DETAILED ACTION
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 .
Applicant's amendments to the claims filed on 06-09-2026 have been received and entered. Claims 1 and 22 have been amended. Claims 4, 6, 15, 17-18, 20, 23, 25, have been canceled. Claims 1-3, 5, 7-14, 16, 19, 21-22, 24, 26-28 are pending in the instant application.
Election/Restrictions
Applicant’s election of Group I (claims 1-3, 5, 7-14, 16, 19, and 21) directed to a vaccine preparation comprising extracellular blebs in the reply filed on 06-09-2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 22, 24, 26-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06-09-2026.
Claims 1-3, 5, 7-14, 16, 19, 21 are under consideration.
Priority
This application is a 371 of PCT/US2022/040963 filed on 08/19/2022 which claims priority from US provisional application 63/235,100 filed on 08/19/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02-15-2024, 03-09-2024 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5, 7-14, 16, 19, 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims are directed to a vaccine preparation comprising extracellular blebs from a fused cell of any antigen presenting cell and any target cell, wherein the fused cell expresses any antigen (known or unknown) that can modulate a subject's immune system wherein the extracellular blebs are produced from the fused cell by treating the fused cell with any blebbing agent, and wherein the antigen is displayed on the surface of the extracellular blebs. Claim 7 is directed to wherein the target cell is selected from any cancer cell, any abnormal or diseased cell, any cell engineered to display an antigen, or any cell that is infected with an infectious agent. Claim 9 is directed to wherein the target cell is any cell that is infected by any virus, any fungus, or any bacterium.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a genus of vaccine preparation that comprises extracellular blebs from fused cell of any antigen presenting cell and any target cell expressing any antigen (known or unknown) that can modulate any subject's immune system. The claims are directed the target cell is selected from any cancer cell, any abnormal or diseased cell, any cell engineered to display an antigen, or any cell that is infected with an infectious agent, and the target cell is any cell that is infected by any virus, any fungus, or any bacterium.
The instant specification only teaches examples for hybridomas (fused cell) of dendritic cells with lymphoma cell without examples for various species of the genus of fusing any antigen presenting cell and any target cell (cell infected by any virus, any fungus, or any bacterium) to produce extracellular blebs that can modulate a subject's immune system encompassed by the claims: The instant specification teaches hybridomas of bone marrow-derived dendritic cells (BMDCs) and T-cell lymphoma cell ([0086], page 31), Polyethylene glycol (PEG) mediated fusion of bone marrow derived dendritic cells with EG7-Oova T cell lymphoma ([0087], page 32). Chemically induced blebbing of hybridoma cells ([0091], page 33). Preparation and characterization of EBs derived from the hybridoma of BMDC and T lymphoma cell ([0092], page 34). Antigen presentation to CD8 T cells by EBs derived from the hybridoma of BMDC and T lymphoma cell ([0093], page 34). Vaccination by EBs derived from tile hybridoma of BMDC and T lymphoma cell ([0094], page 35). EL4 T lymphoma cell fusion with bone marrow dendritic cells ([00100], page 37). Vaccination ofEL4 hybridoma blebs for anti-tumor protection ([00102], page 37). Hybridomas with stably preserved functions of BMDC and T lymphoma cell ([00104], page 38). Preserved antigen presentation and co-stimulation by the hybridoma and their EBs ([00105], page 39).
1. Extracellular blebs (extracellular vesicles) containing unpredictable content (including genus of any known and unknown antigens) from fused cell of any antigen presenting cell and any target cell is unpredictable to modulate any subject's immune system. Extracellular vesicles (EVs) are highly unpredictable for modulating the immune system because they carry thousands of bioactive molecules (proteins, lipids, and nucleic acids) directly reflecting their parent cell, EVs suffer from significant heterogeneity and inconsistent cargo.
Burrello et al (Front. Cell Dev. Biol. 4:83. doi: 10.3389/fcell.2016.00083) teach :
“EVs carry a plethora of molecules that influence their mode of action. These include a variety of receptors, adhesion molecules, proteins involved in cell trafficking, and/or intracellular signal transduction, cytoskeletal proteins, cytoplasmic enzymes, cytokines, chemokines, as well as cell-specific antigens (Ags). Moreover, they are also enriched with a range of nucleic acids, including mRNA, long non-coding RNAs, microRNAs (miRNA), and even extra-chromosomal. The content carried however may vary depending on the type of cell and the state of activation. Once released, these EVs may interact with neighboring cells or diffuse through and circulate in the bloodstream or other organic fluids such as: breast milk, semen, saliva, urine, and sputum.” (Page 2, left column, 2nd para.)
“The immune system can be divided into two branches: the innate immune response (IIR)—an evolutionary conserved system common to all multicellular organisms, and the acquired or adaptive immune response (AIR)—an exclusive feature developed in vertebrates. Within the IIR system, EVs act as paracrine messengers, allowing the propagation of pro-inflammatory signals. However, they have also been reported to contribute as negative regulators of the inflammatory response primarily by carrying molecules such as Transforming Growth factor-β (TGF-β), and other immuno-suppressive mediators. The role of EVs in the regulation of IIR is complex and has not yet been fully elucidated” (Page 2, right column, 2nd -3rd para.).
It can be speculated that tumor-derived EVs carry tumor-specific Ags and that they could be used to stimulate or inhibit the immune anti-tumoral surveillance ….APC-derived EVs can also act as “Ag-presenting vesicles” for in vitro T-cell clones, however this activity appears to be 10–20 times less efficient to that of corresponding APCs probably due to: the small size, vesicle diffusion, and limited number of MHC molecules per vesicle. (Bridging last paragraph on page 2 to page 3).
EVs derived from MSCs are less effective than the cells themselves, as the latter may act either by direct cell-to-cell interaction as well as by releasing several active soluble factors. Moreover, the biological effect of EVs may vary depending extracellular micro-environment. A pro-inflammatory environment for instance may modify the composition of EVs and the consequent biological activities as well as the activation state of immune effector cells targeted by these EVs (Page 7, left column, 2nd para.).
2. Expressing any disease antigen on an APC (Antigen-Presenting Cell) to produce extracellular blebs to modulate immunity in any subject is highly unpredictable due to the complex interplay of dynamic immune variables, including Major Histocompatibility Complex (MHC) turnover, local cytokine microenvironments, and co-stimulatory or co-inhibitory signaling:
Cai et al (Materials Today Bio 38 (2026) 103192, Doi: 10.1016/j.mtbio.2026.103192) teach engineered artificial antigen-presenting cells for tumor immunotherapy (title) that include natural particle-based aAPCs such as biologically derived vesicles (e.g., exosomes), DCs derived vesicles, Macrophages derived vesicles, other cells derived vesicles, synthetic particle-based aAPCs (see entire page 7). Although aAPCs exhibit broad potential in tumor immunotherapy, several critical challenges impede their large-scale clinical application:
“Therapeutic efficacy remains unpredictable due to patient-to patient variability. As highlighted by Butler et al., some patients still require combination therapies to achieve disease control, indicating that identical aAPCs may elicit divergent outcomes across individuals. Such variability is likely attributable to differences in endogenous antigen profiles, complicating the optimization of dosing, administration frequency, and treatment protocols. On the other hand, it should be noted that due to the low proportion of central memory T cells (Tcm) and the rapid depletion of effector T cells, the efficacy of tumor immunotherapy based on aAPCs is not enduring” (Page 23, left column, 4th-5th para.)
The absence of standardized and scalable production protocols for aAPCs represents a substantial barrier to clinical translation. Despite the rapid emergence of diverse aAPC constructs, no industry consensus or expert guidelines currently exist to regulate their manufacturing and quality control. For instance, Dong et al. report that the instability of microemulsion droplets during the fabrication of polydopamine microbubbles results in poor particle size uniformity, a limitation recognized as a key direction for future improvement (page 23, right column, 2nd para.). Advancing aAPC technology requires a deeper understanding of how size, morphology, surface topography, and material composition influence immunostimulatory efficacy. Research has demonstrated that particle size critically impacts T cell activation kinetics. For example, SPIONs exceeding 300 nm facilitate effective engagement with multiple TCR nanoclusters, leading to robust proliferation, whereas smaller counterparts (~50 nm) at equivalent ligand doses elicit significantly weaker responses Particle shape also plays a significant role. Non-spherical geometries (e.g., ellipsoids) often outperform spheres in activation efficiency. This may be due to an enhanced interfacial contact area, altered membrane dynamics that influence ligand clustering, or differential in vivo trafficking and circulation times [61–63]. Surface characteristics such as ligand density, spatial arrangement (achieved with DNA origami, which enables nanoscale precision [87]), and membrane fluidity (exploited in liposomal and biomimetic designs [57, 59,114]), directly modulate TCR triggering strength, synapse stability, and signal integration. The choice of material not only affects biocompatibility and biodegradability, but also influences drug loading/release profiles, mechanical properties (e.g., scaffold stiffness that mimics lymph nodes [125]), and potential off-target effects (page 23, right column, 3rd para.).
Ning et al (Front. Immunol. 15:1483834. doi:10.3389/fimmu.2024.1483834) teach that “Antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages, play a vital role in the capture of tumor-specific antigens and their subsequent delivery to CD8+ cytotoxic T cells. This process initiates a cascade of immune responses aimed at targeting cancerous cells. Nevertheless, the complex mechanisms linked to antigen presentation in HCC and their influence on the anti-tumor immune response remain subjects of ongoing research” (Page 2, left column, 2nd para.) and “Dendritic cells (DCs) are particularly important in this immune response, as they adeptly capture antigens from tumor cells, process them, and present tumor-derived peptides on their surface within the major histocompatibility complex (MHC) framework. This essential interaction between antigens and MHC molecules is recognized by CD4+ and CD8+ T cells, which in turn triggers a specific immune response against Hepatocellular carcinoma (HCC). However, HCC can evade this immune response through various mechanisms that interfere with antigen presentation, leading to immune resistance. Notably, tumor-infiltrating myeloid cells, including DCs, undergo changes that render them immunosuppressive, diminishing their ability to present antigens effectively. Moreover, HCC cells themselves can modulate MHC expression or suppress antigen processing and presentation, enabling them to escape detection by T cells. Therapeutic strategies, such as immune checkpoint inhibitors, are designed to counter these inhibitory signals and enhance antigen presentation, aiming to elicit robust antitumor immune responses, which holds promise in the treatment of HCC” (Page 04, left column, 2nd para.)
3. Fusing efficiency of any antigen-presenting cell (APC) (such as a dendritic cell or macrophage) with any target cell (like a tumor cell or viruses/fungi infected cells) to produce extracellular blebs is unpredictable:
Dittmar et al (Int. J. Mol. Sci. 2022, 23, 16071. Doi: 10.3390/ijms232416071) teach “Fusion among different cell populations represents a rare process that is mediated by both intrinsic and extracellular events. Cellular hybrid formation is relayed by orchestrating tightly regulated signaling pathways that can involve both normal and neoplastic cells. ……Aside from intrinsic factors, cell fusion is particularly affected by extracellular conditions, including an inflammatory microenvironment, viruses, pH and ionic stress, hypoxia, and exosome signaling” (Abstract). For cell–cell fusion, it is assumed that cells have to acquire pro-fusogenic status in order to fuse. In fact, cells are not fusogenic by themselves but must express certain proteins/factors, such as fusogens or PS, the appropriate receptors, to be able to fuse with each other. Similarly, once fusion has occurred, cells must revert to a non-fusogenic state to avoid undesirable subsequent fusion events. Cellular and molecular mechanisms that are important for expression of this hypothetical state remain to be explored. Likewise, clear definitions of pro-fusogenic state need to be articulated (Page 2, 4th para.).
Wang et al (Oncology Letters 22: 530, 2021, DOI: 10.3892/ol.2021.12791) teach “Cell fusion participates in various processes, including reproduction, growth and development, and involves complex genetic and molecular mechanisms that remain unclear. Previous studies have reported that different differentiated cells may not share the same mechanism in cell fusion, such as having different adhesion or recognition molecules and fusogens . Molecules involved in some cell fusion phenomena that occur under physiological conditions in mammals are summarized in Table I.” (Page 2, left column, 2nd para.).
4. When an Antigen-Presenting Cell (APC) fuses with a disease cell (such as a virus-infected cell), the resulting hybrid cell can be infected or die, depending on the nature of the disease cell and the host's immune response. For example, if the fused cell contains an active, replicating virus (e.g., HIV), the fused cell can still be infected and may eventually undergo apoptosis (programmed cell death), which disrupts the antigen-presentation process. Thus, obtaining extracellular blebs from such fusion cells is unpredictable.
Chisompola et al (Biology 2025, 14, 1680. Doi: 10.3390/biology14121680) teach “HIV-induced apoptosis: host defense and viral strategy” (title) and “When the Human Immunodeficiency Virus (HIV) infects a person, it triggers a process called apoptosis, a form of programmed cell death that is normally used by the body to eliminate damaged or infected cells …... While apoptosis is initially a defense mechanism to limit the virus, HIV cleverly hijacks it to kill a massive number of uninfected immune cells, leading to a severe weakening of the immune system. This widespread cell death is a major reason why patients continue to have health problems even with effective antiviral medication” (Abstract). Chisompola et al teach “the activated and HIV-infected cells release neurotoxic substances that cause neuronal injury, dendritic and synaptic damage, and apoptosis” (Figure 2, page 8) and “A profound paradox in viral pathogenesis is presented by the intricate interaction between HIV and host cell death pathways. HIV systematically manipulates apoptosis; a basic defense mechanism intended to eradicate infected cells and stop the spread of the virus to cause immune collapse. Even though there has been a lot of progress in understanding these pathways, integrated therapeutic-focused studies must replace observational studies in the future. The isolated pathways involved in viral pathogenesis have been the main focus of recent research” (Page 19, last para).
Marrero et al (mBio 16:e01257-25 doi: 10.1128/mbio.01257-25) teach “Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection” (title) and “macrophages and dendritic cells (DCs) distinctly respond to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate robust intracellular replication. In contrast, T4SS activity triggers rapid death of DCs, which potently restricts Legionella replication. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single-cell level. Initially, some DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis early during infection. At later time points, other DCs undergo apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our findings suggest a model where Mcl-1 and cFLIP guard host translation in DCs. Furthermore, our work shows that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection” (Abstract)
Thus, there is no evidence on the record that embraced genus of extracellular blebs (from fused cell of any antigen presenting cell and any target cell) and/or genus of any antigen that can modulate a subject's immune system had known structural relationships to each other. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 UsPQ2d 1641, 1646 (1998).
The specification lacks sufficient variety of species to reflect this variance in the genus showing contemplated biological activity of extracellular blebs (from fused cell of any antigen presenting cell and any target cell) and any antigen that can modulate a subject's immune system to prepare a vaccine. The specification does not provide sufficient descriptive support for the myriad of variant embraced by the claims.
Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and function related to that core structure such that the Artisan of skill could determine the desired effect. Hence, the analysis above demonstrates that Applicant has not determined the core structure for full scope of the claimed genus for contemplated any “antigen presenting cell”, any “target cell” (cell infected by any virus, any fungus, or any bacterium), any “antigen that can modulate a subject's immune system” to prepare a vaccine.
The skilled artisan cannot reliably envision the functional combinations encompassed by the limitations of any “antigen presenting cell”, any “target cell”, and any “antigen that can modulate a subject's immune system” other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
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.
Claims 1-3, 5, 7-14, 16, 19, 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kwon et al (Pub. No.: US 2019/0350854 Al, Pub. Date: Nov. 21, 2019) (applicant’s own work) in view of Nicolette et al (Pub. No.: US 2007/0141704 A1, Pub. Date: Jun. 21, 2007).
Claim interpretation:
The specification of the claimed invention teaches that “The term "blebbing agent", as used herein refers to chemical agents, such as sulfhydryl blocking agents, that when administered to cells, induce the cells to undergo plasma membrane blebbing” ([0037], page 10), and “The chemical agent that induces blebbing is a sulfhydryl blocking agent. Examples of sulfhydryl blocking agents include, but are not limited to … paraformaldehyde, dithiothreitol…”. Thus, sulfhydryl blocking agents such as paraformaldehyde (PFA), dithiothreitol (DTT) are interpreted as blebbing agents.
The specification of the claimed invention teaches that “The term "extracellular bleb" or "EB" as used herein, is synonymous with an "induced cell-derived vesicle" or "ICV" and refers to an extracellular vesicle that is formed as a direct result from contacting the cell with a blebbing agent. Accordingly, an EB is not synonymous with a naturally occurring extracellular vesicle, as the latter is formed without the presence of blebbing agent, while the former requires the use of a blebbing agent in order to be produced” ([0038], page 10). Thus, "extracellular bleb" or "EB" is interpreted as an extracellular vesicle that is formed as a direct result from contacting the cell with a blebbing agent.
It is noted that claims 10 , 11 and 12 are all dependent on claim 9 and narrow the scope of claim 9. Each of these claims narrow the scope of “cell that is infected by a virus, a fungus, or a bacterium” recited in claim 9; however, they do not exclude the embodiments of each other (a virus, a fungus, or a bacterium). For example, claim 11 narrows the scope of a fungus in claim 9; however, claim 11 does not exclude the embodiments of a virus or a bacterium recited in claim 9. Thus, claim 11 is included in the instant rejection.
Regarding to claims 1, 2, Kwon et al teach “Extracellular vesicles, their manufacture, and methods of treatment are described. Generally, extracellular vesicles can be generated by applying sulfhydryl blocking reagents on animal cells. Extracellular vesicles can be loaded with compounds for an intended use, such as, for example, loading an extracellular vesicle with a medicament to treat an animal.” (Abstract)
Kwon et al teach cell-free vaccine: “FIG. 22 describes a method of several embodiments where bone marrow dendritic cells (BMDC) were used for immunotherapy, especially in the field of cancer. EVs derived via exposing BMDCs to sulfhydryl blocking reagents can be used for cancer immunotherapy in the form of a cell-free vaccine. Dendritic cells (DCs) activate T cells against antigens, and therefore can be used for developing an immunization against antigens, including cancer-specific antigens…….DC-derived exosomes have been shown to be an alternative to DC adoptive therapy. Vesiculation, in accordance with embodiments of processes described herein, would enable a more efficiently produced cell-free vaccine than is currently available using exosomes” ([0141], page 11). EVs are produced by incubating cells with sulfhydryl blocking reagents. These reagents alter the function of a natural cellular phenomenon known as blebbing ([0078]).
Kwon et al teach Sulfhydryl blocking reagent-induced blebbing results in cells shedding nano-sized EVs ([0110], page 7), and “FIG. 9 demonstrates embodiments of EV production in the presence and absence of sulfhydryl blocking reagents. EL4 cells were incubated at 100,000 cells/mL in 5 mL of either DMEM (without FBS) for 24 hours or PBS with 90 µL 4% PFA solution and 10 µL 1 M DTT for 2 hours at 37° C” ([0111], page 7). In the method described by FIG. 22, bone marrow dendritic cells (BMDC) were isolated from C57BL/6 mice (2202). These cells were pulsed in the presence of the SIINFEKL antigen to cause the cells to display the antigen (2204). The BMDC cells were treated with sulfhydryl blocking reagents (2206) to produce EVs displaying the SIINFEKL antigen ([0142], page 11).
Kwon et al do not teach a fused cell of an antigen presenting cell and a target cell. Nicolette et al cure the deficiency.
Nicolette et al teach “cell fusions and methods of making and using the same” (title) and “The invention features compositions for stimulating an immune system. Accordingly, the invention includes a hybrid cell (or progeny thereof), which is a fusion product of a dendritic cell, e.g., a non-follicular dendritic cell, and non-dendritic cell…… Examples include hybrid cells in which the non-dendritic cell fusion partner expresses a disease-associated antigen such as that derived from a tumor, a bacterium, or a virus.” ([0006], page 1) and “Also within the invention is a vaccine, which contains a hybrid cell and a pharmaceutically acceptable carrier” ([0016], page 2)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Kwon et al by fusing a target cell with a dendritic cell for a dendritic cell-based vaccine as taught by Nicolette et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Nicolette et al teach benefit of intraspecies hybrid of a dendritic and a non-dendritic cell: “This hybrid expresses known and unknown cell antigens from the non-dendritic cells, MHC class I and II molecules, and a B7 costimulatory molecule in an amount effective to stimulate a cytotoxic immune response against the non-dendritic cell antigens” ([0017], page 2) and “The isolated fused cells, which typically express (a) MHC class II protein, (b) B7, and (c) the cell-surface antigen on the non-dendritic parental cells, are useful for stimulating an immune system.” ([0009], page 2), and “This invention provides a substantially pure population of educated, antigen-specific immune effector cells expanded in culture at the expense of hybrid cells, wherein the hybrid cells are antigen presenting cells (APCs) fused to cells that express one or more antigens” ([0012], page 2). . One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Nicolette et al were successful in generation of fused cells that expresses a disease-associated antigen Such as that derived from a tumor, a bacterium, or a virus ([0006], page 1) and stimulate an immune system (e.g., to activate T cells), MHC class II molecules, B7, and the cell-surface antigen ([0007], page 1).
Regarding to claim 3, Kwon et al teach FIG. 25A is a data graph depicting the activation of
T-cells by extracellular vesicles derived from immature dendritic cells, immature dendritic cells presenting the SIINFEKL antigen, mature dendritic cells, and mature dendritic cells presenting the SIINFEKL antigen in accordance with various embodiments of the invention ([0073], page 3).
Regarding to claim 5, Kwon et al teach FIG. 22 describes a method of several embodiments where bone marrow dendritic cells (BMDC) were used for immunotherapy ([0141], page 10).
Regarding to claim 7, Nicolette et al teach “…. Examples include hybrid cells in which the non-dendritic cell fusion partner expresses a disease-associated antigen such as that derived from a tumor, a bacterium, or a virus” ([0006], page 1).
Regarding to claim 8, Nicolette et al teach fusion of human DCs and myeloma cells: “Cell fusion was carried out between DCs and human myeloma cells MY5 to produce fused cells DC/MY5” ([0243], page 21).
Regarding to claims 9, 10, and 12 Nicolette et al teach “Cells infected with an intracellular pathogen can also be used as the non-dendritic partner of the fusion for treatment of the disease caused by that pathogen. Examples of pathogens include, but are not limited to, viruses (e.g., human immunodeficiency virus, hepatitis A, B, or C virus, papilloma virus, herpes virus, or measles virus), bacteria (e.g., Corynebacterium diphtheria, Bordetella pertussis), and intracellular eukaryotic parasites (e.g., Plasmodiuin spp., Schistosoina spp., Leishmania spp., Trypanosoma spp., or Mycobacterium lepre).” ([0101], page 8).
Regarding to claim 13, Nicolette et al teach “The method also provides the embodiment wherein the APCs and the antigen-expressing cells are derived from the same subject or from different subjects (autologous or allogeneic)” ([0113], page 10).
Regarding to claims 14 and 16, Nicolette et al teach “Example III further demonstrates that such fusion cells may even activate energized T cells that are specific for tumor antigens.” ([0108], page 9). And “EXAMPLE IV: activation of tumor-specific CTL by fusions of human dendritic cells and breast carcinoma cells” (Page 23). It is noted that Kwon et al teach “Vesicle Surface: Vesicles will express the same surface markers as parent cells …...” (see Figure 3 of Kwon et al).
Regarding to claim 19, Nicolette et al teach “vaccine composition” ([0016], page 2) and “…The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants…” ([0092], page 7).
Regarding to claim 21, Nicolette et al teach “The invention also involves an intraspecies hybrid of a dendritic and a non-dendritic cell. This hybrid expresses known and unknown cell antigens from the non-dendritic cells, MHC class I and II molecules, and a B7 costimulatory molecule in an amount effective to stimulate a cytotoxic immune response against the non-dendritic cell antigens” ([0017], page 2). Nicolette et al teach “By “B7 is meant any member (e.g., B7-1 or B7-2) of the B7 family of costimulatory molecules” ([0007], page 1) and “human B7-1 (CD80), human B7-2 (CD86)” ([0291], page 25).
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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