DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application. Claims 27, 30-32, 34-38, 40-50, and 52-60 are pending in this application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6 Jul. 2026 has been entered.
Status of Claims
Claims 1-26, 28-29, 33, 39, and 51 are cancelled. Claims 27, 34-36, and 38 are amended. Claims 58-60 are new.
Response to Amendment
The amendments filed on 6 Jul. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 27, 30-43, 49-50, and 52-57 under 35 USC 103 as being unpatentable over Zhang et al. (WO 2013/052167 A2; published 11 Apr. 2013), in view of Meyer et al. (Small; published 2015) and Lai et al. (RSC Adv.; published 2015) is withdrawn.
In view of Applicants amendments, the rejection of claims 27, 30-50, and 52-57 under 35 USC 103 as being unpatentable over Zhang et al. (WO 2013/052167 A2; published 11 Apr. 2013), in view of Meyer et al. (Small; published 2015) and Lai et al. (RSC Adv.; published 2015), in further view of Salzman et al. (US 7,534,449 B2; issued 19 May 2009) is withdrawn.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 35-37, and 52 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Instant claim 35 requires that the polymeric matrix is stretched from above the polymer transition temperature up to the polymer degradation temperature to form an anisotropic polymeric matrix. Instant claim 36 requires that the polyester polymeric matrix is stretched at a temperature above but close to the polymer transition temperature for form an anisotropic polymeric matrix. Instant claim 37 requires that the stretching of the polyester polymeric matrix causes the polymeric matrix to change from a generally spherical to an anisotropic shape. The specification at [0058] defines the term anisotropic to mean a microparticle or nanoparticle that is non-spherical in shape. Claim 35-37 depend to claim 27 that requires a three-dimensional microparticle or nanoparticle having an ellipsoidal shape. It is not clear that claims 35-37 further limit claim 27 since term anisotropic is defined to broader than ellipsoidal. Instant claim 52 is dependent to cancelled claim 29 rendering the claim indefinite. In the case that claim 52 gets amended to be dependent to claim 27, it is not clear that claim 52 would further limit claim 27 since claim 27 requires a cell membrane derived from a red blood cell or platelet.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 27, 30-32, 34-38, 40-43, 49-50, and 52-60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO 2013/0521676 A2; published 11 Apr. 2013), in view of Meyer et al. (Small; published 2015) and Lai et al. (RSC Adv.; published 2015).
Zhang et al. teach membrane encapsulated nanoparticles. Zhang et al. teach nanoparticles comprising a) an inner core comprising non cellular material; and b) an outer surface comprising a cellular membrane. The inner core comprises biocompatible material including poly(lactic-co-glycolic acid) (plga, polyester polymeric matrix, biodegradable polymer) (see [0007],[0015]). The cellular membrane of the outers surface is derived from RBC, platelet, immune cell (t-cell), a tumor cell or cancer cell (see [0009]). The inner core shape may be circular disc or other regular or irregular shapes (see [0011]). Zhang et al. teach shape effects of filaments versus spherical particles in flow and drug delivery (ref. 5). Functional groups such as antibodies (antibody/polypeptide targeting an antigen) and aptamers can be added to the outer surface of the membrane to enhance site targeting such as cell surface epitopes found in cancer cells (see [0070]). The nanoparticle is biocompatible and/or biodegradable (see [0014]). Zhang et al. teach scanning fluorescence microscopy (see [0037]). The nanoparticle has a diameter ranging from 10 nm to about 10 µm such as 1 µm or a diameter from about 50 nm to about 10 µm. The nanoparticle has at least one dimension (height, width, length or diameter) between 1 nm and about 10 µm (see [0073]). Releasable cargo (therapeutic agent, diagnostic agent) may be located inside or on the surface of the nanoparticle (see [0092]-[0093]). Zhang et al. teach that therapeutic agents include antimicrobial, growth factor, etc (see [0093]). Zhang et al. teach method comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising the nanoparticle of the invention (see [0101]-[0105]). Zhang et al. disclose RBC membrane camouflaged NPs
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(see fig. 1). Zhang et al. teach RBC membrane polymeric nanoparticles, PLGA particles of approximately 70 nm. Hydrophobic DiD fluorophore and the lipophilic rhodamine-DMPE dye were loaded into the polymeric core. Particle functionalization can be achieved by inserting modified lipids or transmembrane proteins (see example 1). Zhang et al. teach loading small molecule chemotherapy drugs such as DOX into the NPs (see [00163], [00167]). Zhang et al. teach extending the particle residence time in vivo through modifying NP physiochemical shape property ([0161]). Zhang et al. teach pegylated NPs (see pg. 57). Zhang et al. teach physical encapsulation and chemical conjugation (see [00174]-[00175]). Zhang et al. teach a kit of parts (see [0083]). Zhang et al. teach provides for a method of making the nanoparticles comprising mixing nanoparticle inner core comprising a non-cellular material with a cellular membrane derived from a cell while exerting sonication energy ([0022]).
Zhang et al. do not expressly teach an ellipsoidal shape defined by dimensions (a), (b), and (c) wherein at least one of (a), (b), and (c) is not equal to at least the other dimension (a), (b), or (c) wherein the ellipsoidal shape has at least one surface having a radius of curvature along at least one axis selected of between 11 nm and 100 nm and wherein the three dimensional microparticle or nanoparticle has a particle size of less than 10 microns, less than 5 microns or between about 50 nm and 5 microns and optionally wherein the particle comprises a cell membrane derived from a T-cell or a kit thereof. Zhang et al. do not teach that the polymeric matrix is stretched from above the polymer transition temperature up to the polymeric degradation temperature to form anisotropic polymeric matric or that the polymeric matrix is stretched at a temperature above but close to the polymer transition temperature to form an anisotropic polymeric matrix optionally wherein the stretching of the polymeric matrix causes the polymeric matrix to change from a generally spherical shape to an anisotropic shape. Zhang et al. do not further disclose a method of delivering a therapeutic agent to a diseased cell/tissue such as a cancer cell or tissue of a patient, the method comprising administering to a patient the biomimetic particle of claim 27 optionally further comprising administering to the patient an effective amount of biomimetic particle loaded with a therapeutic agent. Zhang et al. do not teach a method for imaging a diseased cell or tissue of a patient, the method comprising (a) administering to a patient the biomimetic particle of claim 27 further comprising an imaging agent and a targeting agent.
Meyer et al. teach biodegradable nanoellipsoidal artificial antigen presenting cells for antigen specific T-cell activation (see title). Meyer et al. teach that non-sherical, anisotropic nanoparticles have recently gained attention within the biomaterial’s community. Nanoparticles with altered shape offer potentially improved intracellular delivery and in vivo circulation time by aligning with the blood flow and reducing phagocytosis. Prolate ellipsoid (semi-axis: a>b=c) showed the most efficient particle attachment with lowest in vitro internalization rates when compared to oblate ellipsoid (semi axis: a=b>c) or spherical particles (see pg. 1519, col. 2). Meyer et al. teach synthesizing PLGA nanoparticles and casting them into a PVA film and either stretched the film at 90oC or nor (to fabricate ellipsoid or spheroid particles respectively). For example a 2-fold stretch of 200 nm spherical particle produces a prolate ellipsoid with an aspect ratio of 2.8, a radius of curvature along the long axis of 1.14 µm (about 1 µm), and modest surface area gain of 16%. We fabricated the spherical and ellipsoidal nanoparticles into aAPCs by adding peptide loaded anti-CD28 mAb to their surface via EDC/NHS chemistry (see pg. 1520; Fig. 1). Conjugated (a) spherical and (b) 2-fold stretched ellipsoidal naAPC particles encapsulating a near IR fluorophore were injected intravenously into nude mice. The results show that nanoellipsoidal aAPCs circulate at higher concentrations over time periods examined, and have a longer half-life (see Fig. 4). 2-fold stretched ellipsoidal nano aAPCs stimulate T-cells superiorly to spherical nano aAPCs (see Fig. 5). Nanoellipsoidal aAPCs offer multiple advantages over traditional spherical aAPCs (see g. 1524, col. 2; pg. 1525).
Lai et al. teach biomimetic stem cell membrane-camoflaged iron oxide nanoparticles for theranostic applications (see title). Lai et al. teach stem cell membrane (STM)-camouflaged SPIO NPs for biomedical application. The STM-SPIO NPs were prepared using a simple and mild sonication method. The results demonstrated good potential for STM-SPIO NPs for future theranostic applications (see abstract). Lai et al. teach the preparation of STM-SPIO NP by sonication. The mixtures were incubated on ice for 30 min and the subjected to probe sonication (see pg. 98223; scheme 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the particles of Zhang et al. (A kit comprising a biomimetic particle comprising (i) a three-dimensional microparticle or nanoparticles having a defined shape such as a spherical shape and (ii) a naturally derived cell membrane derived from a red blood cell or platelet wherein the three dimensional microparticle or nanoparticle comprises a PLGA polyester polymeric matrix and has a particle size of about 90 nm and wherein the particles comprise a therapeutic agent such as DOX) so that the microparticle or nanoparticle comprises has an ellipsoidal shape, optionally formed by stretching the polymeric matric above but close to the polymer transition temperature to the polymer degradation temperature, as defined by dimensions (a), (b) and (c) wherein at least one of (a), (b), and (c) is not equal to at least one other dimension (a), (b), or (c) and wherein at least one surface as a radius of curvature along at least one axis of between about 11 nm to about 100 nm as taught by Zhang et al. and Meyer et al. because that ellipsoidal shape would have been expected to provide advantages such as improved in vivo properties such as a reduction in non-specific cell uptake and improved circulation time by aligning with blood flow. It would have been further obvious to a person of ordinary skill in the art before the effective filing date to further modify the particles of Zhang et al. so that the surface of the biomimetic particle is functionalized with a targeting agent/therapeutic agent such as a polypeptide or an antibody that has affinity for a tumor associated factor or an antigen as taught by Zhang et al. because the targeting agent would have been expected to advantageously enable enhanced site targeting such as cell surface epitopes found in cancer cells. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the particle of Zhang et al. so that the naturally derived cell membrane is derived from a platelet or T-cell optionally by use of sonification energy as taught by Zhang et al., Meyer et al., and Lai et al. because those membranes would have been expected to advantageously enable particles capable of mimicking platelets and T-cells whereby in the case of T-cells providing immune system activation and modulation.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Zhang et al. by further administering to a patient an effective amount of the obvious ellipsoidal biomimetic particle loaded with DOX to treat cancer whereby delivering the therapeutic agent to cancer cells or tissue of the patient as taught by Zhang et al. and Meyer et al. because the delivering would have been expected to advantageously enable selective delivery and accumulation of the anticancer agent to the cancer cells and providing enhanced treatment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zhang et al. by further administering to a patient the obvious ellipsoidal biomimetic particle further comprising a fluorescence imaging agent and a cancer targeting agent and then fluorescence image the cancer cell and/or tissue of the subject as taught by Zhang et al. and Meyer et al. because the administering and imaging would have been expected to provide visualization of the particle localization and/or fluorescence imaging of cancer cells.
Claim(s) 27, 30-32, 34-38, 40-50, and 52-60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO 2013/0521676 A2; published 11 Apr. 2013), in view of Meyer et al. (Small; published 2015) and Lai et al. (RSC Adv; published 2015), in further view of Salzman et al. (US 7,534,449 B2; issued 19 May 2009).
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Zhang et al. teach as discussed above.
Zhang et al. do not further teach a method of delivering a therapeutic agent wherein the therapeutic agent comprises a biotinylated drug optionally an antibody specific for CD28 or wherein the biomimetic particle is conjugated with a biotin-binding protein optionally avidin or streptavidin.
Meyer et al. teach as discussed above.
Lai et al. teach as discussed above.
Saltzman et al. teach targeted and high-density drug loaded polymeric materials (see title). Saltzman et al. teach that avidin-fatty acid conjugates were prepared and efficiently incorporated into PLGA. Avidin is used as an adaptor protein to facilitate attachment of a variety of biotinylated ligands (see cols 3-4). Saltzman et al. teach targeting ligands which bind to antigens (see col. 2). Saltzman et al. teach that soluble multivalent molecules were combined with a technology that delivers a high density of drug to the cellular target, thereby yielding a versatile, physiologically compatible, multifunctional system that combines high avidity interactions with targeted drug delivery to T cell subsets...Biotinylated antibodies were non-covalently attached to PET chains via streptavidin linkers that were covalently linked to PEG. The constructs were specific and bind to T cells with enhanced avidity (see col. 28). Saltzman et al. teach RGD targeted nanoparticle systems (see table 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Zhang et al. so that the therapeutic agent comprises a biotinylated drug such as an antibody specific for CD28 and the biomimetic particle is conjugated with a biotin-binding protein such as avidin as further taught by Saltzman et al. because it would have been expected to advantageously enable binding to T cells with enhanced avidity. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zhang et al. so that the targeting moiety has affinity for a tumor associated factor or is an antibody that targets an antigen as taught by Zhang et al. and Salzman et al. because it would have been expected to advantageously enable enhanced targeting to cancer cells.
Applicants Arguments
Applicants assert that extensive experimentation was required to arrive at the claimed invention. As provided in the Green Declaration, extensive experimentation was required to arrive at the presently claimed ellipsoidal particles coated with naturally derived cell membrane. In contrast, shown in Fig. 2 are confocal microscopy images of an attempt to coat prolate ellipsoidal microparticles with macrophage membranes by the same method used for the spherical particles shown in Fig. 1. As evidenced in Fig. 2, the prolate ellipsoidal particles were not coated with macrophage membranes. As shown in Fig. 6 of the Green Declaration, prolate and oblate ellipsoidal membrane-coated particles were unexpectedly phagocytosed significantly less than their uncoated counterparts and oblate ellipsoidal particles were unexpectedly phagocytoses significantly less than spherical particles. These data demonstrate that not only did the membrane-coated ellipsoidal particles resist unwanted phagocytic uptake but that the synergy of combining ellipsoidal shape with membrane coating led to a much larger beneficial effect than what was expected. Such unexpected, improved properties were neither disclosed nor suggested by Zhang or Meyer either alone or in combination. These unexpected, improved properties of claimed ellipsoidal particles over spherical particles effectively rebuts a prima facie case of obviousness. The process disclosed by Zhang in view of Meyer and Lai could not be used to arrive at the claimed invention. One of ordinary skill in the art upon review of Zhang would employ extrusion to form a membrane-coated nanoparticle and would employ an extrusion step or even multiple extrusion steps to overcome incomplete particle coating. It was found that an extrusion process was not suitable to prepare supported biomimetic membranes on anisotropic particles due to non-uniform coating. Zhang is silent with respect to forming ellipsoidal particles. One of ordinary skill in the art would not be motivated by Zhang to arrive at the claimed ellipsoidal particles coated with a naturally derived cell membrane. Lai does not cure the defect of Zhang and Meyer. The particles of Lai are designed to enhance cellular uptake spherical particles whereas the instantly claimed ellipsoidal coated particles are designed to reduce cellular uptake. Saltzman does not cure the defects of Zhang, Meyer, and Lai.
Applicant's arguments filed 6 Jul. 2026 have been fully considered but they are not persuasive. Regarding Applicant’s assertion that extensive experimentation was required to arrive at the claimed invention, at [00106] Zhang teaches about 3 different methods for making the biomimetic nanoparticles of the application. At the second method immediately following the use of mechanical energy exerted by extrusion, Zhang teaches and suggests the use of acoustic energy exerted by sonification. Lai teaches, suggests and motivates cell membrane camouflaged iron oxide nanoparticles prepared by the use of acoustic energy exerted by sonication. At abstract, Lai characterizes the sonication method as simple and mild. Accordingly, it would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Zhang without undue experimentation so that obvious RBC membrane camouflaged PLGA ellipsoidal particles are prepared by acoustic energy exerted by sonication because it would have been expected to enable equivalent preparation and advantageous simple and mild preparation of the membrane camouflaged particles. Regarding Applicants arguments that Fig. 6 of the Green Declaration shows that ellipsoidal particles were unexpectedly phagocytosed significantly less than spherical particles, expected beneficial results are evidence of obviousness. Meyer teaches that ellipsoidal nanoparticles provide reduced cellular uptake by macrophages and endothelial cells in vitro and resist hepatic and splenic elimination in vivo. Zhang teaches that RBC membrane coated particles have a longer elimination half-life. A person of ordinary skill would have expected membrane coated particles to be phagocytosed significantly less than their counterpart and phagocytosed less than spherical particles. Although claim 27 has been amended so that the nanoparticle or microparticle comprises a polyester polymeric matrix and a particle size of less than 10 microns, Applicants do not provide any reasoning why these amendments render claim 27 to be commensurate in expected results at Fig. 6 of the Green Declaration. For example, polyesters can be of different densities and stability resulting in different in vivo properties and behavior. Similarly different particles sizes would be expected to exhibit different in vivo properties and behavior.
Conclusion
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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