DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed 4/16/26 in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/16/26 has been entered.
Claims 1, 10-12, 14-15, 17, 19, 87-95 are pending.
Claims 10, 90 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Claims 1, 11-12, 14-15, 17, 19, 87-89, and 91-95 are being acted upon.
The nonstatutory double patenting rejection over application 15/570,799 is withdrawn in view of the abandonment of the application.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 11-12, 14-15, 17, 19, 87-89, and 91-95 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the cells" in line 3 There is insufficient antecedent basis for this limitation in the claim. The claim recites a mature dendritic cell population, but not “cells”. Amendment to claim 1 to recite (a) obtaining “a population of mature dendritic cells”, wherein “the mature dendritic cells”, for example, would be remedial (and similarly correcting the dependent claims). .Alternatively, Applicant could replace the recitation of “the cells” with “the mature dendritic cell population” to provide antecedent basis.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 1, 11, 91-92 and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilgenhof, 2011, in view of US 2011/0306948 (both of record).
Wilgenhof teach a method of treating a patient with melanoma (i.e. a tumor) comprising administering to the patient autologous dendritic cells in conjunction with IFN-alpha (see page 448, 450-452, in particular). Wilgenhof teach that the dendritic cells are mature (see page 450, in particular). Wilgenhof teach that the dendritic cells have been loaded with mRNA antigens from the tumor, see page 449, in particular. Wilgenhof teach administration of the IFN-alpha after the mature dendritic cells (see page 451, in particular). Wilgenhof teach that some of the treated patients achieved an objective response, and had regression of metastases, i.e. reduced tumor volume or inhibition of tumor growth, see page 453, in particular). Other than being loaded with mRNA, the dendritic cells of Wilgenhof are not otherwise genetically modified.
The reference differs from the claimed invention in that it does not explicitly teach that the dendritic cells are loaded with tumor antigen lysate derived from a cancer cell population excised from the patient.
The ‘948 publication teaches dendritic cell vaccines for treating cancer, wherein the dendritic cells are doubly loaded with tumor specific lysate and tumor specific mRNA, and that doing so results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone (see page 1, in particular). The ‘948 publication teaches that the tumor lysate and mRNA can be obtained from surgically resected tumor tissue from the patient (i.e. from a cancer cell population excised from the patient, see page 8-10 in particular). The ‘948 publication teaches that the dendritic cells are autologous (see paragraph 105, in particular). The ‘948 publication teaches that of tumor antigen sources, tumor lysates and mRNA preparations from tumors are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens (see paragraph 6, in particular). The ‘948 publication teaches the use of dendritic cell vaccines for treating a variety of tumor types, including melanoma, renal cell cancer, and tumors of the pancreas (see paragraph 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further load the autologous dendritic cells of Wilgenhof, with tumor cell mRNA and tumor cell lysate from resected tumor tissue of the patient, as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘948 publication teaches that double loading with mRNA and lysate results in superior T cell responses compared to mRNA alone. Furthermore, the ordinary artisan would be motivated to select tumor tissue/cancer cell samples excised from the patient as the source of lysate and mRNA, since the ‘948 publication teaches that they are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method of made obvious above, in patients with pancreatic tumors, as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are also useful in patients with pancreatic tumors.
Applicant’s arguments and the declaration of Inventor Decker, filed 4/16/26, have been fully considered, but they are not persuasive.
Applicant argues that as evidenced by the Decker declaration, the use of IFN-alpha represented standard of care systemic therapy, and accordingly its inclusion in the protocol does not demonstrate that IFN-alpha was views as essential. Applicant further cites other publications by Wilgenhof and colleagues where IFN-alpha was not used. The declaration of Inventor Decker states that interferon-alpha was widely used as a systemic therapy for certain cancers, and that because of this, clinical trials evaluating new cancer immunotherapies often incorporated interferon-alpha. The Decker declaration states that because Wilgenhof does not include a control group where interferon-alpha is not administered, one cannot establish that interferon-alpha contributes to clinical outcome, and subsequent work did not employ interferon-alpha. The declaration states that over the past 15 years, the field has moved away from cytokine based adjuvant toward alternative approaches, including checkpoint inhibitors.
The administration of dendritic cells in conjunction with IFN-alpha was well known in the art, as shown in the cited reference, and Applicant acknowledges it was widely used as a cancer therapy. Wilgenhof teaches that several studies have examined the therapeutic vaccination of melanoma patients with DC but that anti-tumor effect has been minimal, and that one way to improve therapy effect is by concurrent or sequential administration of IFN-alpha (See page 448-449, in particular). Wilgenhof teach that in patients treated with DC and sequential IFN-alpha, 1 had a partial response (5%), and 5 patients had stable disease with regression of metastases (25%) (i.e. inhibition of tumor growth (see page 453 and 454, in particular). Wilgenhof teach that patients treated with DC and IFN-alpha had a pattern of slow regression followed by prolonged disease stabilization, with a favorable survival outcome (See page 454, s). The reference provides a reasonable expectation of success in using DC vaccine in conjunction with IFN-alpha to inhibit tumor growth, as recited in the present claims.
The fact that other treatment combinations exist does not amount to a teaching away or an indication that the use is non-obvious. See MPEP 2123. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Applicant further argues that the invention provides unexpected results.
The Decker declarations are not persuasive of unexpected results for several reasons
As an initial matter, the unexpected results are not commensurate in scope with the instant claims which encompass treating any type of cancer (including in humans), with any amount or route of dendritic cell in conjunction with any amount any Type I interferon, in any dosing schedule. For example, the claims encompass treating “in conjunction” with IFN-alpha, which would encompass sequential treatment weeks apart, or giving IFN-alpha a single time at any location. The experimental data previously cited involved 6 doses of IFN-alpha given concurrently, at the same location, as the DC vaccines is not commensurate in scope with the instant claims. Applicants results in a mouse brain tumor or mouse pancreatic tumor model are also not commensurate in scope with the instant claims which encompass treating any type of tumor, including in human subjects.
Additionally, evidence of unexpected results must compare the claimed invention with the closest prior art. In this case, either Wilgenhof or the ‘948 publication could be considered equally close prior art references. Wilgenhof teaches administering dendritic cells and IFN-alpha, but does not teach loading with mRNA and lysate, and the ‘948 publication teaches administering dendritic cells loaded with mRNA and lysate, but does not teach IFN-alpha. However, the evidence of record is not sufficient to establish unexpected result when compared to either reference. The asserted unexpected results by Applicant in Exhibit B and C is that doubly loaded dendritic cells and IFN treatment reduce tumors, and Wilgenhof teaches combined DC and IFN resulted in regression of metastases, and therefore the results are not unexpected compared to Wilgenhof.
Furthermore, to the extent that Exhibits A and B demonstrate that the double loaded dendritic cells plus IFN-alpha exhibited better inhibition of tumor growth as compared to the singly mRNA loaded DC plus IFN-alpha, this is also not unexpected.
Enhanced anti-tumor response using doubly loaded dendritic cells as compared to mRNA only loaded dendritic cells would be expected based on the teachings of the ‘948 publication. For example, the ‘948 publication teach that double loading of dendritic cells, as compared to mRNA only loading, increases anti-tumor lytic responses in vitro (See Fig. 8, in particular). Regarding the data in the declaration demonstrating that combined doubly loaded dendritic cells plus IFN-alpha is more effective as compared to double loaded dendritic cells alone (i.e. as compared to the teachings of the ‘948 publication), this is also not unexpected. The art recognized that including IFN-alpha as a combined treatment method with DC administration could enhance the treatment of tumors For example, Wilgenhof teach that the combined treatment induced a pattern of slow regression followed by prolonged disease stabilization with favorable survival outcomes (See page 454, in particular). See also Schwaab, which that combined DC vaccination and IFN-alpha treatment lead to a 50% over all response that compares favorably to historical observations that achieved only a 11% response rate to DC vaccination alone (see page 4990). Likewise, Tatsugami teaches that prior studies involving dendritic cell vaccination alone showed very low incidence of significant clinical response, and that additional treatment in combination with DC vaccine is needed (see page 696, in particular). Tatsugami teaches that combined treatment with dendritic cells and IFN-alpha improved progression free survival and tumor area decreased up to 60% following treatment. See also WO 2015/069770 which teaches that combination treatments, which are disclosed to include dendritic cell vaccines, IFN-alpha, and checkpoint inhibition, can be more effective in treating cancer by increasing the number of immune cells. Thus, the art recognized that combination treatment with both IFN-alpha and dendritic cells could enhance tumor treatment and inhibit tumor growth. Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967)152 USPQ 602, 604 (CCPA 1967).
Regarding exhibit D and E, this is not commensurate in scope with the instant claims for the reason set forth above. Furthermore, achieving better T cell responses Is not unexpected. For example, the ‘948 publication teaches dendritic cells that are doubly loaded with tumor specific lysate and tumor specific mRNA, results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone.
Applicant further argues that the rejection fails to account for a clinically meaningful distinction between the claimed invention and the cited prior art, since the present claims demonstrate stabilization at a substantially smaller mass than reported in the prior art.
The present claims do not recite any limitations requiring a particular amount of tumor mass reduction, but rather recite that the method “reduces tumor volume or inhibitors tumor growth”.
Wilgenhof teach that some of the treated patients achieved an objective response, and had regression of metastases, i.e. reduced tumor volume or inhibition of tumor growth, which meets the limitations of the present claims.
To the extent that Applicant is arguing the present invention demonstrates unexpected results of smaller tumors, this not persuasive for the reasons set forth above.
Claim 1, 11-12, 91-92 and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tatsugami, 2008, in view of US 2011/0306948 (both of record).
Tatsugami teach a method of treating a patient with renal cell carcinoma (i.e. a tumor) comprising administering to the patient autologous dendritic cells in conjunction with IFN-alpha (see page 695, in particular). Tatsugami teach that the dendritic cells are mature (see page 695 and Fig. 1, in particular). Tatsugami teach that the dendritic cells have been loaded with tumor cell lysate, obtained from autologous tumor tissue resected from the patient (see page 695, in particular). Tatsugami teach administration of the mature dendritic cells once a week, and administration of the IFN-alpha three times a week. Tatsugami teach that when the patient received DC vaccinations, the IFN-a was administered near the injection of the site of the dendritic cells (i.e. administration of IFN-a after the dendritic cells, see page 695, in particular). The ordinary artisan would also recognize that the administration regimen of Tatsugami involving once weekly administration of mature dendritic cells and IFN-a three times a week would involve administration of the second and third weekly dose of IFN-a within about 1 week of the mature dendritic cells. Tatsugami teach that the method results in prolonged survival and a decrease in the tumor area of 60% following treatment, i.e. the method treated cancer, reduced tumor volume or inhibited tumor growth (see page 696 and Fig. 2, in particular). The dendritic cells of Tatsugami are not genetically modified.
The reference differs from the claimed invention in that it does not explicitly teach that the dendritic cells are loaded with tumor antigen mRNA derived from a cancer cell population excised from the patient.
The ‘948 publication teaches dendritic cell vaccines for treating cancer, wherein the dendritic cells are doubly loaded with tumor specific lysate and tumor specific mRNA, and that doing so results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone (see page 1, in particular). The ‘948 publication teaches that the tumor lysate and mRNA can be obtained from surgically resected tumor tissue from the patient (i.e. from a cancer cell population excised from the patient, see page 8-10 in particular). The ‘948 publication teaches that the dendritic cells are autologous (see paragraph 105, in particular). The ‘948 publication teaches that of tumor antigen sources, tumor lysates and mRNA preparations from tumors are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens (see paragraph 6, in particular). The ‘948 publication teaches the use of dendritic cell vaccines for treating a variety of tumor types, including melanoma, renal cell cancer, and tumors of the pancreas (see paragraph 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further load the dendritic cells of Tatsugami, 2008, with excised tumor cell mRNA as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘948 publication teaches that double loading with mRNA and lysate results in superior T cell responses compared to lysate alone. Furthermore, the ordinary artisan would be motivated to select tumor/cancer cell samples excised from the patient as the source of lysate and mRNA, since the ‘948 publication teaches that they are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method of made obvious above, in patients with pancreatic tumors, as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are also useful in patients with pancreatic tumors.
Applicant’s arguments and the declaration of Inventor Decker, filed 4/16/26, have been fully considered, but they are not persuasive.
The claims stand rejected for the same reasons set forth above.
Applicant argues and the declaration of Inventor Decker states that Tatsugami is a small uncontrolled study without a control arm where interferon alpha is not given. The declaration states that the authors only state that the treatment “has potential”, which reflects uncertainty rather than a demonstrated synergistic effect.
“Certainty” is not the requisite standard for determining obviousness, rather the standard is reasonable expectation of success. Applicant is essentially arguing that even though the prior art teaches effectively using dendritic cell vaccines in conjunction with IFN-alpha for cancer treatment, it nevertheless would not be obvious to do so, because the prior art did not establish with “certainty” that the combination provided synergistic results as compared to dendritic cells alone. This is not the standard for obviousness. To the extent that Applicant is arguing unexpected results, this is also not persuasive for the reasons set forth above.
Regarding Tatsugami, the reference teaches that the combined treatment method improved progression free survival and tumor area decreased up to 60% following treatment (i.e. the treatment reduced tumor volume, see page 696 and Fig. 1, in particular). Tatsugami explains that IFN-alpha was included in their studies since prior studies involving dendritic cell vaccination alone showed very low incidence of significant clinical response, and suggest that additional treatment in combination with DC vaccine is needed (see page 696, in particular). Tatsugami teach that in contrast to DC alone or cytokine alone, the combination treatment significantly extended time to progression (see page 696-697, in particular). Thus, the ability of IFN-alpha to enhance tumor regression or reduce tumor volume when given with a dendritic cell vaccine is an expected result based on the teachings of the cited prior art.
Claim 1, 11-12, 91-92 and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwaab, 2009, in view of US 2011/0306948 (of record).
Schwaab teach a method of treating a patient with renal cell carcinoma (i.e. a tumor) comprising administering to the patient autologous mature dendritic cells in conjunction with IFN-alpha (see pages 4986-4988, in particular). Schwaab teach that the dendritic cells have been loaded with tumor cell lysate, which is obtained from autologous tumor tissue from the patient (see pages 4986-4988, in particular). Schwaab teach administration cycles involving, for example, DC vaccination of day 14, with IFN-alpha given on days 15, 17, and 19 (i.e. 1 day after DC vaccine, see Table 1, in particular). Schwaab teach administering the dendritic cells intranodally (see pages 4986-4988, in particular). The dendritic cells of Schwaab are not genetically modified. Schwaab teaches that combined DC vaccination and IFN-alpha treatment resulted in 50% overall response, that compares favorably to historical observations that achieved only a 11% response rate to DC vaccination alone (see page 4990).
The reference differs from the claimed invention in that it does not explicitly teach that the dendritic cells are loaded with tumor antigen mRNA derived from a cancer cell population excised from the patient.
The ‘948 publication teaches dendritic cell vaccines for treating cancer, wherein the dendritic cells are doubly loaded with tumor specific lysate and tumor specific mRNA, and that doing so results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone (see page 1, in particular). The ‘948 publication teaches that the tumor lysate and mRNA can be obtained from surgically resected tumor tissue from the patient (i.e. from a cancer cell population excised from the patient, see page 8-10 in particular). The ‘948 publication teaches that the dendritic cells are autologous (see paragraph 105, in particular). The ‘948 publication teaches that of tumor antigen sources, tumor lysates and mRNA preparations from tumors are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens (see paragraph 6, in particular). The ‘948 publication teaches the use of dendritic cell vaccines for treating a variety of tumor types, including melanoma, renal cell cancer, and tumors of the pancreas (see paragraph 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further load the dendritic cells of Schwaab, with excised tumor cell mRNA as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘948 publication teaches that double loading with mRNA and lysate results in superior T cell responses compared to lysate alone. Furthermore, the ordinary artisan would be motivated to select tumor/cancer cell samples excised from the patient as the source of lysate and mRNA, since the ‘948 publication teaches that they are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method of made obvious above, in patients with pancreatic tumors, as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are also useful in patients with pancreatic tumors.
Applicant’s arguments and the declaration of Inventor Decker, filed 4/16/26, have been fully considered, but they are not persuasive.
The claims stand rejected for the same reasons set forth above.
Applicant further argues that the treatment in Schwaab incorporates IL-2, and therefore does not anticipate or render obvious the claimed invention.
The claims are directed to a method “comprising” the recited steps, which is an open term that does not exclude unrecited steps or elements, such as further administering IL-2.
Claim 1, 11-12, 14-15, 91-92 and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/069770 in view of US 2011/0306948 (both of record).
WO 2015/069770 teaches a combination immunotherapy methods to treat a subject with a brain (glioma ) tumor comprising administration of a dendritic cell vaccine and a checkpoint inhibitor, and that the combination increased survival reduced tumor burden (i.e. inhibits tumor growth, see page 42-44 and Fig. 3, in particular). The results show synergism as measured by survival (see Fig. 3). WO 2015/069770 teaches that the dendritic cells are loaded with tumor cells lysate, which matures them (See pages 40 and 44, in particular). WO 2015/069770 teaches that dendritic cell vaccines can be combined with checkpoint inhibitors, such as anti-CTLA-4 to enhance an immune responses (see pages 9-11, and 20 in particular). WO 2015/069770 teaches that in the method, a third agent can be further be administered, including IFN-a therapy (see page 28, in particular). WO 2015/069770 also teaches that dendritic cells can be used in combination with any other method to treat a tumor (see page 32, in particular). WO 2015/069770 teaches that checkpoint inhibitors can be combined with combinations of therapeutic agents, such as immunostimulatory agents, T cell grow factors, and vaccines (See claims 1, 6, 9, in particular). WO 2015/069770 teaches that combination treatments can be administered sequentially in any order or concurrently, and therefore claims 11-12 would be obvious(see pages 33, in particular).
The reference differs from the claimed invention in that it does not explicitly teach that the dendritic cells are loaded with tumor antigen mRNA derived from a cancer cell population excised from the patient.
The ‘948 publication teaches dendritic cell vaccines for treating cancer, wherein the dendritic cells are doubly loaded with tumor specific lysate and tumor specific mRNA, and that doing so results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone (see page 1, in particular). The ‘948 publication teaches that the tumor lysate and mRNA can be obtained from surgically resected tumor tissue from the patient (i.e. from a cancer cell population excised from the patient, see page 8-10 in particular). The ‘948 publication teaches that the dendritic cells are autologous (see paragraph 105, in particular). The ‘948 publication teaches that of tumor antigen sources, tumor lysates and mRNA preparations from tumors are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens (see paragraph 6, in particular). The ‘948 publication teaches the use of dendritic cell vaccines for treating a variety of tumor types, including melanoma, renal cell cancer, and tumors of the pancreas (see paragraph 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to load the dendritic cells of WO 2015/069770, with excised tumor cell mRNA and lysate as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘948 publication teaches that double loading with mRNA and lysate results in superior T cell responses compared to lysate alone. Furthermore, the ordinary artisan would be motivated to select tumor/cancer cell samples excised from the patient as the source of lysate and mRNA, since the ‘948 publication teaches that they are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens.
Applicant’s arguments and the declaration of Inventor Decker, filed 4/16/26, have been fully considered, but they are not persuasive.
The claims stand rejected for the same reasons set forth above.
Regarding the asserted unexpected results for glioma (see Decker declaration of 4/29/24), it is noted that Applicant asserts that the unexpected result is that dendritic cells alone did not reduce tumor volume while only a combination treatment of dendritic cells (with IFN-alpha) was effective. However, WO 2015/069770 demonstrates that dendritic cells alone were not effective in a glioma model (see Fig. 3) but that a combination treatment (with checkpoint inhibitor) was effective. Therefore, the results are not unexpected as compared to the closest prior art. Furthermore, the result are not commensurate in scope with the instant claims for the reasons set forth above.
Claim 1, 11-12, 17, 19, 91- 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over 2004/0131587 , in view of US 2011/0306948 and Kameshima, 2012 (all of record).
The ‘587 publication teaches administration of mature dendritic cells to induce an immune response and treat a tumor in a subject, and teaches that the dendritic cells may be administered locally into or near a tumor or into draining lymph nodes (see paragraph 44 and 96, in particular). The ‘587 publication teaches administration of T cell enhancing agents after the mature dendritic cells (see Fig. 1) and also teaches that the T cell enhancing factors can be given concurrently with mature dendritic cells (see paragraph 12, in particular). The ‘587 publication also teaches that the timing of the steps can be optimized by routine experimentation (see paragraph 20, in particular). The ‘587 publication teaches that type I interferons, such as IFN-alpha, are useful T cell enhancing agents (see paragraph 51, in particular). The ‘587 publication also teaches that numerous methods of loading dendritic cells with antigen are known, and development of suitable methods is regarded as routine experimentation (see paragraph 93, in particular). The ‘587 publication teaches that combination therapy may be of significant clinical use in treating various tumors (see paragraph 98, particular).
The reference differs from the claimed invention in that it does not explicitly teach that the dendritic cells are loaded with tumor lysate and tumor antigen mRNA derived from a cancer cell population excised from the patient, or treating pancreatic cancer
The ‘948 publication teaches dendritic cell vaccines for treating cancer, wherein the dendritic cells are doubly loaded with tumor specific lysate and tumor specific mRNA, and that doing so results in superior T cell responses compared to dendritic cells loaded with lysate or mRNA alone (see page 1, in particular). The ‘948 publication teaches that the tumor lysate and mRNA can be obtained from surgically resected tumor tissue from the patient (i.e. from a cancer cell population excised from the patient, see page 8-10 in particular). The ‘948 publication teaches that the dendritic cells are autologous (see paragraph 105, in particular). The ‘948 publication teaches that of tumor antigen sources, tumor lysates and mRNA preparations from tumors are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens (see paragraph 6, in particular). The ‘948 publication teaches the use of dendritic cell vaccines for treating a variety of tumor types, including melanoma, renal cell cancer, and tumors of the pancreas (see paragraph 18, in particular).
Kameshima teach that administration of IFN-alpha has immunotherapeutic benefit for enhancing vaccination in pancreatic cancer patients, and that it confers clinical improvements and enhanced immunological responses.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further load the dendritic cells of the ‘587 publication, with excised tumor cell mRNA as taught by the ‘948 publication. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘948 publication teaches that double loading with mRNA and lysate results in superior T cell responses compared to lysate alone. Furthermore, the ordinary artisan would be motivated to select tumor/cancer cell samples excised from the patient as the source of lysate and mRNA, since the ‘948 publication teaches that they are attractive antigenic sources, since each possesses a full complement of patient specific tumor antigens.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method made obvious above, in patients with pancreatic tumors, as taught by the ‘948 publication and Kameshima. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are useful in patients with pancreatic tumors, and Kameshima teach that administration of IFN-alpha has immunotherapeutic benefit for enhancing vaccination in pancreatic cancer patients, and that it confers clinical improvements and enhances immunological responses.
Applicant’s argument are not persuasive for the same reasons set forth above.
Claim 87-89 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilgenhof, 2011 or Tatsugami, 2008 or Schwaab, 2009 and US 2011/0306948, as applied to claim 1 above, and all in further in view of WO 2012/112079 (of record).
The teachings of the cited references are described above.
The references differ from the claimed invention in that they do not explicitly teach that the dendritic cells are genetically modified to reduce expression of CTLA-4.
WO 2012/112079 teaches dendritic cells that are genetically modified with siRNA to reduce expression of CTLA-4, and that doing so increases the viability and immunogenicity of the dendritic cells (see page 6-7, and 11, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further modify the method of Wilgenhof or Tatsugami or Schwaab and the ‘948 publication, by treating the dendritic cells with an siRNA to reduce the expression of CLTA-4, as taught by WO 2012/112079. The ordinary artisan would be motivated to do so with a reasonable expectation of success since WO 2012/112079 teaches that genetic modification with siRNA to reduce expression of CTLA-4 increases the viability and immunogenicity of the dendritic cells.
Claim 1, 11-12, 17, 19, 91-95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tatsugami, 2008 and Schwaab, 2009 and the ‘948 publication, and further in view of 2004/0131587 (of record)and Kameshima, 2012.
The teachings of Tatsugami, Schwaab and the ‘948 publication are described above.
The references differ from the claimed invention in that they does not explicitly teach that the dendritic cells are administered to a lymphoid tissue that drains the tumor.
The ‘587 publication teaches administration of mature dendritic cells to induce an immune response and treat cancer, and teaches that the dendritic cells may be administered locally into or near a tumor or into draining lymph nodes (see paragraph 44 and 96, in particular). The ‘587 publication teaches administration of T cell enhancing agents after mature dendritic cells (see Fig. 1) and also teaches that the T cell enhancing factors can be given concurrently with mature dendritic cells (see paragraph 12, in particular). The ‘587 publication also teaches that the timing of the steps can be optimized by routine experimentation (see paragraph 20, in particular). The ‘587 publication teaches that type I interferons, such as IFN-a, are useful T cell enhancing agents (see paragraph 51, in particular). The ‘587 publication also teaches that numerous methods of loading dendritic cells with antigen are known, and development of suitable methods is regarded as routine experimentation (see paragraph 93, in particular). The ‘587 publication teaches that combination therapy may be of significant clinical use in treating various tumors (see paragraph 98, particular).
Kameshima teach that administration of IFN-alpha has immunotherapeutic benefit for enhancing vaccination in pancreatic cancer patients, and that it confers clinical improvements and enhanced immunological responses.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method of Tatsugami, Schwaab and the ‘948 publication by administration near the tumor or to a lymph node that drains the tumor, since the ‘587 publication teaches that a preferred embodiment is local administration near a tumor or into a “draining” lymph node to enhance T cell activation. Selecting from known routes for dendritic cell administration would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method made obvious above, in patients with pancreatic tumors, as taught by the ‘948 publication and Kameshima. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are useful in patients with pancreatic tumors, and Kameshima teach that administration of IFN-alpha has immunotherapeutic benefit for enhancing vaccination in pancreatic cancer patients, and that it confers clinical improvements and enhances immunological responses.
Claim 1, 11, 14-15, 91-92, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilgenhof, 2011 and US 2011/0306948, and further in view of WO 2015/069770 (of record).
The teachings of Wilgenhof and the ‘948 publication are described above. Wilgenhof also teaches that the dendritic cells are administered in combination with anti-CTLA-4 antibody therapy (See page 451, in particular).
The references differ from the claimed invention in that they do not explicitly teach that the dendritic cells are administered in combination with both IFN-alpha and said anti-CTLA-4.
WO 2015/069770 teaches combination immunotherapy methods to treat cancer, and that including one or more cycles of checkpoint inhibitor treatment can be more effective in treating cancer by increased the number of immune cells (See page 3, in particular). WO 2015/069770 teaches that dendritic cell vaccines can be combined with checkpoint inhibitors, such as anti-CTLA-4 to enhance an immune responses (see pages 9-11, and 20 in particular). WO 2015/069770 teaches that in the method a third agent can be administered, including interferon (e.g. IFN-a) therapy (see page 28, in particular). WO 2015/069770 also teaches that dendritic cells can be used in combination with any other method to treat a tumor (see page 32, in particular). WO 2015/069770 teaches that checkpoint inhibitors can be combined with combinations of therapeutic agents, such as immunostimulatory agents, T cell grow factors, and vaccines (See claims 1, 6, 9, in particular). WO 2015/069770 teaches that combination treatments can be more effective in treating cancer and that suitable types of cancer for treatment including pancreatic cancer (See page 35, claim 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further administer anti-CTLA-4, as taught by WO 2015/069770, in the tumor treatment method involving administration of mature dendritic cells and IFN-a of Wilgenhof and the ‘948 publication. The ordinary artisan would be motivated to do so since WO 2015/069770 teaches that combination treatments can be more effective in treating cancer by increasing the number of immune cells. Furthermore, the ordinary artisan would have a reasonable expectation of success, since WO 2015/069770 teaches that dendritic cell vaccines can be combined with more than one therapy, in particular teaches combining dendritic cells and checkpoint inhibitor treatment with a third agent such as a IFN-alpha.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to perform the method of Wilgenhof and the ‘948 publication, in patients with pancreatic tumors, as taught by the ‘948 publication and WO 2015/069770. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are useful in patients with pancreatic tumors, and WO 2015/069770 teach that combination treatment methods, which include dendritic cell vaccines, checkpoint inhibition, and IFN-alpha, have immunotherapeutic benefit for treating a variety of tumors, including pancreatic cancer,
Claim 1, 11-12, 14-15, 91-92, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tatsugami, 2008 or Schwaab, 2009 and the ‘948 publication, and further in view of US 2011/0306948 and WO 2015/069770.
The teachings of Tatsugami, Schwaab, and the ‘948 publication are described above.
The references differ from the claimed invention in that they does not explicitly teach administering anti-CTLA-4.
WO 2015/069770 teaches combination immunotherapy methods to treat cancer, and that including one or more cycles of checkpoint inhibitor treatment can be more effective in treating cancer by increased the number of immune cells (See page 3, in particular). WO 2015/069770 teaches that dendritic cell vaccines can be combined with checkpoint inhibitors, such as anti-CTLA-4 to enhance an immune responses (see pages 9-11, and 20 in particular). WO 2015/069770 teaches that in the method a third agent can be administered, including interferon (e.g. IFN-a) therapy (see page 28, in particular). WO 2015/069770 also teaches that dendritic cells can be used in combination with any other method to treat a tumor (see page 32, in particular). WO 2015/069770 teaches that checkpoint inhibitors can be combined with combinations of therapeutic agents, such as immunostimulatory agents, T cell grow factors, and vaccines (See claims 1, 6, 9, in particular). WO 2015/069770 teaches that combination treatments can be more effective in treating cancer (See page 35). WO 2015/069770 teaches that combination treatments can be more effective in treating cancer and that suitable types of cancer for treatment including pancreatic cancer (See page 35, claim 18, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further administer anti-CTLA-4, as taught by WO 2015/069770, in the tumor treatment method of Tatsugami or Schwaab and the ‘948 publication. The ordinary artisan would be motivated to do so since WO 2015/069770 teaches that combination treatments can be more effective in treating cancer. Furthermore, the ordinary artisan would have a reasonable expectation of success, since WO 2015/069770 teaches that dendritic cell vaccines can be combined with more than one therapy, in particular teaches combining dendritic cells and checkpoint inhibitor treatment with a third agent such as a IFN-a.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method of Tatsugami or Schwaab and the ‘948 publication, in patients with pancreatic tumors, as taught by the ‘948 publication and WO 2015/069770. The ordinary artisan would be motivated to do so with a reasonable expectation of success, since the ‘948 publication teaches that dendritic cell vaccines are useful in patients with pancreatic tumors, and WO 2015/069770 teach that combination treatment methods, which include dendritic cell vaccines, checkpoint inhibition, and IFN-alpha, have immunotherapeutic benefit for treating a variety of tumors, including pancreatic cancer,
Applicant argues that the claims are not obvious for the same reasons set forth above.
The claims stand rejected for the reasons set forth above.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 11-12, 14-15, 17, 19, 87-89, and 91-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 8,728,806, or over claims 1-29 of US 9333248, in view of Schwaab, 2009, Kameshima, 2012, WO 2015/069770, 2004/0131587, and WO 2012/112079.
The patents both claim a method for inducing an immune response in a patient comprising administering to the patient mature dendritic cells from the patient, wherein the dendritic cells are primed with mRNA and tumor cell lysate from a tumor source. Although the patents do not specifically claim excising a tumor source or administration in conjunction with IFN-a, it would be obvious to do so to enhance treatment of a cancer patient based on the teachings of Schwaab and WO 2015/069770 for the same reasons set forth above.
Additionally, administration to a tumor draining lymph node would be obvious based on the teachings of the ‘587 publication and Schwaab and genetic modification with CTLA-4 siRNA would be obvious based on the teachings of WO 2012/112079. It would also be obvious to further administer anti-CTLA-4 based on the teachings of WO 2015/069770 for the same reasons set forth above.
The ‘248 patent also claims that the tumor is pancreatic or glioma (i.e. a brain tumor), however, it would also be obvious to perform the method in a pancreatic tumor based on the teachings of Kameshima for the same reason set forth above.
Applicant argues that the present claims are not obvious for the same reasons set forth above.
The claims stand rejected for the same reasons set forth above.
No claim is allowed.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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