Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
Applicant’s preliminary amendment filed March 28, 2023 was received and entered.
Claims 15-17 have been amended.
Claims 1-17 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of PCT/CN2020/118108 filed September 27, 2020.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on March 27, 2023 and November 11, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Receipt is acknowledged of the replacement Sequence Listing in XML format filed July 19, 2023.
Claim Rejections - 35 USC § 112
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.
Claims 7-12 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint regards as the invention.
Claim 7 (step 3) recites “the pharmaceutical composition”. There is no antecedent basis for this limitation in the claims.
Claims 8 and 11-12 are included in the rejection as they depend from or otherwise require all the limitations of a rejected claim and do not clarify the issue.
Claims 7 and 9 (step 3) recite obtaining the DCs or the pharmaceutical composition by subjecting the DCs derived from the tumor patient to viral antigen peptide loading treatment. However, it is unclear whether the DCs that are loaded with viral antigen peptides are the immature DCs obtained from the tumor patient recited in step 1, or if they are the tumor antigen peptide loaded mature DCs recited in step 2.
Claims 11-12 are included in the rejection as they depend from or otherwise require all the limitations of a rejected claim and do not clarify the issue.
Claims 8 and 10 (lines 7-8) recites “a concentration of the viral antigen peptides in an incubation system is 1 mM”. However, it is unclear what “an incubation system” is referring to and there is no definition of the term in the instant specification.
It is suggested to amend the claim to recite, “wherein the concentration of the viral antigen peptides is 1 mM”. Claim 8 (lines 2-8) recites the viral antigen peptides are incubated with the mature DCs, making further mention of incubation (e.g., incubation system) unnecessary.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-6 and 13-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
The claims recite dendritic cells (DCs) and pharmaceutical compositions thereof, wherein the DCs are loaded with tumor antigen peptides and viral antigen peptides; wherein the pharmaceutical composition further comprises autologous DCs derived from a tumor patient and/or allogeneic DCs derived from a healthy individual. Also claimed is a method for improving an immune killing activity of autologous DCs, comprising mixing autologous DCs with allogeneic DCs.
This judicial exception is not integrated into a practical application because the claims can read on natural biological materials like blood cells. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The dendritic cells loaded with tumor antigen peptides and viral antigen peptides as claimed are naturally occurring cells found in various matrices including the blood and tumor microenvironment. As Kim et al. (2015) teach, dendritic cells (DCs) constitute a heterogeneous population of professional antigen-presenting cells (APCs), which can uptake, process, and present different types of antigens [Introduction, pg. 6507]. For example, captured antigens from viruses are processed by the endolytic pathway of DCs. MHC class II-rich compartments in immature DCs allow rapid presentation of exogenous antigens for the activation of CD4+ T helper cells [see Section 3, pg. 6509]. Furthermore, Kim teaches DCs can acquire tumor antigens in vivo by binding exposed actin filaments of necrotic cells, where they are presented on MHC class I molecules. After capturing tumor antigens, the DCs migrate to secondary lymphoid tissues to initiate T cell responses against the tumor, including activation of cytotoxic CD8+ T cells [see Section 4, pg. 6510].
This is evidence that dendritic cells loaded with tumor antigen peptides and viral antigen peptides appears in nature and therefore the claimed invention appears to be a product that is not markedly different in structure from naturally occurring products.
Claims 4-6 recite a pharmaceutical composition comprising a combination of autologous DCs derived from a tumor patient and/or allogenic DCs derived from a healthy individual, wherein a ratio of the number of autologous DCs to the number of allogenic CDs ranges from (20:1) to (3:1). However, without any evidence to the contrary, the functionality and structure of the DCs would not be markedly different from the naturally occurring DCs since there is no interaction by mere mixing. Because there is no difference in the characteristics (structural, functional, or otherwise) between the claimed and naturally occurring dendritic cells, the claimed combination of autologous and/or allogenic DCs does not have markedly different characteristics from what exists in nature, including mixing of DCs in different ratios as recited in the instant claims. See MPEP 2106, Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 591-94, 106 USPQ2d 1972, 1979-81 (2013); Roche Molecular System, Inc. v. CEPHEID, 905 F.3d 1363, 1371, 128 USPQ2d 1221, 1227 (Fed. Cir. 2018).
Accordingly, the claims are directed to a judicial exception. Because the claim does not include any additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter under 35 U.S.C §101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhao et al. (Oncol Lett, 2018; 16:1180-1188) (“Zhao”) as evidenced by Zhou et al. (J Immunotherap, 2002; 25(4):289-303) (“Zhou”).
The instant claims are drawn to dendritic cells (DCs), wherein the DCs are loaded with tumor antigen peptides and viral antigen peptides, wherein the DCs are derived from a tumor patient
Zhao discloses dendritic cells loaded with tumor antigen peptides and viral antigen peptides. Tumor cell lysates (TCLs) have been used as the source of tumor antigens for the development of dendritic cell (DC) vaccines, however, the clinical outcomes of TCL-based DC vaccines have been unsatisfactory owing to the weak immunogenicity of tumor cells. Zhao discloses the use of viruses in DC-based cancer immunotherapy is known in the art, and has been used to improve the efficacy of TCL-based DC vaccines by enhancing antigen delivery thereby increasing the antigen-presenting ability of DCs, adding that virus-induced augmentation of the antigenicity of tumor antigens has been observed in several model systems [Introduction, pg. 1180-1181, par. 1-2].
Zhao isolated immature DCs from the peripheral blood mononuclear cells (PBMCs) of 12 lung cancer patients. Zhao loaded the DCs with the tumor cell lysate from human lung adenocarcinoma A549 cells or the lysate of Newcastle Disease Virus (NDV)-infected tumor cells (NDV-TCL) [Materials and Methods, pg. 1181; instant claims 1-2]. NDV necrotic tumor cells destroyed by the virus are phagocytosed by DCs, which then present process tumor associated antigen (TAA) peptides to T cells [Introduction, pg. 1180, par. 2].
Zhao further discloses that DCs loaded with the lysate of NDV-TCL demonstrated greater T-cell proliferation and anti-tumor cytokine secretion from T cells than DCs loaded only with TCL. These results indicate that loading DCs with NDV-TCL enhances the antigen-presenting ability of the DCs [Abstract, pg. 1180, par. 1]. Increased expression of DC surface markers CD83, CD80, and CD86 on NDV-TCL DCs indicates that the NDV-TCL DCs are more mature than TCL DCs, and thus have a stronger potential to promote T cells to exhibit anti-tumor activity [pg. 1183, col. 1, par. 1].
As evidenced by Zhou, viral vectors containing tumor antigens can also deliver highly immunogenic viral proteins and genes, causing the induction of cellular responses and subsequent tissue damage.
Therefore, absent a showing of any difference, the product disclosed by the prior art is deemed to anticipate the claimed product.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3-5 and 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (Oncol Lett, 2018; 16:1180-1188) (“Zhao”), as applied to claims 1-2 above, in view of Lin et al. (Cancer Research, 2002; 62:6952-6958) (“Lin”), and in further view of Laborde et al. (Front Immunol, 2014; 5:1-5) (“Laborde”).
The instant claims are drawn to dendritic cells (DCs), wherein the DCs are loaded with tumor antigen peptides and viral antigen peptides, wherein the DCs are derived from a tumor patient, wherein the viral antigen peptides are EBV antigen peptides; a pharmaceutical composition comprising the DCs, wherein the DCs are autologous DCs from a tumor patient; also claimed are methods for culturing the DCs and loading the peptides, methods of activating T cells, and treatment of tumors.
The teachings of Zhao are set forth above.
In addition, Zhao teaches the DCs were cultured in serum-free CellGenix GMP DC medium in a CO2 incubator at 37°C. The cultured DCs (1x106 cells/mL) were loaded with TCL or NDV-TCL at a concentration of 100 mg/mL [Materials and Methods, pg. 1181; instant claims 7-10 partial].
Zhao also teaches the autologous NDV-TCL DCs were cocultured ex vivo with allogeneic T cells obtained from a healthy donor at a ratio of 1:5 ??[pg. 1182] resulting in significantly increased proliferation of allogeneic T cells compared with the T cells alone, resulting in enhanced IFN-g and IL-2 secretion by autologous CD4+ and CD8+ T cells [pg. 1184].
Zhao does not teach CD14+ selection, EBV antigen peptides, a pharmaceutical composition comprising autologous DCs, or that the composition can be used to treat tumors.
Lin teaches autologous dendritic cells cultured from PMBCs of 16 patients with advanced nasopharyngeal carcinoma (NPC) using GM-CSF and IL-4 to induce differentiation into immature DCs, followed by maturation by culturing in the presence of TNF-a. Mature DCs (5-10×105 cells/mL) were incubated for 6-8 hours with an EBV LMP2 peptide at a concentration of 100 mg/mL (instant claims 3, 7-10 partial). The DCs were then resuspended in saline containing 1% autologous serum and delivered immediately by ultrasound-guided intranodal injection into one inguinal lymph node (instant claims 4-5) [Materials and Methods]. Lin teaches that EBV is a herpes virus associated with several malignant diseases, including NPC. LMP2 was chosen as the target antigen because it is consistently expressed in NPC and is the most frequently recognized protein by CD8+ CTLs among the few EBV proteins present in the tumor [Introduction and pg. 6955, col. 1]
Lin teaches that patients were evaluated for overall tumor response every 3 months after the fourth injection [Clinical Evaluation, pg. 6953]. Lin found that vaccination with LMP2 peptide-pulsed DCs elicited or boosted epitope-specific CD8+ T-cell responses in all patients, while two patients had regression of metastatic tumors in the bone and blood [pg. 6957] (instant claim 11).
Lin is silent regarding the population of PBMCs that the DCs were isolated from.
Laborde teaches the typical method for generation of ex vivo dendritic cells starts with the purification of CD14+ cells [Abstract] (instant claims 7, 9, 11 partial).
It would have also been obvious to the skilled artisan to combine the protocols of Zhao with those of Lin to obtain steps for culturing the DCs. Although not disclosed, it is likely that both Zhao and Lin isolated DCs from CD14+ PBMCs as evidenced by Laborde. Zhao teaches the incubation protocol for DCs in serum-free medium at 37°C with 5% CO2 and the concentration of DCs prior to antigen loading is 1×106 cells/mL. Although the immature DCs taught by Zhao were matured after uptake of the cellular debris from NDV-infected tumor cells without the addition of exogenous agents, methods for generating mature DCs for vaccination by culturing immature DCs in the presence of exogenous cytokines and loading peptide antigens were well known in the art as evidenced by Lin, which used TNFa for maturation of autologous DCs that were subsequently loaded with EBV antigen peptides. The 6-8 h duration for incubation of the mature DCs with viral antigen peptides taught by Lin offers a reasonable starting point for the ordinary artisan to optimize the uptake of antigenic peptide and to arrive at a 4-6 h incubation as recited in the instant claims. The teachings of Lin differ from the instant claims in that Lin teaches the mature DCs are incubated with a higher concentration of EBV viral antigen peptides (100 mg/mL) versus the concentration recited in the instant claims (1 mM), which may play a factor in the longer peptide loading incubation range taught by Lin.
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), a claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969), claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions. For additional cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical as the specification only incubates the viral antigen peptides at one concentration, 1 mM.
One would be motivated to further modify the protocols of Zhao to load the DCs with an EBV viral tumor antigen peptide such as LMP2, especially when treating EBV-associated malignancies since it highly immunogenic to CD8+ CTLs in the tumor microenvironment as evidenced by Lin. Although Zhao and Lin both load the antigen peptides in a single incubation, one of ordinary skill in the art could easily envisage loading tumor or viral antigen peptides in separate steps to arrive at the method as recited in the instant claims.
Although Zhao never administered the autologous DCs and DC-activated allogeneic T cells to a tumor patient, one would have a reasonable expectation of success in enhancing the anti-tumor activity of the therapy by pairing the DCs with pre-activated effector cells, thus improving T cell infiltration into tumors and increased CD8+ and CD4+ CTL response as evidenced by the in vitro experiments conducted by Zhao. As such, the combination of prior art references provided prima facie case of obviousness for the instantly claimed invention.
Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over de Gruijl et al. (Cancer Immunol Immunother, 2008; 57:1569-1577) (“de Gruijl”).
The instant claims are drawn to a method for improving an immune killing activity of autologous DCs, comprising mixing the autologous DCs with allogeneic DCs at ratio of 20:1 to 3:1, wherein the autologous DCs are derived from a tumor patient and the allogeneic DCs are derived from a healthy individual, wherein the autologous DCs are loaded with tumor antigen peptides and/or viral antigen peptides, wherein the viral antigen peptides are EBV antigen peptides.
de Gruijl teaches dendritic cell vaccines comprising autologous DCs are widely used in the treatment of cancer [pg. 1573, col. 2, par. 2]. DCs can be administered alone, or can be loaded with TAA-derived epitopes, with DC-based tumor vaccines demonstrating anti-tumor immunity and clinical efficacy in various clinical trials. de Gruijl further teaches an alternative approach for DC based vaccines using allogeneic DCs as vaccine vehicles, which allows for the preparation of large clinical-grade batches that can be used for all patients, thus providing a more standardized DC vaccine in terms of phenotype and maturation status. More importantly, allogeneic DC-based vaccines are likely to induce a strong vaccine-specific immune response, as 1-10% of circulating T cells are directed against allo-antigens, including T helper cells, thus aiding in the optimal activation of CTL against the tumor-related payload. However, although various clinical trials show allogeneic DC-based vaccines demonstrate partial clinical responses, accompanied by evidence of tumor-specific T cell activation, on the whole they are less effective than autologous DC-based vaccines [pg. 1573].
Importantly, de Gruijl teaches semi-allogeneic DC that are partially MHC-matched demonstrate the most favorable anti-tumor activity in murine models, because while allogeneic DC MHC class II molecules can activate T helper cells, at least partial MHC class I matching is required for a CTL response to be induced. Furthermore, vaccination with autologous melanoma tumor cell/allogeneic DC hybrids, which present TAA peptides, resulted in clinical responses, long survival times, and high-frequency post-vaccination T cell responses against a broad range of melanoma epitopes. Thus, the studies demonstrate the feasibility of generating TAA-specific T cell responses in vivo on an allo-background [pg. 1573] (instant claims 13-14, 16).
The teachings of de Gruijl differ from the instant claimed invention in that even though the administration of autologous, allogeneic, and autologous/allogeneic hybrid DC based vaccines for the treatment of cancerous tumors is taught, the DC based vaccines are not explicitly taught as being a mixture of both autologous DCs loaded with tumor antigen peptides and allogeneic DCs from healthy donors. Given that de Gruijl teaches autologous melanoma/allogeneic DC hybrids against specific TAA showed remarkable clinical efficacy, a skilled artisan would enjoy a reasonable expectation of success in generating a DC vaccine incorporating both autologous DCs loaded with TAA and allogeneic DCs, as autologous DCs showed better efficacy while allogeneic DCs activate CTLs that are necessary for tumor killing. In addition, a skilled artisan would be further motivated because universal “off the shelf” allogeneic DCs can be prepared for use with all patients based, providing an easy way to boost the immune response of the individualized targeted autologous DC vaccine. Because de Gruijl did not prepare a mixed DC composition, no ratio of autologous to allogeneic DCs are provided. However, a skilled artisan would easily be able to optimize the cell ratios to achieve the desired effect, therefore arriving at a ratio of 3:1 to 20:1 as recited in the instant claims, especially if starting from a ratio of 1:1 (instant claim 15).
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), a claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969), claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions. For additional cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical as the specification only recites the ratio of autologous to allogeneic DCs for 3 mixtures was tested, 20:1, 10:1 and 3:1, however, no data is provided that shows the upper and lower limit of autologous DCs that are able to achieve the recited effects when mixed with allogeneic DCs [0079]. Accordingly, the prior art reference provided a prima facie case of obviousness for the instantly claimed invention.
Claims 6 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (Oncol Lett, 2018; 16:1180-1188) (“Zhao”), in view of Lin et al. (Cancer Research, 2002; 62:6952-6958) (“Lin”), as evidenced by Laborde et al. (Front Immunol, 2014; 5:1-5) (“Laborde”), and in further view of de Gruijl et al. (Cancer Immunol Immunother, 2008; 57:1569-1577) (“de Gruijl”) as applied to claims 1-5 and 7-16 above.
The instant claims are drawn to a pharmaceutical composition comprising autologous DCs and allogeneic DCs in a ratio of 20:1 to 3:1, wherein the DCs are loaded with tumor antigen peptides and viral antigen peptides, wherein the viral antigen peptides are EBV viral peptides.
The teachings of Zhao, Lin, Laborde, and de Gruijl have been set forth above.
Specifically, Zhao teaches autologous DCs loaded with viral killed tumor lysates while Lin teaches autologous DCs that have been loaded with EBV viral antigen peptides for the treatment of cancer and pharmaceutical compositions thereof. de Gruijl teaches dendritic cell vaccines comprising autologous DCs loaded with TAA peptides demonstrate clinical efficacy in various clinical trials and allogeneic DC- based vaccines activate T helper cells and subsequent CTL activity against the tumor. Importantly, de Gruijl teaches more efficacious vaccines comprising semi-allogeneic DCs that activate both T helper and CTL.
The teachings of de Gruijl differ from the instant claimed invention in that even though the administration of autologous, allogeneic, and autologous/allogeneic hybrid DC based vaccines for the treatment of cancerous tumors is taught, the DC based vaccines are not explicitly taught as being a mixture of both autologous DCs loaded with tumor antigen peptides and allogeneic DCs from healthy donors. Given that de Gruijl teaches autologous melanoma/allogeneic DC hybrids against specific TAA showed remarkable clinical efficacy, a skilled artisan would enjoy a reasonable expectation of success in generating a DC vaccine incorporating both autologous DCs loaded with TAA and allogeneic DCs, as autologous DCs showed better efficacy while allogeneic DCs activate CTLs that are necessary for tumor killing. In addition, a skilled artisan would be further motivated because universal “off the shelf” allogeneic DCs can be prepared for use with all patients based, providing an easy way to boost the immune response of the individualized targeted autologous DC vaccine. Because de Gruijl did not prepare a mixed DC composition, no ratio of autologous to allogeneic DCs are provided. However, a skilled artisan would easily be able to optimize the cell ratios to achieve the desired effect, therefore arriving at a ratio of 3:1 to 20:1 as recited in the instant claims, especially if starting from a ratio of 1:1. Further, the skilled artisan would increase the ratio of autologous DCs in the combination because the allogenic DCs serve only as an adjuvant to create a strong, non-specific immune stimulation which boosts the specific tumor targeting response of the autologous DCs (instant claim 6).
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), a claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969), claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions. For additional cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical as the specification only recites the ratio of autologous to allogeneic DCs for 3 mixtures was tested, 20:1, 10:1 and 3:1, however, no data is provided that shows the upper and lower limit of autologous DCs that are able to achieve the recited effects when mixed with allogeneic DCs [0079]. Accordingly, the combination of prior art references provided a prima facie case of obviousness for the instantly claimed invention.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642 /SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642