin-al and NCM, which falls within the scope of the NCM of Appellant’s claim 33, for the benefits suggested by Hadden ’983 (Ans. 8 and 17; see FF 25—27 and 1— 12; see also FF 12—15 (Eisenbach discloses the administration of an exogenous antigen together with a carrier comprising cytokines)). In addition, Examiner reasons that “it would [have been] obvious to administer 27 Appeal 2016-003340 Application 13/653,152 the various treatments on the same day as a matter of convenience” (Ans. 8; see FF 27). We find no error in Examiner’s prima facie case. Appellant contends that Examiner failed to “establish[] that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous antigen to a subject” (App. Br. 22—23 (citing Naylor Decl.)). We are not persuaded. Eisenbach suggests the administration of a composition comprising an exogenous antigen and cytokines to induce an immune response to the exogenous antigen in a subject (see FF 12—15). Hadden ’517 claims a method of immunotherapy, “wherein . . . [NCM] acts as an adjuvant and stimulates in the patient an enhanced antigen-specific immune response to [] at least one exogenous tumor peptide antigen” (FF 25; see also id. FF 26— 27). Hadden ’983 discloses the administration of a composition comprising NCM and thymosin-al to, inter alia, “increase^ T lymphocyte levels in vivo, . . . improved survival rate, [provide] more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass” and further discloses that the composition “may be used with other treatments to improve immune function and treat cancer” (FF 9; cf Spec. 17: 19—23). Thus, notwithstanding Appellant’s contention to the contrary, when taken as a whole, Hadden ’517 in combination with Hadden ’983 and Eisenbach provides a person of ordinary skill in this art with a reasonable expectation of success in inducing an immune response to an exogenous antigen in a subject. See In re O'Farrell, 853 F.2d at 903-904 (Fed. Cir. 28 Appeal 2016-003340 Application 13/653,152 1988) (“Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success”). The provisional rejection over the claims of Hadden ’779 in view of Hadden ’983 and Hadden ’94(a): Based on the combination of Hadden ’779 in view of Hadden ’983 and Hadden ’94(a), Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to substitute Hadden ’779’s NCM composition with a composition comprising thymosin- al and NCM, which falls within the scope of the NCM of Appellant’s claim 33, for the benefits suggested by Hadden ’983 (Ans. 9 and 18; see FF 28—29 and 1—12). In addition, Examiner reasons that “it would [have been] obvious to administer the various treatments on the same day as a matter of convenience” (Ans. 9). We find no error in Examiner’s prima facie case. Appellant contends that Examiner failed to “establish[] that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous antigen to a subject” (App. Br. 24 (citing Naylor Decl.)). We are not persuaded. Hadden ’779’s claimed method comprises the administration of NCM and at least one exogenous antigen to induce an immune response to the at least one exogenous antigen (FF 28—29). Hadden ’983 discloses the administration of a composition comprising NCM and thymosin-al to, inter alia, “increase^ T lymphocyte levels in vivo, . . . improved survival rate, [provide] more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass” and further discloses that the 29 Appeal 2016-003340 Application 13/653,152 composition “may be used with other treatments to improve immune function and treat cancer” (FF 9; cf Spec. 17: 19-23). Thus, notwithstanding Appellant’s contention to the contrary, when taken as a whole, Hadden ’779 in combination with Hadden ’983 and Hadden ’94(a) provides a person of ordinary skill in this art with a reasonable expectation of success in inducing an immune response to an exogenous antigen in a subject. See In re O'Farrell, 853 F.2d at 903-904 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success”). The rejection over the claims of Hadden ’796 in view of Hadden ’983, Hadden ’94(a), andEisenbach: Based on the combination of Hadden ’796 in view of Hadden ’983, Hadden ’94(a), and Eisenbach, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to substitute Hadden ’796’s NCM composition with a composition comprising thymosin-al and NCM, which falls within the scope of the NCM of Appellant’s claim 33, for the benefits suggested by Hadden ’983 (Ans. 9—10 and 18 ; see FF 30—32 and 1—12; see also FF 12—15 (Eisenbach discloses the administration of an exogenous antigen together with a carrier comprising cytokines)). In addition, Examiner reasons that “it would [have been] obvious to administer the various treatments on the same day as a matter of convenience” (Ans. 10). We find no error in Examiner’s prima facie case. Appellant contends that Examiner failed to “establish[] that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous 30 Appeal 2016-003340 Application 13/653,152 antigen to a subject” (App. Br. 25 (citing Naylor Decl.)). We are not persuaded. Eisenbach suggests the administration of a composition comprising an exogenous antigen and cytokines to induce an immune response to the exogenous antigen in a subject (see FF 12—15). Hadden ’796’s claimed method comprises the administration of NCM and an exogenous antigen to treat hepatocellular cancer in a patient (FF 30-32). Appellant offers no persuasive evidence or argument to support a conclusion that Hadden ’976’s method does not result in inducing an immune response to the exogenous antigen. Hadden ’983 discloses the administration of a composition comprising NCM and thymosin-al to, inter alia, “increase^ T lymphocyte levels in vivo, . . . improved survival rate, [provide] more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass” and further discloses that the composition “may be used with other treatments to improve immune function and treat cancer” (FF 9; cf Spec. 17: 19—23). Thus, notwithstanding Appellant’s contention to the contrary, when taken as a whole, Hadden ’796 in combination with Hadden ’983, Hadden ’94(a), and Eisenbach provides a person of ordinary skill in this art with a reasonable expectation of success in inducing an immune response to an exogenous antigen in a subject. See In re O'Farrell, 853 F.2d at 903-904 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success”). The rejection over the claims of Hadden ’519 in view of Hadden ’983: Based on the combination of Hadden ’519 in view of Hadden ’983, Examiner concludes that, at the time Appellant’s invention was made, it 31 Appeal 2016-003340 Application 13/653,152 would have been prima facie obvious to substitute Hadden ’519’s NCM composition with a composition comprising thymosin-al and NCM, which falls within the scope of the NCM of Appellants’ claim 33, for the benefits suggested by Hadden ’983 (Ans. 9 and 18—19; see FF 33—34 and 1—12). In addition, Examiner reasons that “it would [have been] obvious to administer the various treatments on the same day as a matter of convenience” (Ans. 9; see FF 34). We find no error in Examiner’s prima facie case. Appellant contends that Examiner failed to “establish[] that one of ordinary skill in the art would have had a reasonable expectation of success based on the cited art of inducing an immune response to an exogenous antigen upon administering NCM, a thymic peptide, and the exogenous antigen to a subject” (App. Br. 26—27 (citing Naylor Decl.)). We are not persuaded. Hadden ’519’s claimed method comprises the administration of NCM and an exogenous antigen to treat a patient having advanced prostate cancer, wherein the NCM acts as an adjuvant with the at least one exogenous tumor antigen and stimulates an immune response to the at least one exogenous tumor antigen in the patient (FF 33; see also FF 34). Hadden ’983 discloses the administration of a composition comprising NCM and thymosin-al to, inter alia, “increase^ T lymphocyte levels in vivo, . . . improved survival rate, [provide] more rapid recovery, or improvement or elimination of symptoms and in cancer reduction of tumor mass” and further discloses that the composition “may be used with other treatments to improve immune function and treat cancer” (FF 9; cf. Spec. 17: 19-23). Thus, notwithstanding Appellant’s contention to the contrary, when taken as a whole Hadden ’519 in combination with Hadden ’983 provides a person of 32 Appeal 2016-003340 Application 13/653,152 ordinary skill in this art with a reasonable expectation of success in inducing an immune response to an exogenous antigen in a subject. See In re O'Farrell, 853 F.2d at 903-904 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success”). CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness-type double patenting. The rejection of claim 33 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’072 in view of Hadden ’983, Hadden ’94(a), and Eisenbach is affirmed. Claims 34—38 and 40-50 are not separately argued and fall with claim 33. The rejection of claim 33 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’517 in view of Hadden ’983 and Eisenbach is affirmed. Claims 34—38 and 40—50 are not separately argued and fall with claim 33. The provisional rejection of claim 33 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’779 in view of Hadden ’983 and Hadden ’94(a) is affirmed. Claims 34—38 and 40-50 are not separately argued and fall with claim 33. The rejection of claim 33 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’796 in view of Hadden ’983, Hadden ’94(a), and Eisenbach is 33 Appeal 2016-003340 Application 13/653,152 affirmed. Claims 34—38 and 40-50 are not separately argued and fall with claim 33. The rejection of claim 33 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Hadden ’519 in view of Hadden ’983 is affirmed. Claims 34—38 and 40-50 are not separately argued and fall with claim 33. TIME PERIOD FOR RESPONSE 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 34 Copy with citationCopy as parenthetical citation