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
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This application is in response to the papers filed on November 7, 2025. Pursuant to the amendment filed on November 7, 2025, claims 4-8, 16, 27-29, 33-34 and 36-42 are currently pending of which claims 4, 8, 36, 41, and 42 have been amended and claim 35 has been cancelled. Applicant has elected the invention of Group I, e.g., claims 2-8, 16, 27-29 and 33-37, drawn to a programmed delivery vehicle, in the reply filed on April 12, 2024 and made FINAL in the Office Action dated May 22, 2024.
Therefore, claims 4-8, 16, 27-29, 33-34 and 36-42 are currently under examination to which the following grounds of rejection are applicable.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Objections
In view of Applicants’ amendment to the claims dated November 7, 2025, the objection to claim 16 has been withdrawn.
Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendment to the claims dated November 7, 2025, wherein claims 4, 8, 36, 41, and 42 have been amended, the rejection to claims 4-8, 16, 27-29, and 33-42 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, have been withdrawn.
Claim Rejections - 35 USC § 112(d)
In view of Applicants’ amendment to the claims dated November 7, 2025, wherein claims 4, 8, 36, 41, and 42 have been amended, the rejection to claim 36 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form, has been withdrawn. The claim rejection has been withdrawn in view of the amendment to claim 4.
Claim Rejections - 35 USC § 112(a)
In view of Applicants’ amendment to the claims dated November 7, 2025, wherein claims 4, 8, 36, 41, and 42 have been amended, the rejection to claims 4-8, 16, 27-29, 33, 34 and 36-42 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or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, have been withdrawn.
The withdrawn rejection is in view of the Remarks filed on November 7, 2025 that describe methods of overexpressing a cell surface integrin in a source cell by transfecting the source cell with an expression construct coding for the cell surface integrin are well understood in the art, and therefore need not be described in detail in the specification. Additionally, the Applicant points to the Li reference, which is used in the 35 USC 103 rejection, as teaching the transfection of cancer cells to overexpress integrins, and therefore this method is known in the art despite not providing working examples of utilizing transfection with a vector.
Applicants' arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
Claims 4-8, 36, and 38-42 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (Nano letters 16.9 (2016): 5895-5901, of record IDS filed June 21, 2022) in view of Bose et al. (Drug discovery today 23.4 (2018): 891-899; of record) and Li et al. (Journal of cell science 114.14 (2001): 2665-2672; of record).
This is a modified rejection necessitated by Applicants’ amendments to the claims in the response filed on November 7, 2025.
Claim 8 is directed to a method of treating a subject having cancer, the method comprising administering to the subject a delivery vehicle comprising a delivery vehicle membrane comprising at least one protein expressed in a membrane of the cancer, the delivery vehicle membrane encapsulating a cargo, wherein: the at least one protein comprises at least one cell surface integrin that is also found in the cancer; and the delivery vehicle membrane is isolated from a source cell treated to overexpress the at least one cell surface integrin that is also found in the cancer.
Regarding claim 8, Zhu teaches a method of treating a subject having cancer, the method comprising administering to the subject a programmed delivery vehicle comprising a programmed membrane encapsulating a cargo (“To verify this idea, we devised a magnetic iron oxide based nanoplatform that was coated with different types of cracked cancer cell membranes (CCCM) (Figure 1). For the first time, we showed that the biomimetic camouflage with CCCM toward the magnetic iron oxide NPs (MNPs) can achieve highly specific self-recognition to the source cell lines in vitro and the excellent self-targeting “homing” ability to the homologous tumor in vivo even in the competition of another heterologous tumor. In turn, the drug-loaded CCCM-coated nanovehicle showed strong potency for tumor treatment in vivo with high efficiency.” (p 5896, col 1, par 2)). The reference employs human cell membranes of human squamous carcinoma (UM-SCC-7) cell lines for coating nanoparticles in which doxorubicin hydrochloride (DOX·HCl) was electrostatically attached onto the negatively charged Fe3O4 MNPs (p 5896, col 1, par 3). In reference to the limitation of “comprising at least one protein expressed in a membrane of the cancer, the delivery vehicle membrane encapsulating a cargo, wherein the at least one protein comprises at least one cell surface integrin that is also found in the cancer;” Zhu teaches the tumor cells from which the membrane coatings derive comprise integrins based on the agglomeration of tumor cells due to the presence of such proteins on the surface of the cancel cell membranes (p 5895, last paragraph).
Zhu does not explicitly teach the nanoparticles coated membranes contain the integrins found in the source cancer cells. Moreover, Zhu does not teach the source cell is treated to overexpress the at least one cell surface integrin that is also found in the cancer.
Bose teaches cancer cell membrane-coated nanocarriers (CCMCNCs) comprises “membrane receptors, including cadherins, selectins, integrins, the immunoglobulin superfamily (Ig-SF), and lymphocyte-homing receptors (e.g., CD44), which are critical for cell–cell and cell–matrix interactions… integrins are involved in both cell–cell and cell–extracellular membrane (ECM) interactions and have shown cell- and tissue-specific functions. Integrins, such as integrin beta-1 (ITb1), ITa1, ITa2, ITa5, ITb3, ITb4, and ITb5, are highly expressed in the plasma membrane of various cancer cells [33]. Furthermore, integrins have a crucial role in cell proliferation, differentiation, and migration because of their ability to transfer signals from the ECM to the cell.” (p 893; Table 1, Figure 1).
Zhu in view of Bose do not teach the source cell is treated to overexpress the at least one cell surface integrin that is also found in the cancer.
Li teaches the relationship between αvβ3 and metastasis wherein the highly metastatic K1735M2 (M2) cells express the αvβ3 integrin whereas the poorly metastatic K1735C23 (C23) cells do not. These cells were transduced with the β3 integrin subunit cDNA, and the obtained C23-mβ3 cell line produced lung lesions and, in two animals, cardiac metastases, whereas the parental C23 cells did not. By contrast, transduction of the full-length β3 integrin antisense DNA into the M2 cells to obtain M2-Tβ3 cells suppressed metastatic colonization (abstract). Lastly, immunostaining of frozen tumor tissue sections with anti-β3 antibodies localized the integrin to the tumor cell membrane in the C23-mβ3 cells (Fig. 3).
Altogether, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Zhu reference that teaches the targeting of several tumor types by utilizing their respective plasma membrane as coatings for nanoparticles, which, by specifying a specific protein, i.e. an integrin, that are expressed on the surface cancer cell membranes as described by Bose. The Bose reference teaches integrins have a role in cell–cell and cell–matrix interactions, and therefore may assist in homotypic targeting of coated nanocarriers to cancer cells. Therefore, it would have been obvious to modify the Zhu reference in view of Bose based on the reference teachings of the association of integrins with cancer cells, and more importantly usefulness in targeting such cells with these proteins.
Lastly, it would have been prima facie obvious to improve outcomes related to homotypic targeting by increasing the amount of integrins in the cancer cell membrane that would subsequently be used in the coating of the claimed nanoparticles by treating the cancer cells to overexpress a select integrin. This would have an obvious step due to the roles of integrins being known, integrins relationship with metastatic cancers being known, and additionally the technology of increasing expression being known all made obvious by Li.
Regarding claim 4, dependent on claim 8, Zhu teaches the delivery vehicle as described in claim 8, and wherein the NPs are self-targeting because of being coated with homotypic cancer cell membranes (Title). Moreover, the rejection of claim 8, makes obvious of treating the cancer cells to express integrins especially wherein the cancer is metastatic cancer, and furthermore Li teaches cancer cells transfected with a vector to overexpress integrins that are also found in the cancer (abstract).
Regarding claim 5, dependent on claim 4, Zhu teaches wherein the cell surface profile is a metastatic cancer cell surface profile. Zhu describes the cell membranes of highly metastatic human cancer cells have been used to coat NPs which display homotypic recognition with strong internalization into the respective cancer cells (p 5895, col 2, par 1). Furthermore, the reference describes “the high self-recognition to the same cell lines may adumbrate the possibilities of this nanoplatform in seeking and attacking the metastatic cancer cells.” (p 5900, col 2, par 2). Moreover, Bose teaches cancer cell membrane-coated nanocarriers(CCMCNCs) are useful in targeting metastatic cancers (“CCM-coating (CCMC) strategies have been suggested to solve this potential problem by enhancing homologous targeting and the intratumoral penetration of NCs to the primary tumor as well as their metastatic spread [19–21]. In addition, CCMC [cancer cell membrane coats] on the NC [nanocarrier] surface represents a valuable strategy that might prevent the premature release of therapeutics in the bloodstream and increase tumor-specific accumulation, thereby avoiding adverse effects” (p 894, col 2); “For example, CCMs [cancer cell membranes] can be utilized as a targeting strategy for solid tumors (e.g., breast cancer and prostate cancer) and potentially, circulating and metastatic cancers.” (p 897, col 1)).
Regarding claim 6, dependent on claim 5, Zhu teaches wherein the metastatic cancer cell surface profile is a liver metastasis profile (“Murine hepatocellular carcinoma (H22) cell membrane coated MNP@DOX NPs (termed MNP@DOX@ H22) exhibited negligible macrophage engulfment…” (p 5896, col 2, par 3)).
Regarding claim 7, dependent on claim 8, Zhu teaches wherein the cargo is a nanoparticle, a chemotherapy, a drug, an imaging agent, or combination thereof (“we devised a magnetic iron oxide based nanoplatform that was coated with different types of cracked cancer cell membranes (CCCM)” (p 5896, col 1, par 2); “the drug-loaded CCCM-coated nanovehicle showed strong potency for tumor treatment in vivo with high efficiency.” (5896, col 1, par 2)); “the drugs and magnetic NPs were used in this study, showing the favorable performance of magnetic properties, such as magnetic targeting and MRI capability and the strong potency for tumor chemotherapy in vivo.” (p5901, col 1, par 1)).
Regarding claims 36, and 38-42, Zhu teaches the membrane to core weight ratio as seen in Fig. S1 (provided below) wherein it was decided to use a ratio of 1:1 based on better stability observed after three days of synthesis. However, Zhu also provides teaching on using a membrane to core weight ratio of 2:1, 0.5:1, and 0.25:1. In relation to the overexpression of integrins in the cancer cells, this was also made obvious in the claim 8 rejection above as taught by Li.
PNG
media_image1.png
400
630
media_image1.png
Greyscale
Response to Applicants’ Arguments as they apply to rejection of claims 4-8, 36, and 38-42 under 35 USC § 103
Starting on page 8 of the remarks filed on November 7, 2025, Applicants essentially argue the following:
The Claims are not Obvious over Zhu, Bose, and Li.
Bose does not teach overexpressing integrins, and Li teaches the overexpression in a different context, and not in view of the cancer cell membranes for nanoparticles.
“ In fact, the Examiner agrees with this characterization of the references - noting that while "the prior art is well-versed in the technique of engineering cells to express select genes/proteins to be overexpressed as seen in the Li et al., reference .... the prior art is free of employing such [a] step in the context of manufacturing nanoparticles coated with the membranes of these cancer cells."”.
“Further, the inventors have made the surprising and unexpected discovery that overexpressing integrins in their programmable bioinspired nanoparticles (P-BiNPs) significantly improved uptake in cancer cells. Specifically, P-BiNP nanoparticles formed from cells overexpressing αvβ3 showed four times more uptake in cancer cells compared to control BiNP nanoparticles (FIG. 12B). Further, this increased uptake translated to increased cytotoxicity as cells treated with P-BiNPs showed decreased cell viability compared to cells treated with BiNPs (FIG. 12C, [0079]). This surprising result would not have been predicted by Zhu, Bose, and Li.”
In response to the argument it has been fully considered but is not persuasive due to the following reasons:
Regarding the first argument: 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 Bose reference teaches “Looking forward, CCMCNCs could also be endowed with additional properties that are not native to the cell membrane through additional surface functionalization procedures or genetic engineering of the source cells to overexpress proteins of interest (POIs)” (p 897, col 1). Moreover, Bose describes integrins are highly expressed in the cell membranes of various cancers, in addition to describing their diversity of functional roles and being classified as a cancer cell adhesion molecule (CCAM). Therefore, it can be understood that cancer cell membranes used to coat nanoparticles would contain integrins, and furthermore there being ways to increase expression via genetic engineering to improve outcomes related to abundance of integrins on coated nanoparticles. Regardless, the Li reference teaches a specific way in which integrins have been increased in cancer cell membranes, and therefore provides this teaching of overexpression of integrins.
The Remarks describes the Li reference teaching the overexpression of integrins in a different context, and therefore fails to teach or disclose overexpressing the integrin in a cell membrane used
to form a nanoparticle. The examiner disagrees with this rationale along the same lines of reasoning in that the rejections are based on combinations of references as described above, and therefore despite Li not teaching nanoparticles, the reference remains appropriate to be combined as there is no expectation that the method of overexpressing integrins in cancer cell membranes taught therein cannot be applied in combination with the teachings of Zhu and Bose with a reasonable expectation of success to arrive at the claimed invention.
Regarding the second argument, that the prior art is free of employing such [a] step in the context of manufacturing nanoparticles coated with the membranes of these cancer cells, the examiner disagrees with this assessment based on the withdrawn 112(a) rejection based on the Remarks filed therein that such process of overexpression of integrins in cancer cells is well understood in the art, and would be expected to work in conjunction with then isolating the membranes to be used coated onto nanoparticles.
Regarding the third argument, regarding surprising and unexpected results, these results are in relation to P-BiNP nanoparticles formed from cells overexpressing αvβ3, yet the claims are not limited to such integrins, and the method of obtaining these nanoparticles, and therefore it is unclear if such outcomes is expected with the full scope set forth in the claims.
Claims 8, 16, 27-29, 33-34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (Nano letters 16.9 (2016): 5895-5901, of record IDS filed June 21, 2022) in view of Bose et al. (Drug discovery today 23.4 (2018): 891-899; of record) and Li et al. (Journal of cell science 114.14 (2001): 2665-2672; of record), as applied to claim 8, and further in view of Fang et al. (Nano letters 14.4 (2014): 2181-2188; of record IDS filed June 21, 2022; hereinafter ‘Fang-2’).
This is a modified rejection necessitated by Applicants’ amendments to the claims in the response filed on November 7, 2025.
Regarding claim 8, the disclosure of Zhu in view of Bose and Li are applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claim 16, dependent on claim 8, Zhu teaches wherein the cargo is a nanoparticle, a chemotherapy, a drug, an imaging agent, or combination thereof (“we devised a magnetic iron oxide based nanoplatform that was coated with different types of cracked cancer cell membranes (CCCM)” (p 5896, col 1, par 2); “the drug-loaded CCCM-coated nanovehicle showed strong potency for tumor treatment in vivo with high efficiency.” (5896, col 1, par 2)); “the drugs and magnetic NPs were used in this study, showing the favorable performance of magnetic properties, such as magnetic targeting and MRI capability and the strong potency for tumor chemotherapy in vivo.” (p5901, col 1, par 1)).
Zhu does not teach wherein the cargo is a polymeric nanoparticle, and the programmed membrane is coated on the surface of the polymeric nanoparticle, but rather a magnetic iron oxide core. Furthermore, Zhu teaches the membrane to core weight ratio as seen in Fig. S1 (provided below) wherein it was decided to use a ratio of 1:1 based on better stability observed after three days of synthesis.
Zhu in view of Bose and Li do not teach wherein the cargo is a polymeric nanoparticle, and the programmed membrane is coated on the surface of the polymeric nanoparticle, but rather a magnetic iron oxide core.
Fang-2 teaches the coated polymeric nanoparticle with different membrane-to-core ratios (“In order to optimize the membrane coating, CCNPs were synthesized at membrane-to-core weight ratios ranging from 0.125 to 4 mg of membrane protein per 1 mg of PLGA particles (Figure 4a).” (Figure is included below) (p 2183, col 2, par 2)). The reference described the results wherein “At lower membrane-to-core ratios, a significant increase in the hydrodynamic diameter was observed when the particles were transferred to 1× PBS. This suggested incomplete coverage, which exposes the surfaces of the cores to charge screening, resulting in low stability in ionic buffers… samples with membrane coverage lower than 0.25 mg of protein per 1 mg of PLGA aggregated significantly.” (p 2183, col 2, par 2- p 2184, col 1, par 1). Additionally, the reference describes the polymeric PLGA core has the advantage to load a wide array of cargoes (p 2186).
Figure 1:
PNG
media_image2.png
448
862
media_image2.png
Greyscale
Figure 4A:
PNG
media_image3.png
469
861
media_image3.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Zhu in view of Bose and Li that employs nanoparticles with target cell membranes, with having a cargo as a polymeric nanoparticle as taught by Fang-2, i.e., PLGA, based on the aforementioned advantage in using PLGA cores for their loading capacity and diversity of cargo, in addition to being well-known in the art of nanoparticles production and applications.
Regarding claim 27, dependent on claim 16, Zhu teaches the polymeric nanoparticle is extruded (“The MNP@DOX NPs were mixed with UM-SCC-7 CCCM dispersion under vortex stirring and then extruded consecutively through a series of water-phase filters with reducing pore sizes (∼2.0 μm, ∼800.0 nm, ∼450.0 nm).” (p 5896, col 1, par 3)). The claim 16 rejection acknowledges the remaining limitations of polymeric nanoparticles and delivery vehicle membranes, being that Zhu only teaches the programmed membranes. In particular, Fang-2 teaches “In order to coat the PLGA cores with cancer cell membrane, the two components were coextruded through a 200 nm porous polycarbonate membrane.” (p 2183, col 1).
Regarding claim 28, dependent on claim 16, Zhu teaches a ratio of the weight of the delivery vehicle membrane protein to weight of the nanoparticle as being optimized 1:1 (“To provide the better stability, the membrane-to-core weight ratio was eventually optimized at 1:1 throughout the study (Figure S1).” (p 5896, col 1, par 3). The reference supports optimization as viewed in Figure S1 (provided above) that employ membrane to core weight ratios from 0.25-2 on impact of particle size.
Zhu does not teach the ratio in relation to polymeric nanoparticles, but rather with a magnetic iron oxide core.
Fang-2 teaches the coated polymeric nanoparticle with different membrane-to-core ratios (“In order to optimize the membrane coating, CCNPs were synthesized at membrane-to-core weight ratios ranging from 0.125 to 4 mg of membrane protein per 1 mg of PLGA particles (Figure 4a).” (Figure is included below) (p 2183, col 2, par 2)). The reference described the results wherein “At lower membrane-to-core ratios, a significant increase in the hydrodynamic diameter was observed when the particles were transferred to 1× PBS. This suggested incomplete coverage, which exposes the surfaces of the cores to charge screening, resulting in low stability in ionic buffers… samples with membrane coverage lower than 0.25 mg of protein per 1 mg of PLGA aggregated significantly.” (p 2183, col 2, par 2- p 2184, col 1, par 1).
Regarding claim 29, dependent on claim 16, and claim 33, dependent on claim 29, the limitation of the polymeric nanoparticle comprising PLGA is rejected in the claim 16 rejection above.
Regarding claim 34, dependent on claim 8, Zhu teaches wherein the programmed delivery vehicle is administered intravenously to the subject (“ mice bearing a UM-SCC-7 tumor on the right hind limb were intravenously injected with MNP@DOX@ CCCM NPs prepared with different cell membranes” (p 5898, col 1, par 2)).
Regarding claim 37, dependent on claim 16, the rejection to claim 16 makes obvious wherein the coated polymeric nanoparticle is coated at a ratio of 0.5: 1 by weight of the delivery vehicle membrane to weight of the polymeric nanoparticle as seen by Fang-2 teaching polymeric PLGA nanoparticles at such ratio (Fig. 4A).
Conclusion
Claims 4-8, 16, 27-29, 33, 34, and 36-42 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634