DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant's amendment and remarks, filed 8/19/25, are acknowledged.
Claims 1-5, 7-15, 17-21 are pending and are under examination.
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-5, 7-8, 10-15, and 18-21 are rejected under 35 U.S.C. 103(a) as being unpatentable US 2001/0007659, in view of Yu, July 2004, and Pullarkat, 2002.
The ‘659 publication teach a method of producing a population of mature, activated dendritic cells comprising culturing monocytes enriched from peripheral blood by plastic adherence with GM-CSF and IL-4 for 7 days (see Example 3). The ‘659 publication teaches that the culture medium comprises 10% human AB serum. The ‘659 publication teaches that after 3 days of the culture, the adherent monocytes differentiate and become non-adherent suspension cells (i.e. “immature” dendritic cells). The ‘659 publication teaches that after day 3, those cells are transferred to a fresh plastic culture vessel, which causes the cells to reattach and become characteristically dendritic with a phenotype that is mature with expression of CD83, HLA class II (i.e. DR), CD80, CD86, and CD14- (see paragraph 68, Table 2, and paragraph 17 in particular). The ‘659 publication teaches that dendritic cells function to prime naïve T cells and activate both CD4 and CD8, and can elicit CD8+ cytotoxic T cells (see paragraph 5 and 7, in particular). The ‘659 publication teaches using the dendritic cells for phenotypic analysis by flow cytometry (see Example 3). The ‘659 publication also teaches that dendritic cells are known to be potent physiological adjuvants for induction of therapeutic anti-tumor immunity, and that dendritic cells can be pulsed with tumor antigens in vitro and administered therapeutically to a patient (i.e. contacted with naïve human T cells, see paragraph 7 and 46 in particular).
The reference differs from the claimed invention in that it does not explicitly teach that the plastic culture vessel is polystyrene and also does not explicitly teach harvesting, washing the dendritic cells. The reference also does not explicitly teach a glioblastoma lysate as the antigen.
Pullarkat teaches that plastic culture vessels used for culturing dendritic cells are made of polystyrene (see page 174, in particular). Pullarkat teach that dendritic cells are used for treating a variety of cancers after pulsing with antigen peptides or tumor cell lysates (see page 181, in particular). Pullarkat teach that the process by which dendritic cells are harvested for use involves collecting the cells and washing, and resuspension of the cells in appropriate media.
Yu teaches that patient autologous GM-CSF/IL-4 differentiated monocyte dendritic cells can be pulsed with autologous glioblastoma multiforme tumor cell lysate in vitro, for producing a vaccine that can be administered to a cancer patient to elicit a cytolytic T cell response in the patient (i.e. contacting naïve T cells with the dendritic cells, see abstract, page 4974, in particular). Yu also teaches preparing the dendritic cells for administration by a process the involves collecting and washing the cells (see pages 4974-75, 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 use polystyrene as the plastic, and to collect, wash, and resuspend the dendritic cells, as taught by Pullarkat and Yu, in the method of producing dendritic cells taught in the ‘659 publication. It would be obvious to collect and wash the dendritic cells to prepare them for further analysis or for preparation for administration to a patient in order to remove culture contaminants. Furthermore, selecting from known culture procedures for preparing dendritic cells for functional analysis or therapeutic 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 be obvious to use a tumor antigen, such as a tumor lysate, as the type of antigen for preparing the dendritic cells, as taught by Yu for use in patient administration to induce an anti-tumor immune response. Adding the antigen prior to, after, or during the second culture step of the ‘659 publication would be well within the purview of the ordinary artisan based on the teachings of the cited references.
Applicant’s arguments filed 8/19/25 have been fully considered, but they are not persuasive.
Applicant argues that the ‘629 publication teaches that the cells become non-adherent after 3 days, but they were not transferred to a fresh plate until 7 days, wherein they mature.
The ‘629 publication does not explicitly state what day the transfer is performed, but the present claims do not recite any limitations regarding the timing of transfer. For example, the claimed method would encompass transferring after 3 or 7 days of culture with GM-CSF and IL-4.
Applicant further argues that there is no information in the ‘659 publication that the mature dendritic cells are functional. Applicant argues that the ‘659 publication states that the method can be used to stimulate an immune response directed against a tumor antigen, however, the method of the ‘659 publication is to transduce the dendritic cells with a nucleic acid sequence encoding an antigen, and there is no teaching to contact with a tumor associated peptide or protein or lysate. Applicant argues the neither Pullarkat or Yi provide any guidance as to whether the dendritic cells of the ‘659 publication are functional.
The ‘629 publication is directed to methods of making and using dendritic cells presenting an antigen for administration to a subject for inducing an immune response, it is clear the disclosed methods produce functional dendritic cells. Claims 1-2 do not require a tumor peptide as argued by Applicant, but would encompass, for example, dendritic cells transduced with a nucleic acid antigen. Furthermore, even for the claims that do recite a tumor cell lysate, these limitations are rendering obvious in view of the other cited references for the reasons set forth above.
Claims 1-2, 7, and 10-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over Heystek et al., 2000 (of record), in view of US 2001/0007659, Lutz et al., 1999 (of record), as evidenced by product information for Corning and Falcon 3033 plates (of record).
Heystek et al. teach a method for producing a population of activated human dendritic cells consisting of contacting monocyte dendritic cell precursor cells from peripheral blood with GM-CSF and IL-4 to induce the differentiation of immature dendritic cells, harvesting the immature dendritic cells and culturing the immature dendritic cells with complete tissue culture medium with GM-CSF or GM-CSF and IL-4 in culture wells (i.e. contacting with a new, unused tissue culture substrate, see pages 441-442, in particular). Heysteck teach culturing said immature dendritic cells with or without peptide antigen (i.e. incubated with the antigen simultaneously with contacting with the tissue culture substrate, see pages 441-442, in particular). Heysteck et al. teaches culturing in tissue culture medium that comprises fetal calf serum (i.e. conditions suitable for adhesion, see page 441, in particular). Heysteck et al. that the immature dendritic cells treated with GM-CSF/IL-4 have an increased capacity to stimulate T cell proliferation (i.e. are “activated” or “mature”). Heysteck also teach that monocyte derived dendritic cells produced by differentiation in GM-CSF and IL-4 are among the most potent stimulators of naïve T cells compared with other APC (See page 440, in particular). Heysteck et al. teach obtaining the precursor cells from a human patient and contacting the antigen presenting dendritic cells with T cells (see page 442, in particular). Heysteck, teaches tissue culture plates from Corning, which as evidenced by Corning product information are polystyrene (see page 441, in particular). Heysteck teaches harvesting the resulting dendritic cells and washing the dendritic cells for adding to the T cells. It would be obvious that this would involve washing and preparing the dendritic cells in a physiological medium. Washing and resuspending dendritic cells in a physiologically compatible medium would be within the scope of “preparing” the dendritic cells for administration to the patient (the claims here do not actually require administration to a patient, but merely preparing the dendritic cells).
Heysteck et al. do not teach culturing the dendritic cells in a medium supplemented with human AB serum nor enriching the monocytes by plastic adherence.
The ‘659 publication teach that monocytes differentiated with GM-CSF/IL-4 to provide dendritic cells can be obtained from PBMC by adherence to plastic (see paragraph 68, in particular). The ‘659 publication teaches that culture medium for differentiating monocytes into dendritic cells can comprise fetal calf serum or 10% human AB serum, and that the cells detach from the plastic and become a suspension, but if the cells are replated onto a fresh tissue culture flask, they reattach and become characteristically dendritic with a phenotype that is mature with expression of CD83, HLA class II (i.e. DR), CD80, CD86, and CD14- (see paragraph 68, Table 2, and paragraph 17 in particular). The ‘659 publication teaches that dendritic cells function to prime naïve T cells and activate both CD4 and CD8, and can elicit CD8+ cytotoxic T cells (see paragraph 5 and 7, in particular).
Furthermore, as taught by Lutz, harvest and transfer of immature dendritic cells into a new tissue culture plate and reculturing in the presence of GM-CSF can induce maturation of the cells (see page 88 and Fig. 9, in particular of Lutz). Lutz also teaches transferring dendritic cells to tissue culture plates or plastic, such as 3003 Falcon plates, which further increased DC purity (see page 78, and 88, in particular). As evidenced Falcon, said tissue culture plates are polystyrene.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use 10% AB serum and to purify the monocytes by plastic adherence, as taught by the ‘659 publication. Selecting from known monocyte enrichment techniques and culture medium for producing dendritic cells 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, the ordinary artisan would expect to obtain a mature CD14-HLA-DR+CD86+CD83+ phenotype, based on the teachings of Lutz and the 659 publication, which both teach that transfer of the cells to a new tissue culture plate or flask cause the cells to reattach and become characteristically dendritic with a mature phenotype and with expression of CD83, HLA class II, CD80, CD86, and CD14- (see paragraph 68 and Table 2, in partiuclar0.
Thus, the ordinary artisan would have a reasonable expectation of success in obtaining a population of dendritic cells enriched for mature, activated dendritic cells that are CD14-HLA-DR+CD86+CD83+ cells, based on the teachings of prior art.
Applicant’s arguments filed 8/19/25 have been fully considered, but they are not persuasive.
Applicant argues that the amendment to claims 3 and 12 overcomes the rejection as pertaining to the type of antigen.
This is persuasive for claims 3 and 12 and claims dependent therefrom.
Regarding the other claims, Applicant argues that Heystek does not teach maturation of immature dendritic cells, and that there is not teaching in the ‘659 publication that the dendritic cells are functional. Applicant argues that Lutz deals with mouse dendritic cells and cannot be extrapolated to human dendritic cells.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On page 442 Heystek teaches that MoDC were generated in accordance with published protocols by culture of monocytes in media containing GM-CSF and IL-4 for 7 days, after which they are referred to as immature dendritic cells. This meets the limitation of step (i) as recited in the present claims. However, Heystek goes on to teach that after obtaining said immature dendritic cells, they are subsequently harvested washed and re-cultured in the presence of GM-CSF or GM-CSF and IL-4 with or without antigen (see page 441-442, in particular). Heystek teaches that cultures are performed in tissue culture plates and it would be apparent to the ordinary artisan that the process of harvesting, washing, and culturing the immature dendritic cells with GM-CSF/IL-4 would be performed in a new tissue culture plate (i.e. a polystyrene culture substrate). Heystek teaches that doing so increases capacity of the resulting dendritic cells to stimulate T cell proliferation (i.e. are “activated” or “mature”). This was recognized as a means of maturing dendritic cells as specifically taught in the ‘959 publication wherein transfer to a fresh plastic culture vessel causes the cells to reattach and become characteristically dendritic with a phenotype that is mature with expression of CD83, HLA class II (i.e. DR), CD80, CD86, and CD14- Furthermore, Lutz also teaches the same concept, i.e. transferring immature dendritic cells to a fresh tissue culture plate and reculture in GM-CSF which can induce maturation. Thus, based on the combined teaching of the cited references, one or ordinary skill in the art would recognize that the culture process involving transfer of the immature dendritic cells into a fresh polystyrene tissue culture plate would induce activation/maturation of the dendritic cells.
Regarding Applicant’s arguments about mouse versus human dendritic cells, it is noted that it is art recognized that maturation of human and mouse dendritic cells and in vitro culture conditions are similar. For example, see Hochrein which teaches that conditions for maturation and activation of dendritic cells are applicable when using both mouse an human dendritic cells under a wide range of conditions (see page 829, right column). See also Bagley, Jan. 2005 which teaches that both human monocyte derived dendritic cells and murine bone marrow derived dendritic cells produced by culture with GM-CSF are phenotypically equivalent immature dendritic cells, and that both exhibit phenotypic maturation to the same stimuli (in this case, LPS, CT, PMT, see Fig. 1, Fig. 4, and page 413, in particular). Furthermore, as taught by Shortman, mouse and human DC populations have basic similarities, and most discrepancies have reflected differences between culture generated dendritic cells and freshly isolated dendritic cells rather than fundamental species differences. Shortman teach that maturation of DC types from both species in culture have similar characteristics (see page 159, in particular). Thus, the ordinary artisan could reasonably expect to achieve the same activation/maturation described by Lutz, in the dendritic cells of Heysteck, especially since Heystek teaches that harvesting and reculturing immature dendritic cells with GM-CSF increases T cell stimulatory capacity (i.e. the same re-culture produce in a fresh plate as taught by Lutz to also increase maturation phenotype). References may be relied upon for all they suggest to the ordinary artisan.
Claims 1-2, 7, 9-11 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Heystek et al., 2000, in view of US 2001/0007659, Lutz et al., 1999 (all of record), as evidenced by product information for Corning and Falcon 3033 plates, and further in view of in view of Veigh et al., (of record) and Hochrein, 2000 (of record).
The teachings of the references are described above.
They do not teach contacting the immature dendritic cells with IFN-gamma.
Veigh et al. teach that IFN-gamma pretreatment of immature dendritic cells can generate IL-12 production and enhance Th1 responses, and that is further augmented upon subsequent encounter with the cells (see page 72, Fig. 5, and Table 2, in particular). Hochrein teaches that culture with GM-CSF, IL-4 and IFN-gamma enhances dendritic cell activation/maturation (see pages 829-830, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to include IFN-gamma, as taught by Veigh et al, and Hochrein. in the cultures of immature dendritic cells made obvious above. The ordinary artisan would have been motivated to do so, since Veigh et al. teach that IFN-gamma pretreatment of immature dendritic cells can generate IL-12 production and enhance Th1 responses, and that is further augmented upon subsequent encounter with the cells and Hochrein teaches that culture with GM-CSF, IL-4 and IFN-gamma enhances dendritic cell activation/maturation.
Applicant argues that Veigh and Hochrein fail to cure the deficiencies above.
The claims stand rejected for the reasons set forth above.
Applicant further argues that Veigh and Hochrein only teach the use of IFN-gamma to stimulate production of IL-12 in a culture environment including a dendritic cell maturation agent.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The other cited references teach the concept of contacting with a new tissue culture vessel as a means of maturing the dendritic cells for the reasons set forth above.
Claims 1-5, 7-8, 10-15, and 18-21 are rejected under 35 U.S.C. 103(a) over Heystek et al., 2000, in view of US 2001/0007659, Lutz et al., 1999 (all of record), as evidenced by product information for Corning and Falcon 3033 plates, and further in view of Yu, July 2004.
The teachings of the cited references are described above.
They do not teach culturing the dendritic cells with a tumor cell lysate.
Yu teaches that GM-CSF/IL-4 cultured dendritic cells can be exposed to autologous glioblastoma multiforme tumor cell lysate in vitro, for producing a vaccine that can be administered to a cancer patient to elicit a cytolytic T cell response in the patient (i.e. contacting naïve T cells with the dendritic cells, see abstract, page 4974, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to contact the dendritic cells made obvious above, with a tumor cell lysate, as taught by the Yu. The ordinary artisan would have been motivated to do so to induce an anti-tumor antigen specific T cell response. Furthermore, it would be obvious to administer the dendritic cells to induce the T cell response in order to treat a tumor (i.e. contacting with the human naïve T cells in vivo).
Applicant’s arguments filed 8/19/25 have been fully considered, but they are not persuasive.
Applicant argues that Yu does not cure the deficiencies noted above.
The claims stand rejected for the reasons set forth above.
Claims 1-5, 7-8, 10-15, and 18-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Chang et al., 2002 (of record), in view of US 2001/0007659 and Pullarkat, 2002.
Chang et al. teach a method of producing a population of dendritic cells comprising culturing monocytic dendritic cell precursors obtained from adherent PBMC of a human patient in GM-CSF and IL-4, harvesting the immature dendritic cells, and culturing the dendritic cells in a new (i.e. clean and unused) tissue culture flask in medium containing GM-CSF and IL-4 (i.e. differentiation agents) and a patient derived tumor cell lysate (i.e. contacting with a substrate under conditions suitable for adhesion and without a maturation agent, see page 1022, in particular). Chang et al. teach using melanoma cell lysate (see Table 1, in particular). Chang et al. teach administering the dendritic cells back to the patient to stimulate antigen specific T cells (i.e. contacting autologous naive T cells with the antigen presenting dendritic cells). Chang teach that the dendritic cells induce cytolytic CD8 T cells (see abstract). Chang et al. teach that the population of dendritic cells comprises those that are CD83+, CD14-, CD86+, HLA-DR+ cells (see page 1025, in particular). In particular, Chang et al. teach that an average of 17% of the cells in the population are CD83+ mature dendritic cells (see page 1030 in particular). Said CD83+ mature dendritic cells would also be CD86+ HLA-DR+ and CD14-, since these are markers of mature dendritic cells.
Chang et al. do not teach culturing the dendritic cells in a medium supplemented with human AB serum.
The ‘659 publication teach that monocytes differentiated with GM-CSF/IL-4 to provide dendritic cells can be obtained from PBMC by adherence to plastic (see paragraph 68, in particular). The ‘659 publication teaches that culture medium for differentiating monocytes into dendritic cells can comprise 10% human AB serum, and that the cells detach from the plastic and become a suspension, but if the cells are replated onto a fresh tissue culture flask, they reattach and become characteristically dendritic with a phenotype that is mature with expression of CD83, HLA class II (i.e. DR), CD80, CD86, and CD14- (see paragraph 68, Table 2, and paragraph 17 in particular). The ‘659 publication teaches that dendritic cells function to prime naïve T cells and activate both CD4 and CD8, and can elicit CD8+ cytotoxic T cells (see paragraph 5 and 7, in particular). The ‘659 publication also teaches using the dendritic cells even without antigen loading, such as for phenotypic analysis.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to include AB serum and transfer the dendritic cells, as taught by the ‘659 publication, in the dendritic cell culture method of Chang et al. Choosing from the known culture mediums and methods suitable for dendritic cells, such as those comprising AB serum, 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, the ordinary artisan would expected to obtain a mature CD14-HLA-DR+CD86+CD83+ phenotype, based on the teachings of the cited references. For example, the 659 publication teaches that transfer of the cells to a new tissue culture plate or flask causes them to reattach and become characteristically dendritic with a mature phenotype and with expression of CD83, HLA class II, CD80, CD86, and CD14- (see paragraph 68 and Table 2, in particular).
Regarding the limitation that the culture substrate is polystyrene, it is well recognized in the art that plastic tissue culture flasks, such as used in Chang and the ‘659 publication are made of polystyrene (see, for example, Pullarkat, page 174, in particular).
It is noted that claims 5, 15, and 21, are included, since they merely recite further limitations regarding the structure of the brain tumor cell/lysate, however, in claim 4 or 13, or 20, the choice of type of tumor lysate is in the alternative.
Applicant’s arguments filed 8/19/25 have been fully considered, but they are not persuasive.
Applicant argues that the claims are not obvious for the reasons set forth above.
The claims stand rejected for the reasons set forth above.
Applicant further argues that Chang teaches mixing the tumor lysate pulsed dendritic cels with KLH pulsed dendritic cells for administration.
The present claims do not exclude doing so.
Claims 1-5, 7-15, and 17-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Chang et al., 2002 (of record), US 2001/0007659, Yu, July 2004 and Pullarkat, 2002, and further in view of Veigh et al., and Hochrein (of record)
The teachings of the cited references are described above.
They do not teach contacting the immature dendritic cells with IFN-gamma.
Veigh et al. teach that IFN-gamma pretreatment of immature dendritic cells can generate IL-12 production and enhance Th1 responses, and that is further augmented upon subsequent encounter with the cells (see page 72, Fig. 5, and Table 2, in particular).
Hochrein teaches that culture with GM-CSF, IL-4 and IFN-gamma enhances dendritic cell activation/maturation (see pages 829-830, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was to include IFN-gamma, as taught by Veigh et al, and Hochrein. in the cultures of dendritic cells made obvious above. The ordinary artisan would have been motivated to do so, since Veigh et al. teach that IFN-gamma pretreatment of immature dendritic cells can generate IL-12 production and enhance Th1 responses, and that is further augmented upon subsequent encounter with the cells and Hochrein teaches that culture with GM-CSF, IL-4 and IFN-gamma enhances dendritic cell activation/maturation.
Applicant argues that the claims are not obvious for the reasons set forth above.
The claims stand rejected for the reasons set forth above.
No claim is allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644