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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Sept. 19, 2025 has been entered.
Claim Status
Claims 1-10, 12, 14, 20 and 23-25 are currently pending in this application.
Election/Restrictions
Applicant's election without traverse of Group II, claims 10, 12, 14, 20 and 23-25, in the reply filed on July 9, 2024 is acknowledged. Claims 1-9 withdrawn. Claims 10, 12, 14, 20 and 23-25 have been considered on the merits.
Claim Objections
Claims 10 and 25 are objected to because of the following informalities:
In claim 10, the phrase “the loaded syncytiotrophoblast-derived EVs targets” lacks proper verb agreement as EVs is defined as a plural (extracellular vesicles).
Each of claims 10 and 25 recites a list of items: “exosomal markers CD81, CD9, CD63, tumor susceptibility gene 101, and programmed cell death 6-interacting protein (ALIX), efflux transporters P-gp and BCRP” that lacks a clear final conjunctive before the last item in the list and, thus, is not explicitly inclusive, such as when expressed with the final conjunction and as in “and efflux transporters P-gp and BCRP” or “efflux transporter P-gp, and efflux transport BCRP.” Furthermore, the wording of the list “exosomal markers CD81, CD9, CD63, tumor susceptibility gene 101, and programmed cell death 6-interacting protein (ALIX), efflux transporters P-gp and BCRP” is ambiguous, incoherent and unclear as to whether the “efflux transporters P-gp and BCR” are also exosomal markers, or if CD81, CD9, CD63, tumor susceptibility gene 101, and ALIX are all exosomal markers but that the P-gp and BCRP are merely two types of efflux transporters that are not exosomal markers.
Claim Rejections - 35 USC § 112(a), Written Description
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 10, 12, 14, and 20 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.
When claim 10 is analyzed in light of the specification, the instant invention is directed to a composition comprising full-term syncytiotrophoblast EVs each encapsulating either one or a plurality of agents, including at least any combination of the agents listed in instant [0013], such as the combination of all the agents recited in dependent claim 12.
M.P.E.P. §2163 states “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.”
In the instant case, the breadth of claims 10, 12, 14, and 20 regarding the genus of any combination of anti-cancer agents represents a broad genus.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any clear description of a representative number species for this genus or any such single species.
Nowhere does the originally filed application clearly identify any agent as specifically an “anti-cancer” agent instead discussing numerous therapeutic agents such as conventional chemotherapeutic agents and agents for treating an infection ([0013], [0056]). Although claim 10 limits the therapeutic agent to “anti-cancer” agents, the scope of the term “anti-cancer agent” is not defined in the instant application and, thus, encompasses any such agent recognized in the prior art, such as interferon alpha or the antivirals oseltamivir, ribavirin, amantadine/rimantadine, acyclovir, ganciclovir, cidofovir, etc. described in the instant specification as well as vastly different agents in the prior art, such as radionuclides, miRNAs, monoclonal antibodies, and plants like ginseng and turmeric. In view of dependent claim 12 as currently presented, independent claim 10 encompasses any combination of anti-cancer agents, including all of those recited in claim 12. In view of the ordinary meaning of “chemotherapeutic”, all the agents originally described in [0056] are considered “anti-cancer agents” as used in the current claims.
Therefore the instant specification has written description of a limited set of species of anti-cancer agents: alemtuzumab, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin, bicalutamide, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, 2-chlorodeoxyadenosine, cisplatin, colchicine, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, estramustine phosphate, etodolac, etoposide, exemestane, floxuridine, fludarabine, 5-fluorouracil, flutamide, formestane, gemcitabine, gentuzumab, goserelin, hexamethylmelamine, hydroxyurea, hypericin, ifosfamide, imatinib, interferons, irinotecan, letrozole, leuporelin, lomustine, mechlorethamine, melphalen, mercaptopurine, 6-mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, paclitaxel, pentostatin, procarbazine, raltitrexed, rituximab, rofecoxib, streptozocin, tamoxifen, temozolomide, teniposide, 6-thioguanine, topotecan, toremofine, trastuzumab, vinblastine, vincristine, vindesine, and vinorelbine. While these species are representative of a great many more classes of anti-cancer chemotherapeutics and other monoclonal antibodies besides rituximab, these species are not representative of the diversity of anti-cancer materials known in the prior art, which includes radionuclides, nucleic acids, natural materials, gold nanoparticles, antioxidants, and foods (Kaur and Verma, Biotechnol Rep 6: 64-78 (2015) at Table 1).
Thus, the vagueness and the breadth of the term “anti-cancer agent” as used in the instant application results in insufficient written description, even in view of [0058] and amended claim 12. Regarding claim 20, the EVs must comprise at least 40 weight percent paclitaxel but are still broadly directed to such EVs which also comprise at least all the other agents recited in claim 12 or all of those agents listed in the specification ([0013]).
There is no description or guidance of which anti-cancer agents (which includes cobalt isotopes and plant derivatives) are actually suitable for combining into a payload having a plurality of such agents over the scope of such broad claims. Instead, the written description represents an invitation to the skilled artisan to figure out which anti-cancer agents listed in [0056] or otherwise known in the prior art to combine into an EV payload. For example, crushed garlic or ginseng are foods having anti-cancer properties, but can these predictably be encapsulated in the EVs of the present invention and retain such function and/or be combined with radioactive payloads?
In conclusion, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the full scope of the broad genus of any anti-cancer agent known in the art, and any combinations thereof, that may be encapsulated either alone or in combination by the EVs in the claimed composition.
35 USC § 112(a), Enablement
Claims 10, 12, 14, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to produce a composition comprising EVs encapsulating the combination of agents that comprises all the agents recited in claim 12 simultaneously.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of the claims:
As claim 12 is directed to a composition comprising full-term syncytiotrophoblast EVs encapsulating any combination of alemtuzumab, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin, bicalutamide, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, 2-chlorodeoxyadenosine, cisplatin, colchicine, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, estramustine phosphate, etodolac, etoposide, exemestane, floxuridine, fludarabine, 5-fluorouracil, flutamide, formestane, gemcitabine, gentuzumab, goserelin, hexamethylmelamine, hydroxyurea, hypericin, ifosfamide, imatinib, interferon, irinotecan, letrozole, leuporelin, lomustine, mechlorethamine, melphalen, mercaptopurine, 6-mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, paclitaxel, pentostatin, procarbazine, raltitrexed, rituximab, rofecoxib, streptozocin, tamoxifen, temozolomide, teniposide, 6-thioguanine, topotecan, toremofine, trastuzumab, vinblastine, vincristine, vindesine, and vinorelbine; then claim 10 (as well as claim 14) is directed to a composition comprising full-term syncytiotrophoblast EVs encompassing those encapsulating any combination of any heterologous anti-cancer agents, including all of the aforementioned agents recited in claim 12. Regarding claim 20, although the EVs must comprise at least 40 weight percent paclitaxel, these EVs may still encompass those that further comprise at least all the other agents recited in claim 12.
The state of the art:
The prior art teaches EVs can be loaded with various drugs, antibodies, and anti-cancer agents individually. In a few examples, at most 2 drugs and/or miRNAs are loaded into conventional EVs simultaneously (see e.g., Li et al., Drug Deliv 29: 192-202 (2022) at Abstract). The prior art does not teach wherein these EVs are specifically full-term syncytiotrophoblast EVs or wherein three or more anti-cancer drugs is loaded together. Thus, these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such Artisan.
The amount of direction and guidance and working examples provided by Applicant:
The instant specification demonstrates the loading of full-term syncytiotrophoblast EVs with Abraxane® or paclitaxel (Table 3; Examples). However none of these examples show loading a single EV with two or more agents, such as to create an EV comprising all the agents recited in claim 12.
Thus, there is no evidence in the instant application or the prior art of any EV loaded with 10, 20, 30 or more agents at once, even if not a syncytiotrophoblast EV. In particular, there is evidence that the hydrophobicity of multiple agents may need to be matched to each other for co-loading, meaning some agents are challenging to combine merely due to their disparate physiochemical properties (Auquiere J Extracell Vesicles 14: e70097 (2025) at pg. 12, right col., last para., to pg. 13, left col., 1st para.; Fig 2B), whereas a multiplicity of small RNAs having similar properties may be more feasible. There is no evidence in the art or the instant application that the scope of agents encompassed by claim 10 in view of claim 12 could predictability be generated by any method without undue experimentation. Thus, extensive experimentation would be required to determine how to make a composition comprising full-term syncytiotrophoblast EVs simultaneously encapsulating all of the agents recited in claim 12.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to make/use the claimed invention over the full scope of the claims. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims, undue and/or unreasonable experimentation would have been required for one skilled in the art to use the claimed methods to produce the recited product.
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 10, 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Tannetta (Tannetta et al., PLoS One 8(2): e56754 (2013) in view of Bauzon (WO2019050998A1; published Mar. 14, 2019) as evidenced by Holterman (WO2014193999A2; published Dec. 4, 2014), Niu (Niu et al., PLoS One 12(10): e0186534 (2017)), and Afrouzian (Afrouzian et al., Biochemical Pharmacology 156: 467-78 (2018)).
Tannetta teaches compositions comprising syncytiotrophoblast extracellular vesicles (STBMs) isolated from placentas harvested from pregnant humans at full-term (term human placentae), e.g., via elective caesarean section (Abstract; pg. 2, right col., 3rd full para. to last para.) and comprising placental alkaline phosphatase (PLAP) (Fig. 4). Tannetta teaches the STBM vesicle compositions comprise CD9, CD63, and Alix (Fig. 6D-E; pg. 8, right col. 1st full para.). Tannetta teaches syncytiotrophoblast extracellular vesicles are internalized by cells, e.g., endothelial cells (pg. 1, right col., 1st full para.).
Syncytiotrophoblast extracellular vesicles (e.g., STBMs) from human placentas inherently comprise CD81, tumor susceptibility gene 101 protein, P-gp, and BCRP, as evidenced by Afrouzian, Niu, and Holterman. Afrouzian teaches placental vesicles isolated from human, term placenta trophoblast tissues (apical or basal) comprise P-gp (MDR1) and BCRP (Fig 3; pg. 474, right col. 1st full para.; pg. 468, right col., para. 7, to pg. 469, left col., para. 4) and that human syncytiotrophoblasts naturally express placental alkaline phosphatase (Table 1) as well as P-gp and BCRP specifically on the apical membrane (Fig. 10; Table 2-3; Fig. 7A; pg. 472, right col., 5th para.). Niu teaches the tumor susceptibility gene 101 (TSG101) protein, as well as CD63, is present in purified extracellular vesicle preparations from endometrial cells (Fig. 1H, pg. 8, 1st full para.). Holterman teaches vesicles comprise the membrane protein CD81 as a general vesicle component (FIG. 8G; [0045], Example 20, [00971]), and that CD81 is a “housekeeping protein” of vesicles along with CD9 and CD63 ([00185]; [00971]; FIG. 8-E and H).
Regarding claim 10, Tannetta does not teach wherein at least some of the syncytiotrophoblast extracellular vesicles (EVs) are loaded by encapsulating a heterologous anti-cancer agent.
However Bauzon teaches loading EVs with a therapeutic agent payload, such as an anti-cancer drug, anti-cancer biological therapeutic, or oncolytic virus ([0016], [0027]). Bauzon teaches using modified EVs to deliver such anti-cancer therapeutics ([0028]) and that vesicles are ideal for delivering therapeutic materials into cells, e.g., based on their small size and ability to fuse with cell membranes ([0024]), such as to treat cancer ([0083]).
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to modify a full-term placental extracellular vesicle composition of Tannetta by encapsulating within the vesicles an anti-cancer therapeutic agent as taught by Bauzon for use in delivery to a target cell. One of ordinary skill in the art would be motivated to do so because Bauzon teaches using a therapeutic-loaded EVs to deliver a therapeutic to a cell based on their ability to fuse with the plasma membranes of cells and maintain therapeutic molecules in a functional state ([0024]).
Although the combination of Tannetta and Bauzon does not expressly teach that the loaded EVs target a subject’s lung when administered to the subject, for the purposes of applying prior art, an intended use of a claimed product only limits the claim if there is an implied structure not recited in the claims (see Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999) as “it is important not to import into a claim limitations that are not part of the claim.” See MPEP 2111.01.02. In claim 10, the phrase “wherein the loaded EVs target a subject’s lung when administered to the subject” does not imply any structure or feature not already expressly recited. Thus, such a capability is inherently present in the full-term, loaded STBMs taught by Tannetta in view of Bauzon absent evidence to the contrary.
Regarding claim 12, Tannetta does not teach a placental extracellular vesicle composition comprising any specifically recited heterologous therapeutic agent that is an anticancer agent.
However, Bauzon teaches incorporating into a vesicle a therapeutic agent payload selected from cisplatin, carboplatin, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, methotrexate, mercaptopurine, fludarabine, pentostatin, 5-fluorouracil, capecitabine [Xeloda®]), floxuridine, gemcitabine, cytarabine, raltitrexed (tomudex) hydrochloride, daunorubicin (Daunomycin), daunorubicin (liposomal), doxorubicin (Adriamycin), doxorubicin (liposomal), epirubicin, mitoxantrone, vinorelbine, vinflunine, paclitaxel, docetaxel, amsacrine, etoposide, and teniposide ([0151], [0153]-[0154], [0156], [0158]-[0161]) or combinations of aforementioned therapeutic agents ([0195]-[0199]).
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to modify a full-term placental extracellular vesicle composition of Tannetta by encapsulating one or more of the recited therapeutic agents taught by Bauzon. One of ordinary skill in the art would be motivated to do so because Bauzon teaches using EVs to deliver a therapeutic agent generally, and to specifically select such therapeutic agents recited above.
Regarding claim 14, Tannetta teaches syncytiotrophoblast derived vesicle compositions from full-term placenta tissue wherein the vesicle size range is 50-500 nm (Fig. 6A-C) and including microvesicle preparations of a size greater than 290 nm and less than 1,000 nm (Fig. 2, legend). Note a prima facie case of obviousness exists where claimed ranges overlap ranges disclosed in the prior art (MPEP 2144.05).
Thus, the claimed invention as a whole is prime facie obvious in the absence of evidence to the contrary.
Claims 10, 12, 14, 20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Tannetta in view of Bauzon, Holterman, Niu, and Afrouzian as applied above, and further in view of Kim (Kim et al., Nanomedicine 12: 655-64 (2016)).
Regarding claim 20, the combination of Tannetta, Bauzon, Holterman, Niu, and Afrouzian does not teach the full-term placental syncytiotrophoblast-derived extracellular vesicle composition encapsulating paclitaxel at a level of at least 40 percent weight of the composition.
However Kim teaches a method of encapsulating paclitaxel (PTX) in purified vesicles (exosomes) via a sonication method that provides a higher loading capacity than the alternatives of electroporation or incubation (Fig. 1). Kim’s paclitaxel sonication method specifically comprises 6 cycles of 30 seconds on/off with a two minute cooling period between each cycle, at a 20% amplitude setting, and with a one hour recovery incubation period at the end (pg. 656, right col., last para.). Kim teaches this sonication method achieving a paclitaxel loading capacity of about 30% (pg. 662, right col., last para.).
It would have been prima facie obvious to one of ordinary skill in the art at the effective time of filing to make the full-term placental extracellular vesicle composition taught by the combination of Tannetta and Bauzon using the sonication method taught by Kim. One of ordinary skill in the art would be motivated to do so because Kim teaches their specific sonication method produces improved paclitaxel vesicle loading than other methods. Furthermore, it is within the skills of one of ordinary skill in the art using routine experimentation to optimize such a sonication method to achieve as high as 40% weight encapsulated paclitaxel in such an EV composition, especially in light of the expectation of producing 30% loading capacity as taught by Kim without any optimizations.
Regarding claim 25, Bauzon teaches encapsulating into extracellular vesicles the specific anti-cancer agent paclitaxel ([0159], [0157]). Thus, it would have been prima facie obvious to one of ordinary skill in the art at the effective time of filing to make the full-term placental extracellular vesicle composition encapsulating paclitaxel taught by the combination of Tannetta and Bauzon using the sonication method taught by Kim. One of ordinary skill in the art would be motivated to do so because Kim teaches their specific sonication method produces improved paclitaxel vesicle loading than other methods. Furthermore, it is within the skills of one of ordinary skill in the art using routine experimentation to optimize such a sonication method to achieve as high as 40% weight encapsulated paclitaxel.
While Tannetta teaches full-term syncytiotrophoblast extracellular vesicles naturally comprise placental alkaline phosphatase (Fig. 4), the combination of Tannetta, Bauzon, and Kim does not expressly teach the full-term placental extracellular vesicles are characterized by the presence of the exosomal markers CD81, CD9, CD63, tumor susceptibility gene 101, and programmed cell death 6-interacting protein (ALIX), efflux transporters P-gp and BCRP.
However as evidenced by Afrouzian, Niu, and Holterman, syncytiotrophoblast extracellular vesicles from human placentas inherently comprise CD81, CD9, CD63, tumor susceptibility gene 101 protein, P-gp, and BCRP, as set forth fully above.
Thus, the claimed invention as a whole is prime facie obvious in the absence of evidence to the contrary.
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Tannetta in view of Bauzon as applied above, and further in view of Kim (Kim et al., Nanomedicine 12: 655-64 (2016)).
Regarding claim 23, Bauzon teaches encapsulating into extracellular vesicles the anti-cancer agent paclitaxel ([0159], [0157]); nonetheless, the combination of Tannetta, and Bauzon does not expressly teach the full-term placental syncytiotrophoblast-derived extracellular vesicle composition encapsulating paclitaxel at a level of at least 40 percent weight of the composition.
However Kim teaches a method of encapsulating paclitaxel (PTX) in purified vesicles (exosomes) via a sonication method that provides a higher loading capacity than the alternatives of electroporation or incubation (Fig. 1). Kim’s paclitaxel sonication method specifically comprises 6 cycles of 30 seconds on/off with a two minute cooling period between each cycle, at a 20% amplitude setting, and with a one hour recovery incubation period at the end (pg. 656, right col., last para.). Kim teaches this sonication method achieving a paclitaxel loading capacity of about 30% (pg. 662, right col., last para.).
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to make the full-term placental extracellular vesicle composition taught by the combination of Tannetta and Bauzon using the sonication method taught by Kim. One of ordinary skill in the art would be motivated to do so because Kim teaches their specific sonication method produces improved paclitaxel vesicle loading than other methods. Furthermore, it is within the skills of one of ordinary skill in the art using routine experimentation to optimize such a sonication method to achieve as high as 40% weight encapsulated paclitaxel in such an EV composition, especially in light of the expectation of producing 30% loading capacity as taught by Kim without any optimizations.
Although the combination of Tannetta, Bauzon, and Kim does not expressly teach that the paclitaxel-loaded EVs target a subject’s lung when administered to the subject, for the purposes of applying prior art, an intended use of a claimed product only limits the claim if there is an implied structure not recited in the claims. In claim 23, the phrase “wherein the full term placental EVs encapsulating paclitaxel target a subject’s lung when administered to the subject” does not imply any structure or feature not already expressly recited. Thus, such a capability is inherently present in the full-term, loaded STBMs taught by Tannetta, Bauzon, and Kim absent evidence to the contrary.
Regarding claim 24, Tannetta teaches syncytiotrophoblast derived vesicle compositions from full-term placenta tissue wherein the vesicle size range is 50-500 nm (Fig. 6A-C) and including microvesicle preparations of a size greater than 290 nm and less than 1,000 nm (Fig. 2, legend). Note a prima facie case of obviousness exists where claimed ranges overlap ranges disclosed in the prior art (MPEP 2144.05).
Thus, the claimed invention as a whole is prime facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments submitted 8/20/2025 and the Declaration of Rytting submitted 9/10/25 have been fully considered but are not found to be persuasive.
Applicant traverses, at least in part, by arguing that Afrouzian does not teach which markers are present on syncytiotrophoblast-derived extracellular vesicles, instead teaching P-gp and BCRP are merely expressed by syncytiotrophoblast cells and marking trophoblast vesicles (pg. 6-7). However Afrouzian states that BCRP and P-gp are expressed on the apical (brush border) membrane of syncytiotrophoblasts of term placentas (Fig. 6 and 10, Tables 2-3), and when vesicles are prepared from placental apical membranes (e.g., via chemical disruption, filtering, and purification by centrifugation), these syncytiotrophoblast vesicles comprise BCRP (Fig. 3; pg. 468, right col., last para., to pg. 469, left col., 2nd para.). As the instant application teaches making the syncytiotrophoblast extracellular vesicles composition of the instant claims by agitating villous tissues (AVT) to obtain nanovesicles ([0059]), the making of apical membrane vesicles via chemical disruption of tertiary villi placenta tissues shown in Afrouzian are representative of, or at least overlapping with, the vesicles derived from the apical membrane described by Afrouzian. Regardless, Afrouzian clearly teaches both P-gp and BCRP are present in the apical membrane of the syncytiotrophoblast, and forcing vesicle formation from a membrane would necessarily produce a composition comprising at least some vesicles comprising the same transmembrane components of that undisrupted membrane.
Applicant also traverses by arguing that the claimed invention differs from the prior art due to the method of making it (AVT). However the present claims encompass syncytiotrophoblast-derived extracellular vesicles regardless of how they are made, and such compositions can be made by various methods, such as DPPL or AVT as explained in the instant specification ([0017], [0015]; FIG. 1; [0058]-[0059]). Thus, any arguments specific to AVT-prepared syncytiotrophoblast extracellular vesicles are moot for not being commensurate in scope with the claims, including differences in expression profiles, drug encapsulation efficiency, lung targeting, and safety profiles (see Exhibits B-C).
Applicant also presents the Declaration of Rytting arguing that the prior art fails to teach the specified marker levels and high drug loading capacity of 40.8% by weight for paclitaxel (para. 3; Exhibit A or instant FIG. 1). However as noted in the rejection above, Tannetta in view of Bauzon as evidenced by Holterman, Niu, and Afrouzian teaches the expected presence of the same markers, and further in view of Kim achieving paclitaxel loading capacity of about 30% by weight, it is within the skills of one of ordinary skill in the art using routine experimentation to optimize this to 40% weight percent using the EVs taught by Tannetta and as motivated by Bauzon, such as syncytiotrophoblast-derived extracellular vesicles generated by mechanical disruption as taught by Tannetta (pg. 2, right, para. 4; Fig. 2D; Table 1).
It is further noted that the expression of CD9 and ALIX in AVT-EVs shown by western analysis in instant FIG. 1 and Exhibit A appears lower than control, and DPPL-EVs comprise all the same markers as AVT-EVs in FIG. 1 ([0071]).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638