DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments, And/Or Claims
The Applicants amendments/remarks received 9/19/2025 are acknowledged. Claims 43 and 55 are amended; claims 1-42 and 44 are canceled; claims 43 and 45-62 are pending; claims 50-62 are withdrawn; claims 43 and 45-49 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement submitted on 9/23/2025 has been considered by the examiner.
Response to Amendment
The declaration under 37 CFR 1.132, filed 9/19/2025 by inventor Anat Aharon, is insufficient to overcome the rejections of claims 43-49 based upon Seeger, Hu and Li as set forth in the last Office action because: The declaration presents opinion evidence of one of the inventors which is unpersuasive that the claims are NON-OBVIOUS over Seeger in view of Hu.
It is noted that opinion evidence as to a legal conclusion is not entitled to any weight and an affidavit of an applicant as to the advantages of their claimed invention is less persuasive than that of a disinterested person (MPEP 716.01(c)(III)).
The declaration is drawn to alleging that Seeger inappropriately terms their extracellular vesicles (EVs) “exosomes” (¶6-10). The inventor alleges that the EVs isolated and administered in Seeger are too big to be labeled “exosomes” (¶12) because exosomes generally measure 30-150 nm in diameter (¶8); hence, a person of ordinary skill in the art at the time of filing would have found it non-obvious to apply the teachings of Hu to the compositions and methods of Seeger because Hu is properly drawn to exosomes, while Seeger recites exosomes but they are not true exosomes because they are too large. This is completely unpersuasive. Firstly, Seeger is drawn to producing exosomes (in actuality, they are EVs larger than exosomes as inventor points out) which can have a mean size of 173 nm (with a Gaussian size distribution; thus, the EVs are 30-1000 nm, at least 25% of the EVs have a particle size diameter of above 150 nm and wherein the mean size of the EVs is at least 160 nm) which can be from genetically modified T-cells expressing chimeric antigen receptors wherein the CAR can target HER2/neu (see rejection below for details and citations); hence, the compositions of Seeger meet all the limitations of claims 43, 45-46 and 48 except that Seeger is silent on stimulating the T-cells before EV isolation. Secondly, Hu is not relied on for teaching the isolation of the extracellular vesicles, rather, Hu is relied on for disclosing that activation of the CAR T-cells with the CAR antigen improves the effectiveness of the CAR-containing vesicles (see rejection below for details and citations). The MPEP is clear that a person of ordinary skill in the art is not an automaton but a person of ordinary creativity who can fit the teachings of multiple patents together like pieces of a puzzle; hence, examiners may take into account the inferences and creative steps that a person of ordinary skill in the art would employ (MPEP 2141.03(I)).
Therefore, it is within the capabilities of a person of ordinary skill in the art to realize that Hu’s teachings that the activity of exosomes comprising CARs from T-cells is increased when the T-cells are activated with the CAR antigen can be applied to the EVs of Seeger; hence, a person of ordinary skill in the art would conclude that the activity of the EVs of Seeger comprising CARs from T-cells can be increased by activating the T-cells with the CAR antigen regardless of the fact that Seeger uses the wrong nomenclature. Thus, the declaration is insufficient to overcome the rejections set forth below.
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.
Claims 43, 45-46 and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Seeger et al., US 2016/0243192 (cite A, PTO-892, 6/23/2025; herein “Seeger”) in view of Hu et al., US 2021/0030801 (cite A, PTO-892, 12/6/2024; herein “Hu”).
Seeger teaches immune cell-derived exosomes, i.e., EVs [0039], wherein the EVs have a mean particle size of 158 nm when isolated with an “ExoQuick” protocol, a mean particle size of 173 nm when isolated with an ultracentrifugation protocol and a mean particle size of 155 with isolated with a precipitation protocol; wherein the distribution of particles, i.e., EVs, has a Gaussian profile (Fig. 2B, D; [0020]) and wherein the immune cells that the EVs are derived from can be T-cells or genetically engineered T-cells ([0009], [0033], [0039-40], [0042], [0047]; claim 17) wherein the produced EVs can comprise chimeric antigen receptors (CARs) [0082] wherein the CAR can target HER2/neu ([0078], [0082]). Hence, Seeger teaches isolated EVs derived from T-cells expressing a chimeric antigen receptor (CART-cells), wherein the EVs are 30-1000 nm, at least 25% of the EVs have a particle size diameter of above 150 nm and wherein the mean size of the EVs is at least 160 nm because Seeger demonstrates that the EVs, when isolated by Seeger’s ultracentrifugation protocol, have a Gaussian distribution centered on the mean EV size of 173 nm; therefore, ≥50% of the EVs have a diameter which is larger than 173 nm.
Hence, Seeger teaches compositions of isolated extracellular vesicles (EVs) derived from T-cells expressing a chimeric antigen receptor (CART-cells), wherein the EVs have a particle size of from 30 nm to 1000 nm and at least 25% of the EVs have a particle size diameter of above 150 nm and wherein the mean size of the EVs is at least 160 nm, i.e., Seeger produces compositions comprising all the limitations of claim 1 except that Seeger is silent on stimulating the T-cells before EV isolation.
Seeger teaches that the EVs can be from activated natural killer cells [0008], but does not specifically teach that the CAR T-cells are activated with HER2 or HER2-expressing cells before the isolation of the EVs; however, a person of ordinary skill in the art at the time of filing would have found it obvious for the CAR T-cells to be activated with HER2 or HER2-expressing cells before the isolation of the EVs in view of the disclosure of Hu.
Hu teaches producing chimeric antigen receptor (CAR)-carrying exosomes derived from immune cells wherein the immune cells can be T-cells, comprising preparing CAR-expressing immune cells and antigen-specific activation of the CAR-expressing immune cells (Abst.; [0017-44]). Hu teaches that the antigen to which the CAR is targeted can be HER2 or CD19 [0031]. Hu teaches that activation of the CAR T-cells before collection of vesicles comprising the CAR greatly enhances the effectiveness of the CAR-containing vesicles ([0015], [0028-32]).
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to isolate EVs according to the methods of Seeger wherein the CAR T-cells of Seeger comprise a CAR which is anti-HER2, wherein the EVs comprise the CAR and wherein the CAR T-cells are activated CAR T-cells activated by antigen-specific activation as taught by Hu; therefore, claims 43 and 45-46 are prima facie obvious.
CD3, CD38 and HLARD are activated T-cell markers and Hu teaches that the activated CAR exosomes exhibit a very strong antitumor effect; hence, a person of ordinary skill in the art at the time of filing would have found it obvious that the CAR-carrying activated EVs made obvious by Seeger in view of Hu would comprise at least 10% of the EVs expressing CD38 antigen; at least 20% of the EVs expressing CD3 antigen; at least 20% of the EVs expressing HLARD antigen; and/or the EVs being cytotoxic EVs; therefore, claim 48 is prima facie obvious.
Hu teaches that the CAR-carrying activated EVs can comprise toxins or radioactive particles [0015]; hence, a person of ordinary skill in the art at the time of filing would have found it obvious that the EVs made obvious by Seeger in view of Hu can comprise toxins or radioactive particles; therefore, claim 49 is prima facie obvious
Response to Arguments
Applicant's arguments filed 9/19/2025 have been fully considered but they are not persuasive.
Regarding the rejection of claims 43-46 and 48-49 under 35 U.S.C. 103 over Seeger in view of Hu, Applicant does not deny that Seeger teaches immune cell-derived EVs wherein the distribution of EVs has a Gaussian profile, wherein the EVs can have a mean particle size of 173 nm (when isolated with an ultracentrifugation protocol), wherein the immune cells that the EVs are derived from can be T-cells or genetically engineered T-cells, wherein the produced EVs can comprise chimeric antigen receptors (CARs), wherein the CAR can target HER2/neu, rather, Applicant emphasizes that Seeger’s preferred embodiment is producing exosomes from NK cells which comprise Fc receptor, wherein the NK cells can be activated by IL-2 (Remarks, pp. 6-9). MPEP 2123(I) clearly states that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments; hence, Applicant’s arguments based on the preferred embodiment of Seeger (EVs from NK cells activated by IL-2 and purified by precipitation) concluding “The claimed EVs have a mean size of at least 160 nm, which is larger than disclose in Seeger et al. let alone Hu et al.” is unpersuasive.
Applicant alleges that a person of ordinary skill in the art at the time of filing would have found it non-obvious to apply the activation described in Hu to Seeger’s production of EVs because Seeger uses the term “exosome” improperly (pp. 8-9) referencing the inventor’s declaration discussed on pp. 2-4 above.
Applicant further argues that the teachings of Hu cannot be relied on in any rejection of the instant claims because Hu teaches away from the present invention because Hu isolates vesicles which are 30-150 nm (pp. 8-9). In other words, Applicant is arguing that no prior art can be used which does not meet every limitation of the claims. This is clearly unpersuasive. 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).
Seeger is drawn to producing “exosomes” (EVs larger than exosomes actually as inventor points out) which can have a mean size of 173 nm (with a Gaussian size distribution; thus, the EVs are 30-1000 nm, at least 25% of the EVs have a particle size diameter of above 150 nm and wherein the mean size of the EVs is at least 160 nm) which can be from genetically modified T-cells expressing chimeric antigen receptors wherein the CAR can target HER2/neu; hence, the compositions of Seeger meet all the limitations of claims 43, 45-46 and 48 except that Seeger is silent on stimulating the T-cells before EV isolation. Hu is not relied on for teaching the isolation of the extracellular vesicles, rather, Hu is relied on for disclosing that activation of the CAR T-cells with the CAR antigen improves the effectiveness of the CAR-containing vesicles. The MPEP is clear that a person of ordinary skill in the art is not an automaton but a person of ordinary creativity who can fit the teachings of multiple patents together like pieces of a puzzle; hence, examiners may take into account the inferences and creative steps that a person of ordinary skill in the art would employ (MPEP 2141.03(I)).
Therefore, it is within the capabilities of a person of ordinary skill in the art to realize that Hu’s teachings that the activity of exosomes comprising CARs from T-cells is increased when the T-cells are activated with the CAR antigen can be applied to the EVs of Seeger; hence, a person of ordinary skill in the art would conclude that the activity of the EVs of Seeger comprising CARs from T-cells can be increased by activating the T-cells with the CAR antigen regardless of the fact that Seeger uses the wrong nomenclature.
Applicant alleges “Therefore, contrary to the Examiner's assertion, a person of ordinary skill in the art aware of a method activation of NK cell from both Seeger and the art, i.e. by IL-2, would not seek activating NK cells as described in the present application” (p. 8). This is unpersuasive as neither the instant claims nor any prior assertion by the examiner is drawn to activating NK cells.
In summary, Applicant does not present any persuasive argument against modifying the EVs of Seeger by the activation of the T-cells taught by Hu motivated by Hu teaching that activation of the T-cells with the CAR antigen gives vesicles with greater activity; hence, the rejection is maintained with modification to address claim amendments and for clarity.
Claims 43 and 45-49 are rejected under 35 U.S.C. 103 as being unpatentable over Seeger in view of Hu and Li et al., 2008 (cite V, PTO-892, 12/6/2024; herein “Li”).
The discussion of Seeger and Hu regarding claims 43, 45-46 and 48-49 set forth in the rejection above is incorporated herein.
Hu does not specifically teach that the anti-HER2 CAR is N29 CAR; however, it would be prima facie obvious in view of the disclosure of Li.
Li teaches genetically engineering T-cells to express a HER2-specific CAR wherein the single chain Fv is derived from the N29 monoclonal antibody specific for p185HER2 (Abst.).
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to produce the activated CAR EVs made obvious by Seeger in view of Hu wherein the anti-HER2 CAR is an N29 CAR; therefore, claim 47 is prima facie obvious.
Response to Arguments
Regarding the rejection of claims 43-49 under 35 U.S.C. 103 over Seeger in view of Hu and Li, Applicant argues that Li does not remedy the deficiencies of Seeger and Hu (p. 9). This is unpersuasive in view of the discussion of Seeger in view of Hu set forth on pp. 8-10 above. The rejection is maintained with modification to address claim amendments.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Trent R Clarke whose telephone number is (571)272-2904. The examiner can normally be reached M-F 10-7 MST.
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/TRENT R CLARKE/ Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651
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