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 .
Claim Status
Claim listing filed on January 9, 2026 is pending. Claims 2-3, 5-13, 16-18, 20-22, 25-26, 29-31, 33, 35-36, 38-40, and 42-52 are canceled. Claims 1, 4, 19, 23-24, 27-28, and 34 are amended. Claims 1, 4, 14-15, 19, 23-24, 27-28, 32, 34, 37, and 41 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 2-3, 7, 18, 20, and 49-50 have rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the specification and claims have overcome all objections of record, and the specification objections and claim objections are withdrawn.
The rejection of claims 1, 4, 14-15, 19, 23-24, 32, 34, 37, and 41 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. In particular, defining the IL-12 moiety as an IL-12 protein or a fragment thereof (Claims 1 and 19) provides structure for the claimed functional language and overcomes the indefiniteness rejection.
The rejection of claims 1, 4, 14-15, 19, 23-24, 27-28, 32, 34, 37, and 41 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. In particular, Claim 1 is now directed to a method of treating a cancerous tumor wherein “treating” does not include prophylactic treatment. Further, Claim 1 defines the structure of the IL-12 moiety and defines wherein the STING agonist and the IL-12 protein are associated with separate EVs (a first EV and a second EV).
Claim Objections (New, necessitated by amendment)
Claim 23 is objected to because of the following informalities: Claim 23 should recite a colon after wherein (“wherein:”) to be grammatically consistent with the other claims that comprise lists (such as Claims 24, 27, and 34). Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Modified, necessitated by amendment)
The rejection of Claims 27-28 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 is maintained.
Claim 27 defines the first EV as a product-by-process reciting “the first EV is produced by a cell that overexpresses PTGFRN protein by at least 2-fold relative to a cell that does not overexpress PTGFRN.” The patentability of a product does not depend on its method of production, but instead the structure implied by the process steps should be considered when assessing the patentability of a product-by-process (MPEP § 2113.I). However, the structure of the first EV as implied by the process is unclear because the process comprises indefinite functional language and relative terminology. First, the cell that produces the first EV is described by what it does (overexpresses PTGFRN) rather than by what it is (MPEP § 2173.05(g)). Because of this indefinite functional language, it is unclear what cell types produce the first EV. Second, the cell overexpresses PTGFRN by at least 2-fold relative to a cell that does not overexpress PTGFRN. This relative terminology is indefinite because it is unclear what the PTGFRN expression level is in cells that “do not overexpress PTGFRN.” This value is not defined in the specification, and The Human Protein Atlas (2026) teaches that endogenous PTGFRN expression varies depending on tissue type. It is unclear to what value the 2-fold overexpression is being compared. Due to the indefinite functional language and relative terminology, one of ordinary skill would not understand the structural metes and bounds of the first EV as defined by a product-by-process in Claim 27(i). Claim 28 is rejected for its dependence on Claim 27.
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that one of ordinary skill would readily understand that the overexpression of PTGFRN in a cell is relative to that in a cell that does not overexpress PTGFRN. Examiner maintains that the baseline level of PTGRN expression in a cell that does not overexpress PTGFRN is unclear for the reasons outlined above, and the rejection is maintained.
Claim Rejections - 35 USC § 101 (Maintained)
The rejection of Claim 19 under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon or a product of nature without significantly more is maintained.
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that amended Claim 19 is directed to a composition comprising a first EV loaded with a STING agonist and a second EV loaded with an IL-12 protein, and under Prong One of the Step 2A analysis, the claim does not recite a natural phenomenon. The specification defines “loaded” as a status or process of having a first moiety (e.g. a STING agonist and/or an IL-12 moiety) associated with a second moiety (e.g. an EV) (paragraph [0084]). The specification defines “associated with” as encapsulation of a first moiety (e.g. a STING agonist and/or an IL-12 moiety) into a second moiety (e.g. an EV), or to a covalent or non-covalent bond formed between a first moiety and a second moiety (paragraph [0082]). Therefore, amended Claim 19 is still directed to a STING agonist encapsulated or bound to an EV and an IL-12 protein encapsulated or bound to an EV. As of record in the non-final office action filed 10/17/2025, Gentili teaches that exosomes package cGAMP (a naturally occurring STING agonist) for transmission between cells which defines “a first EV loaded with a STING agonist” as a natural phenomenon. As of record in the non-final office action filed 10/17/2025, Fitzgerald teaches that IL-12 was found in EVs in most sampled tissue types which defines “a second EV loaded with an IL-12 protein” as a natural phenomenon. As both EVs loaded with a STING agonist and EVs loaded with an IL-12 protein naturally occur in the human body, Prong One of the Step 2A analysis is YES, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (Modified, necessitated by amendment)
The rejection of Claims 1, 4, 14-15, 19, 24, 27-28, 32, 34, and 37 under 35 U.S.C. 103 as being unpatentable over Iyer WO 2019/161171 (of record) in view of Meraz et al. Mol Pharm. 2014 (of record) is maintained.
Due to the amendments in Claim 1, dependent Claims 27-28 are now fully enabled. Iyer teaches that the nanoparticles further comprise a targeting moiety such as an antibody to direct the conjugate to a particular location (page 173) which reads on instant Claim 27(ii). Iyer does not teach wherein the STING agonist is linked to a PTGFRN protein (instant Claim 28).
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that Iyer does not teach an IL-12 protein associated with a second EV, and Meraz does not teach a first EV in combination with a STING agonist. However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (MPEP § 2145.IV).
Applicant argues that Iyer teaches away from the combination of an EV comprising a STING agonist administered with an IL-12 moiety, because Iyer discloses that the nanoparticle can further comprise an interleukin but does not specifically list IL-12. However, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (MPEP § 2123.II). In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004), "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." (MPEP § 2123.II). Therefore, just because IL-12 was not included in the list of alternative interleukins in Iyer does not constitute a teaching away from combining the STING agonist EV with the IL-12 EV taught by Meraz.
Applicant argues that Meraz’s finding that IL-12 works within a combination therapy using MPL-containing liposomes is irrelevant to the combination therapy involving a composition comprising an EV and a STING agonist of the present claims. On the contrary, Meraz teaches that the MPL-containing liposomes induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α (abstract). The combination of IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ (abstract). IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor (abstract). Therefore, MPL-containing liposomes and IL-12 had shared mechanisms of action (increased expression of IL-1β and TNF-α) and were favorable in combination to promote an anti-tumor immune response. It is of record in the non-final office action filed 10/17/2025 that Iyer teaches that the STING nanoparticles can be administered to treat cancer tumors because the STING pathway is an important innate immune sensing pathway that detects the presence of a tumor and drives dendritic cell activation and subsequent T cell priming against tumor-associated antigens (page 181, paragraph 2). It would be clear to one of ordinary skill that the STING agonist EVs of Iyer have the same anti-tumor mechanism as the IL-12 EVs of Meraz, namely promoting dendritic cell activation and T cell priming to ultimately induce an anti-tumor immune response. Because Meraz teaches combining immunostimulant anti-tumor therapies, it would be obvious to combine the STING agonist EVs and the IL-12 EVs based on their overlapping mechanisms of action. Note, new sections of Meraz are cited solely in response to Applicant’s arguments and not as a new ground of rejection.
Applicant argues that one of ordinary skill in the art would readily understand that simply combining two moieties that individually possess recognized anti-cancer properties would not necessarily lead to improved outcomes. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). MPEP § 2145. While the combination of STING agonist EVs and IL-12 EVs would not have been absolutely predictable prior to the time of filing, the agents could have been combined with an expectation of success in stimulating an anti-tumor immune response that one of ordinary skill would have found reasonable. As outlined in the paragraph above, both EVs were understood to produce anti-tumor immune responses by parallel mechanisms of action (dendritic cell activation and T cell priming). Meraz teaches combining the IL-12 EVs with agents of similar mechanism of action (MPL-containing liposomes – see above paragraph). Iyer also anticipates combination therapy by teaching that the STING agonist nanoparticles can be administered in combination with other known anti-cancer agents and immunooncology agents (pages 194-195). These teachings are aligned with what was understood in the state of the art prior to filing, namely that combining known anti-cancer agents to administer a combination therapy is standard practice in oncology (as evidenced by Thundimadathil J Amino Acids. 2012 and Gotwals et al. Nat Rev Cancer. 2017). Even if two agents lack synergy, there is still a benefit to using both agents in combination to improve the probability of response across genetically diverse patient populations and reduce the likelihood of acquired resistance (Palmer et al. Cell 2017; abstract). Thus, there is ample support both from the cited references and the state of the art prior to filing to combine two agents (both known to induce an anti-tumor immune response by dendritic cell activation and T cell priming) with a reasonable expectation of success in treating cancer.
Applicant argues that the instant application provides unexpected results in that a combination of STING agonist containing exosomes and IL-12 containing exosomes yielded a significant reduction in tumor growth rate compared to either treatment alone (Example 2 and Fig. 2C). These results are not surprising in view of Meraz which teaches that combining IL-12 EVs with agents sharing similar immunostimulant properties (MPL-containing liposomes) induced greater tumor volume reduction than either single agent alone (Fig. 4A). Note, new sections of Meraz are cited solely in response to Applicant’s arguments and not as a new ground of rejection. These results are also not surprising in view of the state of the art prior to filing which teaches that combining two anti-cancer agents is more effective than single agents either due to synergy (Thundimadathil abstract) or by improving the probability of response and overcoming resistance (Palmer abstract). Therefore, the instant results showing that two anti-tumor agents are more effective than either single agent are not surprising given that (1) both single agents were known in the art to have anti-tumor efficacy and (2) combination therapy in oncology is known to have numerous mechanistic benefits. Applicant’s arguments have been considered but are not persuasive, and the rejection is maintained.
The rejection of Claims 1, 4, 14-15, 19, 23-24, 27-28, 32, 34, and 37 under 35 U.S.C. 103 as being unpatentable over Iyer WO 2019/161171 (of record) in view of Meraz et al. Mol Pharm. 2014 (of record) as applied to Claims 1, 4, 14-15, 19, 24, 27-28, 32, 34, and 37 above, and further in view of Moniz WO 2020/191361 (of record) is maintained.
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that Moniz does not remedy the deficiencies of Iyer and Meraz. The alleged deficiencies of Iyer and Meraz have been addressed above, and the rejection is maintained.
The rejection of Claims 1, 4, 14-15, 19, 24, 27-28, 32, 34, 37, and 41 under 35 U.S.C. 103 as being unpatentable over Iyer WO 2019/161171 (of record) in view of Meraz et al. Mol Pharm. 2014 (of record) as applied to Claims 1, 4, 14-15, 19, 24, 27-28, 32, 34, and 37 above, and further in view of Stephan US 2020/0123219 (of record) is maintained.
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that Stephan does not remedy the deficiencies of Iyer and Meraz. The alleged deficiencies of Iyer and Meraz have been addressed above, and the rejection is maintained.
Double Patenting (Maintained)
1. The provisional rejection of Claims 1, 14, 19, 23-24, 27, 32, and 41 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 4-5, 14, 27, 46, 60, and 65 of U.S. App. No. 17/040,805 (of record) in view of Meraz et al. Mol Pharm. 2014 (of record) is maintained.
2. The provisional rejection of Claims 1, 14-15, 19, 24, 32, 34, and 37 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 33-36 of U.S. App. No. 18/042,068 (of record) in view of Iyer WO 2019/161171 (of record) is maintained.
3. The provisional rejection of Claims 1, 14-15, 19, 24, 27, 32, 34, and 37 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 6-8, and 15-16 of U.S. App. No. 19/220,569 (of record) in view of Iyer WO 2019/161171 (of record) is maintained.
4. The provisional rejection of Claims 1, 14, 23-24, 27, and 32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 24, 29, 39, 55, 57, and 68 of U.S. App. No. 18/000,799 (of record) is maintained.
Applicant's arguments filed January 9, 2026 have been fully considered but they are not persuasive. Applicant requests that the provisional double patenting rejections be held in abeyance until otherwise allowable subject matter is found. MPEP § 804.I.B.1 states that “as filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.” As no terminal disclaimer has been filed and no showing has been made that the instant claims are patentably distinct from the copending claims, the provisional double patenting rejections are maintained.
Conclusion
No claim is 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.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675