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 .
Claims 1-16, 19-21, 25-26, 28-66, and 68 remain cancelled.
Claims 73-74 are new.
Claims 17 and 67 are amended.
Claims 17-18, 22-24, 27, 67, and 69-74 are pending and under examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/31/2026 has been considered by the examiner.
Maintained-Claim Interpretation
The limitation recited in claim 73 [‘wherein the transfected cells express OX40L at least 5000-fold higher than non-transfected cells’] is not drafted to represent active methods steps. The limitations are notably drafted to reflect results effected by and flowing from practicing the active steps of the method using the claimed products. Where the active steps of the method using the claimed products are anticipated and/or made obvious, so too will the results passively achieved thereby be considered to be anticipated and/or made obvious.
Withdrawn Objections and Rejections
The rejections of claims 17-18, 22-24, 27, 67, and 69-74 for lack of written description under 35 USC 112(a) for the genus of cancer cells to be transfected is withdrawn in light of the amendments to the claims dated 04/17/2026. The rejections under 35 USC §103 presented in the previous office action dated 12/23/2025 have been modified to account for the new scope of the claims resulting from Applicant’s claim amendments dated 04/17/2026.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
Maintained-Partial Lack of Enablement
Claims 17-18, 22-24, 27, 67, and 69-74 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administration of exosomes produced from HEK293T cells overexpressing OX40L paired with an antibody against CTLA4 is therapeutic in a B16F10 (murine metastatic melanoma cell line) model (see for example, instant figures 7A and 7E and the caption), does not reasonably provide enablement for use of exosomes produced by other cells for treating any generic cancer(s) (noting the lack of a closed or limiting definition; see for example, paras 0064-0065 of the specification). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors 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.
The breadth of the claims
Claims 17-18, 22-24, 27, 67, and 69-74 are broadly directed to a method of treating cancer in a patient in need thereof, the method comprising: (a) stably transfecting dendritic cells, epithelial cells, or mesenchymal cells with an OX40L expression vector; (b) collecting and purifying exosomes expressing OX40L on their surface from the stably transfected cells, wherein at least 50% of the collected and purified exosomes comprise an OX40L molecule on their surface; (c) administering to the patient a pharmaceutical composition comprising: (i) the collected and purified exosomes; and (ii) an adoptive T cell therapy, an anti-PD1 antibody, an anti-CTLA-4 antibody, an anti-PD-L1 antibody, and/or an immune checkpoint inhibitor. The recitation of “treating cancer in a patient in need thereof” encompasses a broad range of cancers (affecting different tissues/cells and involving different underlying pathologies) and cell types (bearing divergent features and originating from different sources).
The nature of the invention
Claims 17-18, 22-24, 27, 67, and 69-74 are broadly directed to a method for treating cancer comprising the use of exosomes. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
Malacards (TNFSF4; obtained from: https://www.malacards.org/search/results?q=TNFSF4 (accessed: 12/15/2025)) and Pathcards (TNFSF4; obtained from https://pathcards.genecards.org/search/results?q=TNFSF4 (accessed 12/16/2025)) provides that, as of 2025, the OX40/OX40L superpathway is associated with certain cancers (including certain solid tumor, liquid tumor, and hematologic cancers; see the references in their entirety) [noting that TNFSF4 is synonymous with OX40L (see Genecards, (obtained from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNFSF4 (accessed 12/17/2025))]. However, cancer is a highly heterogenous disease (as evidenced by Allison et al, (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014); at paragraph 1 of the Introduction)) and there is no reason to expect that an exosome expressing OX40L and a checkpoint inhibitor would function to treat all cancer as there is there no single/universal (one) cure for cancer (as evidenced by American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html)(2021)).
The level of one of ordinary skill
As the claims are directed to treatment of cancer, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
With respect to the teachings of Malacards and Pathcards (even assuming public availability as of the filing date, which is not conceded at this time), the prior art teaches that research has determined that a correlation between a biomarker and a disease state does not mean that the biomarker is a drug target. For example, Kempf et al (2006, Cir. Res. 98:351-350) show a correlation between elevated GDF-15 levels and adverse cardiovascular events. Such may suggest that treatment with anti-GDF-15 would be beneficial to patients. However, it was discovered that GDF-15 expression was elevated in response to the cardiovascular event as a way for the body to attempt to protect its tissues from ischemia/reperfusion injury. Accordingly, administration of an anti-GDF-15 agent would have been harmful to patients. Therefore, discovery of a correlation alone is not enabling for a method of treatment. Additionally, markers can be elevated as a result of the disease, or as part of a body’s response to a disease, and cannot be presumed to be causative or contributory to the disease without significant further research. For example, with respect to G-protein coupled receptor perturbations in the disease hypertension, "it has been difficult to determine whether they are the cause or consequence of the disease" (Feldman, 2002, Molecular Pharmacology. 61(4): 707-709). With respect to temporal lobe epilepsy, Janigro (2008, Epilepsy Currents 8(1): 23-24) teaches that "[a]s with many pathological findings in neurodegenerative diseases, it is difficult to determine if the changes are a cause or consequence of epileptic seizures" (p. 23). Likewise, Zips et al. (2005, In Vivo 19:1-8) indicate that while in vitro assays are useful as a first step, a cancer therapeutic must be evaluated in vivo for therapeutic benefit (abstract, top of p. 3, p. 6 conclusion).
More generally, Sun et al (Acta Pharmaceutica Sinica B 2022;12(7):3049e3062) teach that ninety percent of clinical drug development fails despite implementation of many successful strategies. Sun et al further note that current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity–relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity (see for example, the abstract). Additionally, Chen et al-2022 (BioRiv preprint posted February 6, 2022, ORCID: https://orcid.org/0000-0002-9534-6199; doi: https://doi.org/10.1101/2022.01.30.478394) teach that simple elevation of protein/gene expression level in a disease state does not mean the gene/protein is causal for the disease nor targeting it would be effective for therapeutic efficacy. The increase in expression might only suggest it is correlated with disease progression. Differentiating “causality” from “correlation” is a crucial step in identifying a promising disease target (see for example, the first paragraph of the Introduction at page 3). Furthermore, Bryant et al (THE LANCET, Infectious Diseases Vol 4 February 2004, https://doi.org/10.1016/S1473-3099(04)00930-2) teach that knowledge that a gene is expressed under a particular condition is not an answer in itself but only the first step in understanding. For example, whether expression of a gene is vital for host defense or involved in tissue injury requires further investigation. In addition, expression of a gene does not always translate into production of a protein. Although gene expression reveals nothing directly about translational and post-translational events, protein activation status alterations can and do frequently alter the expression of downstream target genes (see for example, column 2 of page 110). Finally, The Marshall Protocol (Differences between in vitro, in vivo, and in silico studies, obtained from: https://mpkb.org/home/patients/assessing_literature/in_vitro_studies (2015)) discuss the deficiencies in predictable translation of results from in vitro, in vivo, and in silico studies with respect to treatment of an organism (see reference, generally).
(F) The amount of direction provided by the inventor
Applicant has only disclosed production of exosomes using HEK293T cells co-administered with an anti-CTLA4 antibody to reduce/suppress tumor volume/growth in B16F10 cells (metastatic melanoma).
The existence of working examples
While there are 3 labeled ‘Examples’, they are effectively 1 embodiment given that only HEK293T cells are used to produce exosomes and only B16F10 cells are treated.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There is effectively a single working example provided and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
In light of the contradictory findings in the prior art, a showing that the claimed method reduces tumor volume/suppresses tumor growth in a B16F10 cell line is not enabling for a method of treating all cancers. In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention in its full scope, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph. Only a method of stably transfecting dendritic, epithelial, or mesenchymal cells to treat a solid tumor cancer, such as melanoma, is deemed enabled.
New-35 USC § 112(b)
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 17-18, 22-24, 27, 67, and 69-74 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.
It is unclear whether claim 17 intends to require that the administered exosomes are the 50% or more that are actively screened to confirm OX40L expression or if all of the purified and collected exosomes are administered (those expressing OX40L and those not confirmed by screening to express OX40L). Artisans are left to dispute which interpretation is required and would therefore infringe the claim. Therefore, the metes and bounds of the claim are indefinite as drafted. Dependent claims 18, 22-24, 27, 67, and 69-74 incorporate, via dependency from claim 17, this ambiguity and fail to remedy the noted indefiniteness and are therefore included in this rejection.
New-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 17, 18, 22-24, 27, 69-70, and 73-74 are rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al (Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016 Jan;52:50-66. doi: 10.1016/j.ejca.2015.08.021. Epub 2015 Nov 30) in view of Johnsen et al (A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochem Biophys Acta. 2014 Aug;1846(1):75-87. doi: 10.1016/j.bbcan.2014.04.005. Epub 2014 Apr 18), Alvarez-Erviti et al (Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341–345 (2011); as cited on the 01/27/2021 IDS and as cited and incorporated by Johnsen et al), and Grasso et al (Anal Bioanal Chem. 2015 Jul;407(18):5425-32. doi: 10.1007/s00216-015-8711-5. Epub 2015 Apr 30).
Regarding claims 17 and 73, Aspeslagh et al teach that immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Aspeslagh et al go on to teach that, besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently being tested in early phase cancer clinical trials (see for example, the abstract of Aspeslagh et al at page 50). Adaptive immunity relies on the specific recognition of antigens (mostly peptides) presented by major histo-compatibility (MHC) molecules expressed at the surface of antigen presenting cells (APCs) to the T-cell receptor (TCR). This is the first step required for T-cell activation. However, for a full blown T-cell triggering, the first MHC/TCR signal requires the involvement of co-stimulatory molecules of the B7 family (that can be further dampened by signalling through co-inhibitory receptors expressed on T-cells (such as CTLA4 or PD1)). OX40 has only one known ligand called OX40L (CD252), which is classically expressed on activated antigen-resenting cells (APCs) (see for example, section 2 of Aspeslagh et al at page 51). OX40 expression on tumour infiltrating lymphocytes (TILs) has been studied in different tumour settings, such as breast cancer, melanoma, B-cell lymphoma, and head and neck cancer. In colon cancer, high expression of OX40 on TILs, in mesenteric lymph nodes or in invasive margin lymphoid aggregates correlated with better overall survival. In lymphoma, OX40 expression was dramatically increased in CD4 T-cells, more specifically in Tregs TILs for whom OX40 expression could in fact be used as a marker of tumour antigen-specific Tregs (see for example, section 4 at page 52). Note that effects of OX40 stimulation are taught in table 1 of Aspeslagh et al (see page 52). In vitro experiments show that anti-OX40 will enhance CD4 and CD8 survival (see for example, Figure 2 at page 52). Interestingly, in contrast to anti-OX40 antibodies, OX40L-Fc also activated DCs and vascular endothelial cells within the tumour bed in a T-cell independent manner (see for example, section 5 at pages 52, 55, and 62; see also for example, table 2 of Aspeslagh et al at pages 53-55).
Anti-OX40 and OX40L-Fc therapy show a strong effect in mice bearing small tumours. However, the efficacy against more bulky tumours or metastases, a situation, which is much closer to the status of cancer patients, is less impressive. Hence, different modalities of treatment combinations have been attempted to overcome resistance to anti-OX40 molecules (Ox40 agonists). In order to strengthen anti-OX40 therapy, three strategies have proved to be successful: (1) increasing antigen release (through surgery, radiotherapy, chemotherapy and vaccination), (2) adoptive T-cell therapy and (3) tackling immunosuppression (see for example, Tables 3A-B at pages 56-62). These strategies can be overlapping (for example, cyclophosphamide is a chemotherapy killing cancer cells, but is also known to induce Treg suppression). Because OX40 signalling strongly extends the survival of antigen activated CD8+ and CD4+ T-cells (which is reasonably held to read on the result of immunomodulation as recited in instant claim 18 given the lack of a closed definition of the term ‘immunomodulation’ and the guidance that the immunomodulatory molecule may be OX40L expressed on the surface of an exosome which enhances or inhibits an immune response (see paragraphs 0054-0055 of the instant specification)), therapies that increase the antigenic release/load can synergize with agonistic anti-OX40/OX40 binding OX40L. Therefore anti-OX40/OX40L can act as an adjuvant to an endogenic vaccination (surgery, radiotherapy, chemotherapy) or exogenic vaccination (see for example, section 6 at pages 62-63 of Aspeslagh et al). Aspeslagh et al teach that one study successfully examined the effect of OX40L-Fc in combination with chemotherapy and vaccination in a glioma model. For example, for adoptive T-cell therapy, it was shown that anti-OX40 mAbs prolong life of the transferred T-cells. In addition, a suppressive action on Tregs (through Treg depletion or diminution of Treg suppression) by anti-OX40 could enhance the survival of CD4+ and CD8+ T effectors. Combining strategies to counteract all kinds of immunosuppression with anti-OX40 mAbs resulted in dramatic synergistic effects against disseminated malignancies. In an established ovarian cancer model, combined anti-PD1/OX40 mAbs treatment markedly increased survival resulting in half of the mice being tumour free at 90 days. Similarly, combined intra-tumoural injections with a combination of a TLR9 agonist (CpG), anti-CTLA4 and anti-OX40 mAbs lead to tumour regression through Treg depletion even in cases of brain tumour deposits (see for example, sections 6-8 and table 4 at pages 62-64 of Aspeslagh et al).
While the teachings of Aspeslagh et al teach a fusion of co-administration (motivating the synergistic combination of OX40L (OX40 agonist) and a checkpoint therapy such as an anti-CTLA4 antibody), Aspeslagh et al do not teach the use of an exosome engineered to express OX40L on its surface and does not clearly teach transfection of an-exosome-producing cell as a means for producing exosomes which express a given molecule (such as OX40L) on their surface.
However, Johnsen et al teach that exosomes are endogenous nanocarriers mediating intercellular communication which are often characterized by cancer-associated changes. Their endogenous origin makes exosomes advantageous as drug carriers/vehicles for cancer treatment (see for example, the abstract). Moreover, methods of engineering exosomes to express a given molecule appear to be well known in the art (see for example, the graphical abstract at page 2/43 showing the use of a vector to produce drug-loaded exosomes whereupon the drug appears to be surface-expressed on the exosome). In recent years, several studies have highlighted situations, in which an exosome-based drug delivery system has improved disease conditions, including studies performed on different cancer models (see for example, section 4 at exemplary pages 7/43-9/43). Successful delivery of substantial amounts of therapeutic cargo from exosomes highly depends on an efficient method of their loading. Johnsen et al further teach that the most common means of loading therapeutic cargo into exosomes is by transfecting the exosome donor cell to overexpress a certain gene product that the cell will package into the exosome lumen or membrane for secretion and further cites studies demonstrating successful use of this method, including studies transfecting HEK293 cells [known to be an epithelial cell/epithelial cell model] (see for example, table 2 and section 4.3.3 at pages 13/42-16/43). The use of a targeting peptide or protein is a requirement for targeted therapies, and thus must be present on the surfaces of exosomes for these to be relevant drug delivery vehicles, especially for applications in cancer treatment if chemotherapeutics with major adverse side effects are to be delivered. At the moment, a substantial amount of papers have been published with regard to using exosomes in drug delivery (see for example, section 4.4 and Table 3 at pages 17/43-18/43).
The combined references do not explicitly teach a step of screening the exosomes to confirm expression of OX40L at the surface.
However, Grasso et al teach a generic method to detect and identify the molecular profile of exosomes either derived from cultured cell lines or isolated from biofluids (see for example, the abstract. Noting that the step of screening is recited generically, any prior art method of screening is presumed to meet the limitation as drafted. Furthermore, the step of screening does not change the % of exosomes having OX40L surface expression, it merely confirms the expression obtained from the steps of transfecting the cell to produce exosomes having surface expressed OX40L. The method of Grasso, being generic by se of SPR, would only need to use OX40 (as taught by the combined prior art references) to determine OX40L as present or absent on the exosomal surface using otherwise commercial instruments/reagents as taught by Grasso et al (see for example, column 1 of age 5426).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al would have realized and found obvious that the combination of OX40L (as a functional equivalent of the anti-OX40 agonist of the prior art) and other known anti-cancer therapies such as an anti-PD-L1 antibody, anti-CTLA-4 antibody, and/or adoptive T cell therapy act synergistically to enhance treatment, enhance the immune response to cancer, and to evade/overcome primary and secondary resistance to any of the treatments as monotherapies (noting additionally that OX40L activated a greater variety of immune cells in the tumor bed as compared to anti-OX40 treatment [see for example, the discussion of Aspeslagh er al above]). The MPEP provides that it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to swap an Fc-OX40L fusion for an OX40L molecule where the required function is simply to bind OX40 in an agonistic manner (see MPEP sections 2143(I)(B) and 2144.06 (II)).Where the prior art references teach and make obvious the use of OX40L for enhancing OX40 signalling, the artisan would have understood that the antigen binding portion of Ox40L is what is required to achieve said function and would have understood that any means known in the art for delivering said portion to OX40 would have been expected to predictably function with respect to OX40-signalling. Thus, where the prior art references make obvious the use of exosomes as delivery vehicles where OX40L is expressed on the surface of the exosome by means known in the art (such as those taught by Johnsen et al) to allow for the exosomal OX40L to bind to OX40 to enhance OX40 signalling which is known to be beneficial for cancer therapy, modification of the prior art to arrive at an exosome expressing surface-level OX40L without the Fc portion would have been obvious to the artisan as of the effective filing date. Note that, with regard to step b, the screening step does nothing to alter the percentage of exosomes expressing OX40L, but merely confirms the percent of exosomes expressing surface OX40L as obtained by upstream active steps. Where the combined prior art references make obvious the steps of transfecting a mesenchymal, dendritic, or epithelial cell to produce an exosome with surface-expressed OX40-L and the art is silent as to the percent of cells expressing the surface level OX40L, the art, making obvious the claimed steps, is presumed to make obvious the results of practicing the method resulting from the combined prior art. Where the combined prior art makes obvious transfection of cells to produce exosomes that express OX40L to treat cancer, the artisan would have found it obvious to optimize the percentage of exosomes expressing the OX40L for treating cancer and would have found it obvious to use a prior art screening method, such as the generic method taught by Grasso et al, to screen for OX40L to have more of the exosomes contemplated to be therapeutic for administration in the method of treating cancer. The artisan would have been motivated to screen the exosomes for OX40L expression as a basic quality control measure (to ensure the exosomes produced expressed surface OX40L as intended) because Aspeslagh et al and Johnsen et al motivate production of OX40L-expressing exosomes such that confirming and optimizing the amount of OX40L-expressing exosomes produced would have obviously been desirable before the effective filing date of the instant invention. There is no reason made of record to doubt that the prior art method would result in at least 50% of the resulting exosomes expressing OX40L. Additionally, the limitation of claim 73 that the transfected cells exhibit a 5000-fold increase in OX40L expression relative to non-transfected cells represents a passively obtained result flowing from practicing the active steps using the components made obvious by the cited prior art. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 18, as discussed in the rejection of claim 17 above, because OX40 signalling (which is promoted by the OX40L of the composition administered in claim 18, from which claim 18 depends) strongly extends the survival of antigen activated CD8+ and CD4+ T-cells, practicing the method of claim 17 is deemed to cause immunomodulation in the patient to whom the composition is administered (where it is noted that no closed definition of the term ‘immunomodulation’ is provided, but the disclosure does provide guidance that the immunomodulatory molecule may be OX40L expressed on the surface of an exosome which enhances or inhibits an immune response (see paragraphs 0054-0055 of the instant specification)). Thus, claim 18 recited a result flowing from practicing the method of claim 17 and is made obvious for the reasons that claim 17 is rendered obvious by the cited prior art combination.
Further regarding claims 22 and 70, Johnsen et al further teach and discuss studies where the exosomes, in addition to containing large amounts of let-7a, also were endowed with a targeting peptide to facilitate efficient delivery after intravenous injection (see for example section 4.3.3 at pages 16/43-17/43 and note also that Table 4 at pages19/43-20/43 teaches other methods of administration and dosing, including intravenous, oral, intratumoral, intraperitoneal, intraventricular, subcutaneous, and intranasal). Note that doses and dosage regimens are result effective variables. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). As both doses and dosage regimens were known to the ordinary artisan, it would have been obvious to optimize both the dosages and dosage regimens, including the particular dosing/dosing ranges and timing of dosing recited in the claims to treat cancer by administering known cancer agents through known means/methods/routes. It is not inventive to discover the optimum or workable ranges by routine experimentation, In re Aller, 220 F.2d 454, 456 (CCPA; see also In re Peterson, 315, F.3D, 1325 (Fed. Cir. 2003).
Only if the results of optimizing a variable are unexpectedly good can a patent be obtained for the claimed critical ranges, In re Geisler, 116 F.3d 1465, 1469, (Fed. Cir. 1997) quoiting in re Antoine, 559 F.2d 618, 620 (CCPA 1977) (Discovery for an optimum value or a result effective variable in a known process is ordinarily with the skill of the art. In re Boesch 617 F,2d 272, 276 (CCPA 1980)).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al and Johnsen et al. The artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al and Johnsen et al teach that exosomes are useful, particularly in combination, in treating cancer and Johnsen et al support that intravenous injection (as well as the modalities listed in table 4) is a known and predictable means of administration (said administration being required to bring about the therapeutic effects from the exosomes). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 23-24, as discussed above, the efficacy of anti-OX40/OX40L-Fc therapy against larger tumours or metastases such as naturally-occurring, in vivo cancer is less than desirable. Different modalities of treatment combinations have been attempted to overcome resistance to anti-OX40 molecules. In order to strengthen anti-OX40 (such as OX40L) therapy, three strategies have proved to be successful: (1) increasing antigen release (through surgery, radiotherapy, chemotherapy and vaccination), (2) adoptive T-cell therapy and (3) tackling immunosuppression (see for example, Tables 3A-B at pages 56-62 of Aspeslagh et al). Anti-OX40/OX40L can act as an adjuvant to an endogenic vaccination (surgery, radiotherapy, chemotherapy) or exogenic vaccination (see for example, section 6 at pages 62-63 of Aspeslagh et al).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al teach that surgery, radiotherapy, chemotherapy and vaccination are therapies that increase antigen release/load and that therapies that increase the antigenic release/load can synergize with agonistic anti-OX40/OX40 binding OX40L. The artisan looking to enhance OX40L therapy through synergistic increase in antigenic release/load would have found it obvious to use one of the enumerated options in conjunction with the therapy of instant claim 17 where the surgery, radiotherapy, chemotherapy is the second therapy as recited in instant claims 23-34. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 27, note that while Johnsen et al teach that there may be motivation to develop non-autologous exosomes, Johnsen et al teach that autologous exosomes are commonly used in the art (suggesting that use of autologous exosomes is most enabled/suggested in the art and more obvious to use with ease given the present state of the art (see for example section 6 of Johnsen et al at exemplary pages 24/43-25/43)).
Regarding claim 69, as discussed above, Johnsen et al teach that exosomes are endogenous nanocarriers mediating intercellular communication which are often characterized by cancer-associated changes. Their endogenous origin makes exosomes advantageous as drug carriers/vehicles for cancer treatment (see for example, the abstract and section 1 at pages 2/43-3/43). Moreover, methods of engineering exosomes to express a given molecule appear to be well known in the art (see for example, the graphical abstract at page 2/43 showing the use of a vector to produce drug-loaded exosomes whereupon the drug appears to be surface-expressed on the exosome). In recent years, several studies have highlighted situations, in which an exosome-based drug delivery system has improved disease conditions, including studies performed on different cancer models (see for example, section 4 at exemplary pages 7/43-9/43). Successful delivery of substantial amounts of therapeutic cargo from exosomes highly depends on an efficient method of their loading. Johnsen et al further teach that the most common means of loading therapeutic cargo into exosomes is by transfecting the exosome donor cell to overexpress a certain gene product that the cell will package into the exosome lumen or membrane for secretion and further cites studies demonstrating successful use of this method, including studies transfecting HEK293 cells [known to be a type of epithelial cells] (see for example, table 2 and section 4.3.3 at pages 13/42-16/43). The use of a targeting peptide or protein is a requirement for targeted therapies, and thus must be present on the surfaces of exosomes for these to be relevant drug delivery vehicles, especially for applications in cancer treatment if chemotherapeutics with major adverse side effects are to be delivered. At the moment, a substantial amount of papers have been published with regard to using exosomes in drug delivery (see for example, section 4.4 and Table 3 at pages 17/43-18/43). Johnsen et al further review therapeutic cargo loaded into exosomes, including anti-cancer cargo in supplemental table 1.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Johnsen et al teach that exosomes are natural and well validated drug-delivery vessels for cancer treatment, where different anti-cancer drug therapies have been validated as cargo. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 74, as discussed in the rejection of claim 17 above, the artisan would have been motivated to make and use the invention as claimed because Aspeslagh et al would have realized and found obvious that the combination of OX40L (as a functional equivalent of the anti-OX40 agonist of the prior art) and other known anti-cancer therapies such as an anti-PD-L1 antibody, anti-CTLA-4 antibody, and/or adoptive T cell therapy act synergistically to enhance treatment, enhance the immune response to cancer, and to evade/overcome primary and secondary resistance to any of the treatments as monotherapies
Claims 71-72 are rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al, Johnsen et al (citing Alvarez-Erviti et al), and Grasso et al as applied to claims 17, 18, 22-24, 27, 69-70, and 73-74 above, in further view of Frederick et al (US20180369374 A1; as cited in the Final Office Action dated 11/13/2024).
Aspeslagh et al, Johnsen et al, and Grasso et al teach the method of claim 17, but do not explicitly teach the use of an antimicrobial agent.
Regarding claims 71-72, Frederick et al teach mRNA combination therapy for cancer wherein, in some embodiments, a polynucleotide of any of the combination therapies disclosed herein, e.g., an mRNA encoding an immune response primer polypeptide, an mRNA encoding an immune response co-stimulatory signal polypeptide, an mRNA encoding a checkpoint inhibitor polypeptide, or a combination thereof, can be formulated in exosomes. The exosomes can be loaded with at least one polynucleotide and delivered to cells, tissues and/or organisms (see for example, the abstract and paragraph 3457). Frederick also teaches pharmaceutical compositions suitable for administration to subjects (needed to effect the methods of treatment further disclosed in Frederick et al (see for example paragraph 2813)).
Frederick et al further teach a formulation comprising a polynucleotide, a carrier, an excipient, and a delivery agent (see for example, paragraph 0457), wherein the excipient may be a preservative (see for example, paragraph 0497), which may be an antimicrobial preservative such as benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal (see for example, paragraph 3477).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al, Johnsen et al (citing Alvarez-Erviti et al), Grasso et al, and Frederick et al. The artisan would have been motivated to make and use the invention as claimed because Frederick et al teach that this would be therapeutically function and would be effective as an excipient in such a formulation for administration. Deciding upon which agent to use would be mere routine optimization of the formulation (see MPEP section 2144 (II)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Aspeslagh et al, Johnsen et al (citing Alvarez-Erviti et al), and Grasso et al as applied to claims 17, 18, 22-24, 27, 69-70, and 73-74 above, in further view of Kamerkar et al (Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017 Jun 22;546(7659):498-503; as cited in the Final Office Action dated 11/13/2024).
Regarding claim 67, as discussed above, Aspeslagh et al, Johnsen et al, and Grasso et al teach the method of instant claim 17.
The combined references do not explicitly teach that the exosomes expresses CD47 on their surface.
However, Kamerkar et al further teach that their results support that the presence of CD47 on exosomes allows for evasion from phagocytosis by the circulating monocytes and increases exosomal half-life in the circulation (see for example, paragraph 2 of the discussion at page 11/41).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Aspeslagh et al, Johnsen et al (citing Alvarez-Erviti et al), and Grasso et al in view of Kamerkar et al. The artisan would have been motivated to make and use the invention as claimed in order to prolong/enhance the half-life/longevity of the exosomes as taught by Kamerkar et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues that the claims for treating any and all cancers are enabled. Applicant asserts that their data and teachings are not limited to melanoma citing to points in the specification where the definition of cancer is much broader and stating their data is not to be construed as conveying a desire to be limited to melanoma treatment, but should be understood as proof-of-concept data (see pages 5-6 of the remarks dated 04/17/2026). Applicant cites to Sharma and Allison (exhibit A) and Shama (Exhibit B) along with 4 clinical trials as enabling the claimed scope of cancer treatment (see pages 7-8 of the remarks dated 04/17/2026).
Response: The Examiner agrees that Applicant did not wish to be limited to treatment of melanoma and concedes that the specification provides a much broader definition of cancer. The concern regarding enablement is not what Applicant wishes to claim, but what scope of the claim Applicant has shown enablement for, such as by proof of concept data. Likewise, Applicant notes that the mechanism (via T cell function/action) would operate the same throughout all cancers. As cancers are highly heterogenous, this cannot be taken as a given premise without proof. However, even this argument fails to address the concern noted in the enablement rejection. The concern is not merely whether the mechanism is the same across cancers, but whether that mechanism (T cell function/action) would be sufficiently therapeutic so as to treat all cancers. Again, Applicant has only demonstrated proof-of-concept of treatment in a melanoma model. As cancers are highly heterogenous and their treatment is unpredictable with no single, universal cure, the prior art cannot step in to supply enablement where the instant Applicant has failed to enable the full scope of what is claimed. Applicant argues that Sharma and Allison (Exhibit A) teach that immune checkpoint therapy targets T cells, not the tumor itself “perhaps even without specific knowledge of the antigenic targets of those responses or even the type of cancer.” A suggestion that, perhaps, the T cell is targeted without specific knowledge of the antigenic targets of those responses or even the type of cancer is insufficient to provide enablement as it does not show that immune checkpoint therapy treats all cancers. Even if this were shown, it would not suffice to show immune checkpoint therapy and administration of the claimed exosomes would still function to treat all cancers (as the effect of the exosomes on the immune checkpoint therapy have not been shown across all cancers). Furthermore, the claims are not drafted to require immune checkpoint therapy. Note that claim 17 could have adoptive T cell therapy and the exosomes being the only administered agents. Similarly, the teaching of Sharma and Allison that OX40 is an immune pathway involved in T-cell regulation is insufficient to enable treatment of all cancers and does not overcome the art cited in the rejection under 35 USC 112(a) (Malacards) showing that the OX40/OX40L pathway is only present or understood to be involved in a limited number of cancers. Therefore, this is unpersuasive to overcome the rejections for lack of enablement. Applicant then discusses the teachings of Sharma that the therapeutic efficacy of an anti-CTLA4 “was not limited to a single tumor model”. This is not evidence that the anti-CTLA4 was effective for all cancers or even a representative number of cancers. Additionally, it is not clear what effect the administration of the claimed exosomes would have on the therapeutic efficacy of administering an anti-CTLA4. Notably, the claims are not drafted to require administration of an anti-CTLA4, as that is only one option listed in the alternative to be co-administered with the claimed exosomes. Further still, Sharma was first published in 2023, after the effective filing date (09/11/2020), and is therefore not available as art to support enablement. Likewise, the 4 clinical trials Applicant discusses are dated 2026, which is well after the effective filing date of the instant Application, rending them unavailable as prior art regarding support of enablement. The MPEP provides that:
“The state of the art existing at the filing date of the application is used to determine whether a particular disclosure is enabling as of the filing date. Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004) (Stating that “a patent document cannot enable technology that arises after the date of application.”). Information published for the first time after the filing date generally cannot be used to show what was known at the time of filing. In reGunn, 537 F.2d 1123, 1128, 190 USPQ 402,405-06 (CCPA 1976); In re Budnick, 537 F.2d 535, 538, 190 USPQ 422, 424 (CCPA 1976) (In general, if an applicant seeks to use a patent to prove the state of the art for the purpose of the enablement requirement, the patent must have an issue date earlier than the effective filing date of the application.),”
(see MPEP §2164.05(a)). Applicant discusses the legal standard citing MPEP §2164 that only a ‘general quality’ running through the class must be disclosed for enablement. Presently, no general quality running through all cancers so as to have a predictably therapeutic effect has been convincingly evidenced on the record so as to meet the required disclosure for enablement. Therefore, Applicant’s arguments and cited art are unpersuasive to overcome the rejections for lack of enablement and said rejections are maintained at this time.
B. Applicant argues that the prior art does not make obvious an exosome expressing surface OX40L and articulates differences between the prior art Fc-OX40L fusion and the OX40L molecule (see for example, pages 10-11 of the 04/17/2026 remarks). Applicant alleges the combination of Aspeslagh and Johnsen is not obvious, but is the result of hindsight bias (see for example, page 11 of the 04/17/2026 remarks). Applicant then alleges surprising results, but does not articulate what result is considered surprising or why (see for example, page 12 of the 04/17/2026 remarks). Applicant, again, cites to Luo et al as showing unpredictability so as to overcome the rejections under 35 USC 103 (see for example, page 12 of the 04/17/2026 remarks).
Response: As discussed above, the prior art makes obvious an exosome with surface-expressed OX40L because OX40L is a functional equivalent for the prior art fusion or agonistic anti-OX40 because the required function is to bind OX40 to promote OX40 signalling and its therapeutic effect for cancer treatment, as taught and made obvious by the prior art. Because there is no reason to expect that the OX40L molecule and the prior art fusion would not both function to bind and agonize OX40, this argument is unpersuasive because the fusion and the molecule are functional equivalents until an evidenced and sufficient showing to the contrary is presented in rebuttal. There is nothing in Aspeslagh et al to suggest that the therapeutic effect of the anti-OX40 or Fc-OX40L fusion is effected through or by the Fc portion. Rather Aspeslagh et al discuss that the agonistic binding to OX40 is the therapeutic aspect. Where the Examiner has articulated rationale motivating the combination of the prior art references as relied upon in the rejections (here, Aspeslagh and Johnsen) a mere allegation of hindsight is insufficient to rebut the presumption of obviousness iterated in the rejections of record. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Applicant then argues, citing to Luo et al (ACS Nano. 2025 Feb 11;19(5):5193-5216. doi: 10.1021/acsnano.4c09688. Epub 2025 Jan 27), that it is surprising to arrive at 50% of exosomes expressing OX40L because Luo et al show that not every immunomodulatory molecule expressed in a cell will produce more than 50% of exosomes expressing an immunomodulatory molecule. This is unpersuasive. The cited portion of Luo et al does nothing to dispute motivation to optimize purity and expression of exosomes collected and does not show that said expression is unpredictable when the immunomodulatory molecule is OX40L. This does nothing to suggest unpredictability in the state of the art nor does it suggest that the method made obvious by the cited prior art would not result in the same expression yield. The prior art makes obvious the production and use of an exosome with surface-expressed OX40L, where the result of 50% of exosomes expressing surface-OX40L is inherent (a result naturally flowing from the claimed active steps using the claimed products) to the obvious method. The cited portion of Luo et al essentially compares apples and oranges and is not deemed sufficient to support a surprising/critical result or to persuasively dispute enablement/predictability of the methods of the prior art to achieve what appear to be inherent, passively achieved results flowing naturally from the active steps of the claimed method. It is further noted that the claims must be commensurate in scope with surprising/critical results in order to overcome a rejection under 35 USC §103. While such as result is not conceded, it is noted that Luo et al also only transfect HEK293T cells. Therefore, the claims which transfect a wider variety of cells types, would not be commensurate in scope with what Applicant alleges and argues to be surprising. There being no convincing, evidenced argument, the rejections are maintained.
C. Applicant argues that the amendment to claim 17, requiring an active step of screening to confirm that at least 50% of the exosomes comprise an OX40L molecule on their surface, was not addressed in the prior art rejections presented in the previous office action. This argument is further applied as rationale for withdrawal of all of the pending rejections under 35 USC §103.
Response: The Examiner notes that this active step was not required by the claim as drafted at the time of the previous examination and directs Applicant to review the rejections as modified to address this newly added limitation. The rejections under 35 USC §103 as presented in this Office Action are maintained and deemed to meet the claims as drafted at present.
Conclusion
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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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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