DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Status of the Claims
Claims 1-20 are pending. Claims 11-20 are withdrawn. Claims 1-10 are under consideration in this action.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on March 2, 2026 is acknowledged.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 2, 2026.
Claim Rejections - 35 USC § 103
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 1-4, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma) (Journal of Translational Medicine; published 2011) and Wang (US 2019/0160174 A1; published May 30, 2019).
With regards to Claims 1-4, 6, and 7, Ma discloses that dendritic cells (DC) are the most potent professional antigen-presenting cells (APC), having the ability to initiate primary immune responses. Therefore, immunotherapy utilizing DC has become a promising therapeutic modality in recent years. However, the lack of efficient and long-lasting antigen presentation by DC in vivo has been a major difficulty in the development of effective vaccines. Ma discloses that these obstacles could be circumvented through the development of nanoparticles, which can efficiently deliver the antigenic peptides into the APC (p.1, col.2, para.2 to p.2, col.1, para.1).
Thus, to address this issue, Ma discloses polylactic-co-glycolic acid (PLGA) nanoparticles incorporating (i) two MHC class I-restricted clinically relevant peptides (reading on peptide antigen), (ii) an MHC class II-binding peptide (reading on peptide antigen), and (III) a non-classical MHC class I-binding peptide (reading on peptide antigen). Ma loaded human and murine dendritic cells (DC) with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL) in vitro (abstract; p.2, col.1, para.3-5; p.2, col.2, Nanoparticle formulation).
Ma discloses that they have confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. Ma also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with a more efficient generation of peptide-specific CTL and T helper cell responses (abstract).
Ma discloses that encapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production (abstract; p.7, col.1-2; p.8, Conclusions).
Direct peptide delivery to dendritic cells using particulate delivery systems is a promising new approach. In addition to having a depot effect on the peptide antigens, inherent properties of the particles themselves engender immunogenicity of the peptides, and allow uptake of an immunogenic package of peptides and other molecules (p.6, col.1, para.1).
Ma discloses that the efficiency of the antigen presentation by human DC was significantly enhanced after just 1-hour incubation with the nanoparticles discussed above (p.3, col.1, Nanoparticle uptake imaging studies; p.6, Fig.4; p.8, col.1, para.2) (reading on loading the dendritic cells with antigen by contacting the cells with the nanoparticles).
Ma does not appear to explicitly disclose (i) covalently linking the antigen to a lipid to form a conjugate (Claim 1). Wang is relied upon for this disclosure. The teachings of Wang are set forth herein below.
Wang discloses a cell surface anchoring conjugate comprising at least one antigen covalently bonded to a lipid moiety (Wang claim 1). The conjugate may be encapsulated in PLGA nanoparticles (para.0104). In an embodiment, the antigen is a peptide antigen (Wang claim 10).
The antibody binding molecule-cell surface anchoring molecule conjugate can enhance the killing of cancer cells and/or antigen presenting is called cancer cell inactivating agent (para.0004).
To increase the duration of the anchors on the cell membrane because of dissociation processes or endocytotic disappearance from the cell membrane, the number of hydrophobic anchoring groups can be increased. The cell membrane anchoring molecule can be a lipid (para.0064).
The cell membrane/surface anchoring molecule can be a lipid molecule, such as a fatty acid or its derivative, phospholipid glycerolipid, glycerophospholipid, sphingolipid, ceramide, glycerophosphoethanolamine, sterol, or steroid (para.0071).
The conjugates facilitate the lysis of cancer cells, can enhance the killing of tumor/cancer cells, and is called cancer cell inactivating agent (para.0032). The conjugate may be administered by intravenous, intramuscular, subcutaneous, or intratumoral injection (para.0028, 0032).
Wang discloses methods to treat tumor cell and cancer and to boost immunity against tumor cell. The method comprises giving patents said cancer cell inactivating agent and/or agent can enhance cancer cell antigen presenting or in combination with an immune activity enhancing agent (immunity boosting agent) and exogenous antibody that can bind with the cancer cell inactivating agent (para.0033).
In some embodiments, the principle of cancer cell inactivating agent/agent that can enhance cancer cell antigen presenting in the current invention is to direct antibody or cytotoxic T cell to cancer cells, releasing tumor antigen for cancer immunotherapy. It will form in situ cancer vaccine and promote strong immune response with the locally injected immune activity enhancing agent (para.0043).
With regards to the step of covalently linking the antigen to a lipid to form a conjugate as recited in the instant Claim 1, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to combine the teachings of Ma and Wang and conjugate Ma’s peptide antigens to a lipid prior to encapsulating into the PLGA nanoparticles. One of ordinary skill in the art would have been motivated to do so in order to obtain the advantage of anchoring the conjugate onto the cell surface and enhancing the killing of tumor/cancer cells and promoting a strong immune response in the subject. One of ordinary skill in the art would have had a reasonable expectation of success in doing so as both Ma and Wang are directed to use to peptide antigens for immunotherapy, in particular those encapsulated within PLGA nanoparticles.
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention.
Claims 5, 8, and 9 is rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma) (Journal of Translational Medicine; published 2011) and Wang (US 2019/0160174 A1; published May 30, 2019) as applied to Claims 1-4, 6, and 7 set forth above, further in view of Von Andrian et al. (Von Andrian) (US 2010/0233251 A1; published Sept. 16, 2010).
The teachings of Ma and Wang and the motivation for their combination as they apply to Claims 1-4, 6, and 7 are set forth above and incorporated herein.
The combined teachings of Ma and Wang do not appear to explicitly disclose (i) wherein the lipid is selected from those recited in Claim 5; (ii) wherein the antigen-specific T cell response is immune tolerance (Claim 8), or (iii) wherein the antigen-specific T cell response is immune stimulation (Claim 9). Von Andrian is relied upon for these disclosures. The teachings of Von Andrian are set forth herein below.
Von Andrian discloses compositions and systems for delivery of nanocarriers to cells of the immune system. The invention provides vaccine nanocarriers capable of stimulating an immune response in T cells and/or in B cells. The invention provides methods of prophylaxis and/or treatment of diseases, disorders, and conditions comprising administering at least one inventive vaccine nanocarrier to a subject in need thereof (abstract).
Von Andrian discloses the encapsulation of antigens into nanocarriers (para.0022, 0223; Von Adrian claim 387). Von Andrian’s inventive prophylactic and/or therapeutic protocols involve administering a therapeutically effective amount of one or more inventive vaccine nanocarriers into a subject such that an immune response is modulated (e.g., stimulated in both T cells and/or B cells) (para.0118). The compositions comprising the nanoparticles can be administered by a variety of routes, such as parenterally (par.0119-0121; Von Andrian claim 412).
The nanocarriers further comprise one or more of an immunomodulatory agent, an immunostimulatory agent, and a targeting agent (para.0006). In an embodiment, the vaccine nanocarrier comprises an immunomodulatory agent that stimulates an immune response in B cells or stimulates an immune response in T cells (para..0082). In an embodiment, the nanocarrier comprises an immunostimulatory agent which is an immunosuppressant or agent that induces regulatory T cells to promote the acquisition of tolerance to an antigen (para.0029).
Von Andrian discloses that a target for their targeting moieties includes a lipid, such as steroid, e.g., cholesterol (para.0226, 0229).
With regards to Claim 5, as discussed above, the combined teachings of Ma and Wang are directed to loading dendritic cells with antigen by contacting the cells with the nanoparticles which have loaded therein the lipid-antigen conjugate. With regards to the specific lipid used, Wang discloses that among the suitable lipids include steroids. One of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the instant invention to further combine the teachings of Ma and Wang with the teachings of Von Andrian, and use cholesterol as the specific lipid in the lipid-antigen conjugate of the combined teachings of Ma and Wang. One of ordinary skill in the art would have been motivated with a reasonable expectation of success in doing so as Von Andrian discloses that cholesterol is a steroid lipid known to be suitable for use with nanocarriers used to modulate an immune response in a subject.
With regards to Claims 8 and 9, as discussed above, the combined teachings of Ma and Wang are directed to loading dendritic cells with antigen by contacting the cells with the nanoparticles which have loaded therein the lipid-antigen conjugate to formulate vaccines. One of ordinary skill in the art would have found it prima facie obvious before the effective filing date to further combine the teachings of Ma and Wang with the teachings of Von Andrian and further include an immunomodulatory agent or an immunostimulatory agent in the nanoparticle of the combined teachings of Ma and Wang in order to promote either immune stimulation or immune tolerance, respectively, based on the needs of the patient receiving the vaccine. One of ordinary skill in the art would have been motivated to do so in order to better fit the vaccine to the needs of the subject receiving the vaccine and be personalized to the subject’s cancer and state of the immune system of the subject. One of ordinary skill in the art would have had a reasonable expectation of success in doing so as Von Andrian discloses that immunostimulatory agents and immunomodulatory agents may be incorporated into the nanoparticles with the antigens.
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Ma) (Journal of Translational Medicine; published 2011) and Wang (US 2019/0160174 A1; published May 30, 2019) as applied to Claims 1-4, 6, and 7 set forth above, further in view of Baldin et al. (Baldin) (Cancers; published Mar. 5, 2020).
The teachings of Ma and Wang and the motivation for their combination as they apply to Claims 1-4, 6, and 7 are set forth above and incorporated herein.
The combined teachings of Ma and Wang do not appear to explicitly disclose (i) wherein the antigen loading is performed ex vivo or in vivo (Claim 10). Baldin is relied upon for these disclosures. The teachings of Baldin are set forth herein below.
Baldin discloses that dendritic cells (DCs) are known to be loaded with antigen with either ex vivo loading or in vivo targeting to generate DC vaccine generation (title; abstract).
In vivo strategies of cancer antigen delivery to DCs are based on employing DC surface molecules and their receptor machinery. This approach implies the utilization of DC receptor ligands, adjuvants, anti-receptor antibodies and other types of substance that can accurately bind to their target on DCs, followed by their uptake or changes to the DCs’ phenotype. Prepared vaccines consisting of cancer antigens in complex or fused to DC-targeting substances will be delivered directly to the DCs after being administered in patients’ tissues (p.4, 2. In Vivo Dendritic Cell Targeting, Fig.1). After administration into a DC-rich site of the organism, the antigen-containing vaccine is recognized by immature DCs, followed by its internalization (p.5, Fig.1 caption). Suitable administration routes include subcutaneous, intradermal, intranodal, intralymphatic, and intravenous (p.4-5, Fig.1 caption).
Loading of dendritic cells may also be done ex vivo. The major difference of in vivo DC targeting compared to ex vivo DC loading is that antigen uptake by DCs and the DC maturation process take place in a natural microenvironment, or in an artificially created environment (p.19, 3.1. Methods of Ex Vivo Dendritic Cell Generation, Fig.2). The ex vivo approach provides the possibility of applying a wide spectrum of more efficient antigen loading methods that cannot be applied in vivo (p.18, 3. Ex Vivo Dendritic Cell Loading).
Baldin discloses that both in vivo DC targeting and ex vivo DC loading have advantages and disadvantages. As cancer is a heterogeneous disease, the next generation of DC-based vaccines should be optimized for selective use in individual patients based on their tumor biology (p.26, para.1; p.27, Table 4).
With regards to Claim 10, as discussed above, the combined teachings of Ma and Wang are directed to loading dendritic cells with antigen by contacting the cells with the nanoparticles which have loaded therein the lipid-antigen conjugate to formulate vaccines. One of ordinary skill in the art would have found it prima facie obvious before the effective filing date to further combine the teachings of Ma and Wang with the teachings of Baldin and perform the DC loading step using the ex vivo or in vivo methods disclosed by Baldin based on patient’s specific cancer and tumor biology. One of ordinary skill in the art would have had been motivated with a reasonable expectation of success in doing so as Baldin discloses loading DC with antigens is known to be performed either in vivo or ex vivo, each having their pros and cons, with the specific method being selected based on the individual patient’s need. In vivo targeting and ex vivo loading would also allow for more personalized design of vaccines to the particular cancer or tumor biology.
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, because the combined teachings of the prior art references is fairly suggestive of the claimed invention.
Conclusion
Claims 1-10 are rejected. No claims are allowed.
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/MONICA A SHIN/Primary Examiner, Art Unit 1616