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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 18 November 2025 has been entered.
Status of Application, Amendments and/or Claims
The amendment of 18 November 2025 has been entered in full. Claims 1 and 11 are amended. Claims 8-10 and 18-20 are cancelled.
Claims 1-7 and 11-17 are under consideration in the instant application.
Withdrawn Objections and/or Rejections
1. The rejection of claims 1-7 and 11-17 under 35 U.S.C. 102(a)(2) as being anticipated by Xu et al. (US 2020/0264185) as set forth at pages 4-5 of the previous Office Action of 27 August 2025 is withdrawn in view of amended independent claims 1 and 11 (18 November 2025). Markers PD-L1 and PD-1 have been deleted from the claims and Xu et al. do not teach identifying extracellular vesicles in a sample from a mammal having cancer, wherein said sample comprises a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2.
Claim Rejections - 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.
1. Claims 11-17 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.
1a. Claims 11-17 are rejected as being indefinite because claim 11, lines 2-4 are confusing (see “a mammal identified as having extracellular vesicles (EVs) in a sample from said mammal, that comprises a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2…”). For example, it is not clear what element in the claim comprises reduced levels of checkpoint polypeptides—the sample or the EVs? One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Please note that this issue could be overcome by amending claim 11 to recite, for example:
Claim 11. A method for treating a mammal having cancer, wherein said method comprises administering a cancer treatment to a mammal that is identified as having cancer based on obtained from said mammal[,] that comprises extracellular vesicles (EVs) comprising a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2, and wherein said cancer treatment is selected from the group consisting of surgery, radiation therapy, chemotherapy, tumor treating fields (TTF) therapy, targeted therapy, hormone therapy, angiogenesis inhibitor therapy, tumor vaccination, checkpoint blockade therapy, and any combination thereof.
Claim Rejections - 35 USC § 112(a)
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.
2. Claims 1-7 and 11-17 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 a method for treating a mammal having glioblastoma, wherein said method comprises: (a) identifying extracellular vesicles (EVs) in a sample from said mammal as comprising a reduced level of one or more cell cycle checkpoint polypeptides selected from CD28 and CD278; and
(b) administering a cancer treatment to said mammal, wherein said cancer treatment is selected from the group consisting of surgery, radiation therapy, chemotherapy, tumor treating fields (TTF) therapy, targeted therapy, hormone therapy, angiogenesis inhibitor therapy, tumor vaccination, checkpoint blockade therapy, and any combination thereof, does not reasonably provide enablement for a method for treating a mammal having cancer, wherein said method comprises:
(a) identifying extracellular vesicles (EVs) in a sample from said mammal as comprising a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2; and
(b) administering a cancer treatment to said mammal.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1, in its entirety, is directed to a method for treating a mammal having cancer, wherein said method comprises:
(a) identifying extracellular vesicles (EVs) in a sample from said mammal as comprising a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2; and
(b) administering a cancer treatment to said mammal, wherein said cancer treatment is selected from the group consisting of surgery, radiation therapy, chemotherapy, tumor treating fields (TTF) therapy, targeted therapy, hormone therapy, angiogenesis inhibitor therapy, tumor vaccination, checkpoint blockade therapy, and any combination thereof.
Claim 11 recites a method for treating a mammal having cancer, wherein said method comprises administering a cancer treatment to a mammal identified as having extracellular vesicles (EVs) in a sample from said mammal, that comprises a reduced level of one or more cell cycle checkpoint polypeptides selected from the group consisting of CD28, CTLA-4, CD278, and PD-L2, and wherein said cancer treatment is selected from the group consisting of surgery, radiation therapy, chemotherapy, tumor treating fields (TTF) therapy, targeted therapy, hormone therapy, angiogenesis inhibitor therapy, tumor vaccination, checkpoint blockade therapy, and any combination thereof.
The specification of the instant application teaches that as demonstrated herein, density gradient ultracentifugation (DGU) can be used to isolate a pure exosome population from normal donors’ and glioblastoma (GBM) patients’ plasma (page 2, lines 20-21). The specification continues to disclose that plasma exosomes from GBM patients have a distinct cargo from healthy donors (page 2, lines 22-23). The specification indicates that GBM patient exosomes have tumor-specific cargo such as tumor antigens (IDH1) and reduced immunomodulatory molecules (IFN-γ, IL-10, IL-13, B7-1 (CD80), B7-2 (CD86), and ICOSL) (page 2, lines 23-26; page 18, lines 25-32; Figures 5A-5C, 6). Regarding cell cycle checkpoint polypeptides, the specification teaches that plasma exosomes from GBM patients show a decreased concentration of CD80, PD-L1, CD86, and ICOSL in comparison to normal donors (page 7, lines 11-15; page 19, lines 4-13; Figures 7A-7D). At page 20, Table 2 also shows a decreased concentration of CD28 and CD278 in plasma exosomes from GBM patients. Table 2 demonstrates that CTLA-4 does not seem to be expressed on plasma exosomes from GBM patients or normal donors as there is “0” measured. Lastly, Table 2 actually indicates that PD-L2 is increased in plasma exosomes from GBM, which is in opposite of the limitations as presently claimed in independent claims 1 and 11.
The instant claims broadly recite that extracellular vesicles (EVs) in a sample from a mammal having any possible cancer are identified by having reduced levels of one or more cell cycle checkpoint polypeptides, CD28, CTLA-4, CD278, and PD-L2, and then a cancer treatment is administered. However, the instant specification is silent regarding a nexus or association between reduced levels of CD28, CTLA-4, CD278, or PD-L2 in EVs and all possible cancers. The specification only teaches a decreased concentration of CD28 and CD278 in plasma exosomes from glioblastoma patients (page 20, Table 2).The specification does not teach any methods or working examples that indicate reduced levels of CD28, CTLA-4, CD278, or PD-L2 in extracellular vesicles are indicative of all possible cancers. Thus, the skilled artisan must resort to trial and error experimentation to determine a nexus between reduced levels of CD28, CTLA-4, CD278, and PD-L2 in EVs in all cancers and then administer a cancer treatment to treat the cancer. Such experimentation is considered undue.
Applicant is reminded that a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). The present invention is unpredictable and complex because extracellular vesicles, such as exosomes, have been shown to have diverse protein expression patterns indicative of different cancers and non-malignant diseases (see Mosquera-Heredia et al. Biomedicines 9: 1061, 2021 (Table 2 and pages 14-19);; Shen et al. Mol Biomed 1: 3, 2020 (Table 1);; entirety of Delshad et al. Biomolecules 15: 587, 2025). In other words, a reduction in extracellular vesicle expression levels of CD28, CTLA-4, CD278, and/or PD-L2 (as recited in the instant claims) may not be associated with all possible cancers (i.e., one pattern does not fit all). For example, extracellular vesicles comprising elevated levels of PD-L2 are actually found to be associated with triple negative breast cancer patients at a high risk for relapse (Hoffman et al., J Cancer Res Clin Oncol 149: 1159-1174, 2023; abstract; page 1166; page 1168). Additionally, one skilled in the art would not be able to predict that CTLA-4 and PD-L2 are reduced on EVs from a mammal having any cancer because the specification clearly demonstrates that CTLA-4 is not even expressed on plasma exosomes from GBM patients or normal donors and PD-L2 is increased in plasma exosomes from GBM (see Table 2 of specification).
Thus, one skilled in the art would not be able to predictably rely upon the detection of reduced levels of one or more cell cycle checkpoint polypeptides selected from CD28, CTLA-4, CD278, and PD-L2 to successfully identify extracellular vesicles in a sample from a mammal with all possible cancers. The teachings of the specification of decreased concentrations of CD28 and CD278 in plasma exosomes from GBM patients are not adequate guidance for the breadth of the instant claims, but are merely an invitation to the artisan to use the current invention as a starting point for further experimentation. The courts have stated that patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be patentable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 (1997).
Due to the large quantity of experimentation necessary to determine a nexus between reduced levels of CD28, CTLA-4, CD278, and PD-L2 in extracellular vesicles in all cancers and then administer a cancer treatment to treat the cancer; the lack of direction/guidance presented in the specification regarding the same; the lack of working example; the complex nature of the invention; the state of the art (see Mosquera-Heredia et al., Shen et al., Delshad et al., Hoffmann et al., above); and the unpredictability of detecting reduced levels of one or more cell cycle checkpoint polypeptides selected from CD28, CTLA-4, CD278, and PD-L2 in extracellular vesicles from a sample obtained from a mammal with any possible cancer, undue experimentation would be required of the skilled artisan to use the claimed invention.
Conclusion
Claims 1-7 and 11-17 are rejected.
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BEB
Art Unit 1647
24 November 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647