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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-16) in the reply filed on 10/11/2025 is acknowledged.
Claims 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/11/2025.
Claims 1-16 are under consideration in this office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16 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 the following:
A method of imparting an immune response against a tumor in a subject, the method comprising: (a) subjecting tumor cells from the subject to non-thermal plasma to induce immunogenic cell death (ICD) in said tumor cells, thereby producing tumor cells undergoing ICD; and (b) administering the tumor cells undergoing ICD to the tumor in said subject to impart an immune response against said tumor, wherein said immune response reduces tumor volume in said subject.
The specification does not reasonably provide enablement for the following:
1) a method of vaccinating a subject against cancer wherein said vaccinating prevents cancer forming in a subject;
2) the claimed method that uses any type of cell and pretreats it with any type of plasma;
3) a method of vaccinating a subject with a tumor results in any other phenotype than reducing tumor volume.
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.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: The application describes the use of plasma to induces immunogenic cell death in cancer cells that facilitates an immune response against cancer cells in a subject. The method of the claims use this concept to develop a cancer vaccine.
Breadth of the Claims: Independent claim 1 is the broadest claim, generically reciting “a method of vaccinating a subject against cancer”. Vaccinating against a cancer broadly encompasses a preventative vaccination method that protects a subject not having cancer from getting it. Vaccinating against cancer also encompasses a therapeutic method of administering a vaccine to a subject with cancer and eliminating or reducing the cancer in the subject.
The method steps generically recite “treating a cell with plasma”. The breadth of the treating step is applying any type of plasma to any healthy cell, non-healthy cell, or cancerous or non-cancerous tumor cell. Although the specification describes the term, “plasma” in terms of one of the physical states of matter, the specification does not define or limit the term as such. As such, the breadth of plasma can include blood plasma. Other types of plasma include but are not limited to non-thermal plasma, cold atmospheric plasma, dielectric barrier discharge treatment, among others. Step b reciting incubating the cell for a sufficient time to produce a vaccine. The nature of the vaccine is not defined. As such, the vaccine can be any type of agent that can elicit some type of immune response. The method further specifies inoculating the subject with the vaccine provided in step b. The method does not specify how the subject is inoculated. Thus the vaccine can be administered to the subject by any means. The claims do not further specify particular result that occurs by inoculating with the vaccine. As such, the breadth of the claims encompass inoculating with the vaccine and getting any response or no response at all. As such, the claims are quite broad.
Specification Guidance: The specification provides the following guidance (citations from the Pre-Grant Publication):
[0004] Non-thermal atmospheric plasma jets (APPJ) based on dielectric barrier discharge (DBD) have attracted considerable interest in the recent decades [1-3]. Multiple research groups have studied these plasma sources for various applications like surface modification [5, 6], decontamination [6-9], cancer treatment [10-12], including plasma-induced immunotherapy and direct tumor ablation.
[0007] Immunogenic cell death is characterized by the emission of danger signals that facilitate activation of an adaptive immune response against dead-cell antigens. In the case of cancer therapy, tumor cells undergoing immunogenic death promote cancer-specific immunity. Identification, characterization, and optimization of stimuli that induce immunogenic cancer cell death has tremendous potential to improve the outcomes of cancer therapy.
[0010] The potential of NTP to induce immunogenic cancer cell death is only recently being explored. Bekeschus, et al. has demonstrated that NTP treatment of two murine cell lines in vitro, the B 16F10 melanoma cells and the CT26 colorectal cancer cells, increased immunogenic cell surface molecules such as major histocompatibility complex I (MHC-I) and surface exposed calreticulin (ecto-CRT). [56-57] We have reported successful in vitro ICD induction in two human cell lines, a radiation resistant primary nasopharyngeal carcinoma cell line (CNE-1) and the A549 lung carcinoma cell line in response to NTP exposure. [58-59]
[0079] Non-thermal, atmospheric pressure plasma can be operated to induce immunogenic cell death in an animal model of colorectal cancer. In vitro, plasma treatment of CT26 colorectal cancer cells induced the release of classic danger signals. Treated cells were used to create a whole-cell vaccine which elicited protective immunity in the CT26 tumor mouse model. Moreover, plasma treatment of subcutaneous tumors elicited emission of danger signals and recruitment of antigen presenting cells into tumors. An increase in T cell responses targeting the colorectal cancer-specific antigen guanylyl cyclase C (GUCY2C) were also observed. This is evidence that non-thermal plasma induces immunogenic cell death and highlights its potential for clinical translation for cancer immunotherapy.
[0080] In these examples, the CT26 murine colorectal tumor model was used to explore the potential of NTP to induce ICD in vivo. NTP generated by a nanosecond-pulsed dielectric barrier discharge (nspDBD) plasma system induced the expression of two key surrogate markers of ICD in these cancer cells: ecto-calreticuline (ecto-CRT) and secreted adenosine triphosphate (ATP). A vaccination assay, used to determine if a stimulus is an ICD inducer, showed partial protective immunity against tumor challenge in syngeneic Balb/c mice immunized with NTP treated CT26 cells. Furthermore, treatment of subcutaneous colorectal tumors expressing the cancer antigen guanylyl cyclase C (GUCY2C) resulted in higher expression of ICD markers in tumors, recruitment of antigen presenting cells (APCs), and generation of more GUCY2C-specific T cells. This establishes that plasma may be used for cancer immunotherapy via ICD.
Working Examples:
Vaccination with Plasma-Induced ICD Cells Provides Protection Against Tumor Challenge in Mice
[0098] To ascertain whether the DAMP signals elicited by plasma could enhance immune responses against cancer, a vaccination assay was performed. Balb/c mice were immunized with CT26 cells treated in vitro with plasma at the ICD-inducing regime (29 kV, 30 Hz, 1 mm gap distance, 10 seconds). Cells were prepared for inoculation and injected into the left flank as a whole-cell vaccine to allow an immune response to develop. One week after immunization, mice were challenged with live CT26 cancer cells on the opposite flank and tumor growth was monitored twice a week until day 26 when the study was terminated as a subset of the animals reached IACUC-approved endpoints (FIG. 8A). CT26 cells treated with media only or Cisplatin (50 μM for 24 hours), a non-ICD inducer, [60] were used as controls.
[0099] Challenge tumors in the media and Cisplatin groups grew rapidly while tumors in the plasma group developed relatively slowly (FIGS. 8B-8D). The mean tumor volume for the plasma immunized group was significantly smaller compared to that of the media group (414.7±104.3 mm.sup.3 vs 847.4±141.5 mm.sup.3; p<0.001) or the Cisplatin group (1041.8±208.3 mm.sup.3) at day 26 (FIG. 8E). Indeed, 90% of the mice in the plasma immunized group had tumor volumes smaller than the mean tumor volume of the media group (850 mm.sup.3), suggesting that these mice were partially protected by vaccination. Moreover, 3 out of the 10 mice in the plasma group did not develop subcutaneous tumors at the challenge site (FIG. 8F).
Thus while the specification provides specific guidance to treating cancer cells with non-thermal plasma that induces immunogenic cell death in the cancer cells and administering the treated cancer cells a subject comprising a tumor comprising untreated cancer cells, the specification does not provide any guidance to the treatment of any other cell type than cancer cells using any other plasma type other than non-thermal plasma. Further, the specification teaches that the cancer cells undergoing immunogenic cell death promotes cancer-specific immunity, providing a highly specific nexus between non-thermal plasma treatment of cancer cell and cancer-specific immunity. As such, the specification fails to provide any guidance to any other types of plasma treatment to any other types of cell that could function as a vaccine against cancer as claimed. Further, the specification provides no guidance to the use of the vaccination method as one that prevents cancer development in a health subject. Further, the specification and working examples teach that the plasma treated cell prepared by the claimed method fails to prevent the mouse from developing tumors, and only reduced the tumor volume size. As such, specification teaches that the claimed vaccination method fails to be against cancer in that it fails toprevents formation of cancer in a subject and only provides the therapeutic effect of reducing tumor volume in subjects given the vaccine. As such, the breadth of the claims lack enablement by the specification.
State of the Art: The state of the cancer vaccines art before the time of effective filing and continuing after the time of effective was highly unpredictable. Becker and Rathmell (J Clin Invest. 2025;135(13):e195673. https://doi.org/10.1172/JCI195673. Pp 1-4) report that while vaccine against viruses that cause cancer have been met with success, most cancers are not virally mediated. Becker and Rathmell report, “interventions such as the Bacillus Calmette-Guérin (BCG) vaccine acts as a nonspecific agent eliciting an immune reaction at the bladder mucosa applied in non-muscle invasive bladder cancer were developed and remain a standard of care today…. These and other early tools were limited, however, by the lack of antigen specificity. The discovery of tumor-specific antigens hailed a coming of-age for precision therapy by enabling cancer vaccines against proteins found specifically on cancer cells. Despite astounding safety profiles for cancer vaccines, first generation designs and the underestimation of cancer’s fierce resistance to an immune response resulted in a series of disappointing attempts to show substantial clinical response... Renewed hope for cancer vaccines rebounded with the approval of the first dendritic cell-based vaccine immunotherapy in 2011, known as sipuleucel-T. But enthusiasm was premature; sipuleucel-T can prolong survival in subsets of prostate cancer patients…, but the expense and modest extension in survival in individual patients limited the impact. Ultimately, what may create the largest opportunity for vaccine therapy to emerge as a game changer is the rise in immune checkpoint inhibitors (ICIs)…. ICIs function by tipping the delicate internal balance of CD8+ T cells from self-tolerance towards cancer elimination. ICIs are widely acclaimed for long-lasting responses that can occur in many cancer patients, which drives a population-level impact on outcome; however, individual responses are unpredictable and variable.” As such, while much promising research has forwarded the possibility for the use of vaccine to prevent and/or cancer, before the time of effective filing and continuing post-filing, cancer vaccine were highly unpredictable and vaccines that prevent cancer that is not mediated by cancer causing viruses had not been successfully produced.” See page 1. As such, the art at the time of effective filing and after teaches that cancer vaccines were not predictably able to prevent or treat cancer in a subject.
Before the time of effective two modalities were being used to apply low temperature plasma for potential use as a cancer treatment. The first was direct plasma application to cancer cells in vitro or in vivo on a orthotopic tumor in mice. The section applying plasma to media and then placing cancer cell in treated media or injecting treated media into orthotopic tumors in mice. Both modalities demonstrated positive anti-cancer capacity both in vitro and in vivo. Further, low temperature or cold plasma treatment was demonstrated to have a selective impact on cancer cell causing apoptosis in cancer cell lines but not normal cells (Yan et al. Oncotarget 8(9):15977-15995, 2017). Further research has demonstrated that plasma’s anti-cancer effects in impart due to induction of ICD in cancer cells and a stimulation of anti-tumor effects in macrophages (Lin et al. Plasma Process. Polym. 2015, 12, 1392–1399; Lin et al. Int. J. Mol. Sci. 2017, 18, 966; doi:10.3390/ijms18050966. Page 1-24).
Thus, the art before the effective filing date and after, fails to provide specific guidance to the use of plasma treated cells as a vaccine against cancer as claimed. Further it is noted that the selective nature of plasma treatment against normal cells bring into question to predictability of the use of any cell other than cancer cells in the claimed method because the art suggests plasma treatment did not impact normal cells.
Amount of Experimentation: While the state of the art and the present guidance by the specification provide promising research towards the possible development of a plasma-induced whole cell vaccine, significant discovery research would be needed to overcome the unpredictability of cancer vaccines taught in the art and that is not supplement by the teachings of the specification which teach that the plasma treated cancer cells failed to vaccinate against cancer as claimed. This level of experimentation goes beyond routine experimentation and thus would be undue.
In conclusion, the claims lack enablement for the full breadth of the claims because the specification sole provides much narrower guidance to a method of imparting an immune response against a tumor in a subject by treating cancer cells from the tumor with plasma to induce ICD and administering the plasma treated cancer cell to the tumor in the subject to reduce tumor volume and does not provide enabling guidance to the any immunity such as preventing cancer by vaccination using any plasma treated cells other than cancer cells from the subject and inoculating the subject in any way other than to the tumor. The state of the art before the time of effective filing fails to provide specific guidance to the embodiments not adequately described by the specification and further teaches unpredictability in developing such vaccines. As such, the art fails to supplement the shortcomings of the specification. Further, to enable the instant claims further experimentation would be needed to determine if a preventative and therapeutic vaccine could be achieved overcoming art described unpredictability. This level of experimentation goes beyond routines experimentation and thus would be considered undue.
Examiner’s Comment
Lin et al. (Int. J. Mol. Sci. 2017, 18, 966; doi:10.3390/ijms18050966. Page 1-24) is the closest prior art. Lin et al teaches treating cancer cell with plasma which induces ICD in the lung cancer cells facilitating anti-tumor activity (abstract). Lin et al states “These initial in vitro results have been expanded and validated in an in vivo study of murine colorectal cancer using the CT26 cell line (manuscript in preparation). Included is a vaccination assay, the “gold-standard” test that shows that plasma is a bone fide ICD-inducer…. Our results support the feasibility and clinical potential of plasma-induced ICD for cancer immunotherapy”. See page 12, last paragraph before section 4. As such, Lin et al suggests that future work involves using the findings for vaccine development using a vaccination assay. While suggestive of aspects of the claimed methods, Lin et al falls short of actually providing an enabling disclosure of the instant claims. As such, Lin et al is not prior art under 35 USC 102 or 103.
Lin et al 2015 discussed above is another close prior art. However there is no teaching or suggestion of vaccination against cancer.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632