DETAILED ACTION
Status of Claims
The amendment submitted October 14, 2025 has been entered.
Claims 1-20 are pending and under consideration.
Claims 2-3, 9-10, and 12-15 are amended.
Claims 1-20 are under consideration in the instant office action as explained below in the Election/Restriction section
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 the following species in the reply filed on October 14, 2025 is acknowledged.
Torin-2 and Ceralasertib (AZD6738) as species of ATR inhibitor.
Lung cancer as a species of tumor.
A platinum compound as a species of DNA replication stress inducing agent.
Abemaciclib as a species of CDK 4/6 inhibitor.
Olaparib as a species of PARP inhibitor.
HLM006474 as a species of E2F inhibitor.
Information Disclosure Statement
Three information disclosure statements (IDS) submitted on October 21, 2024; November 9, 2022 and July 29, 2022 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Abstract Objections
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract is less than 50 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
Claims 1-20 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation 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. See MPEP § 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors they relate to the pending claims follows.
Breadth of Claims and Nature of the Invention
Claims 1-16 are directed towards “A method of treating a tumor in a subject, comprising: delivering an ATR inhibitor to the tumor and applying a tumor treating field to the tumor a frequency between approximately 50kHz and approximately 1,000 kHz.”
Claim 2 is directed towards “wherein the ATR inhibitor is Torin-2, Ceralasertib.”
Claim 3 is directed towards “wherein the tumor comprises a lung cancer cell.”
Claims 4-7 are directed towards varying intensities, frequencies and dosing schedule of the tumor treating field.
Claims 8-11 are directed towards delivering DNA replication stress inducing agents.
Claims 12-15 comprise administering additional agents such as E2F inhibitors, CDK 4/6 inhibitors and PARP inhibitors.
Claims 16-17 are directed towards additionally delivering radiation therapy.
Claim 18 is directed towards “A method of preventing/reducing proliferation of a cell, comprising: delivering at least one DNA replication stress inducing agent to the cell, wherein the DNA replication stress inducing agent comprises an ATR inhibitor; and applying a tumor treating field to the cell at a frequency between approximately 50 kHz and approximately 1,000 kHz.”
Claims 19-20 are directed towards “A method of treating a tumor in a subject, comprising: delivering at least two DNA replication stress inducing agents to the tumor, wherein at least one of the DNA replication stress inducing agents comprises an ATR inhibitor; delivering a radiation therapy to the tumor; and applying tumor treating fields to the tumor at a frequency between approximately 50 kHz and approximately 1,000 kHz.”
On page 11, paragraph [0045] of Applicant’s specification, tumor is defined as “In certain embodiments, the tumor can include at least one of non-small cell lung cancer (NSCLC), pancreatic cancer, GBM, mesothelioma, pancreatic cancer, lung cancer, ovarian cancer, and cervical cancer. Any cancer of the head, thorax or abdomen is among the conditions that may be affected by the present disclosure. In one example, the tumor can include at least one a lung cancer cell, a breast cancer cell, a pancreatic cancer cell, a glioblastoma cell, a prostate cancer cell, a liver cancer cell, a fallopian tube cancer cell, a peritoneal cancer cell, a cervical cancer cell, a skin cancer cell, or an ovarian cancer cell.”
Cancer, including tumors is a broad class of heterogenous diseases for which there exists no general treatment or prevention. Hanahan explains that “there are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs” (Hanahan, Douglas, and Robert A. Weinberg. "The Hallmarks of Cancer." Cell 100, no. 1 (2000): 57-70).
The cancers cited are heterogenous and diverse in terms of origin, etiology, growth speed, molecular and genetic diversity, treatment plan, and disease progression.
Additional, tumors are not limited by Applicant to solely being cancerous.
The National Cancer Institute teaches that “Different body tissue types give rise to different tumors, both benign and malignant (“Tumor List,” National Cancer Institute SEER Training Modules, https://training.seer.cancer.gov/disease/categories/tumors.html, Accessed: February 13, 2026) and provides examples based on tissue, benign tumor and malignant tumors.
By example only, Johns Hopkins Medicine teaches that “There are more than 120 different types of brain tumors, lesions and cysts, which are differentiated by where they occur and what kinds of cells they are made of. Certain types of tumors are typically benign (noncancerous), while others are typically malignant (cancerous) (“Brain Tumor Types,” Johns Hopkins Medicine, https://www.hopkinsmedicine.org/health/conditions-and-diseases/brain-tumor/brain-tumor-types, Accessed: February 13, 2026).
Additionally, it is well-known that tumor heterogeneity is a challenge in cancer treatment.
El-Sayes teaches that “Despite great advances in cancer therapy, tumor heterogeneity continues to be a great barrier for the successful treatment of cancer. It has long been established that tumor heterogeneity is prevalent in most cancer patients and is a major driver of acquired resistance to all forms of cancer therapy (El-Sayes, Nader, Alyssa Vito, and Karen Mossman. "Tumor heterogeneity: a great barrier in the age of cancer immunotherapy." Cancers 13, no. 4 (2021): 806).”
El-Sayes also teaches that “Major challenges with universal cancer therapy have historically been attributed to the large number of subtypes of the disease and the biological differences associated with cancers arising in different parts of the body. While this locational diversity remains a challenge for unifying cancer treatment across various types, it has now become clear that even patients with phenotypically identical cancers often have dichotomous responses to treatment.”
El-Sayes further teaches that “Patients with the same type of malignancy may experience vastly different clinical outcomes, both before and after treatment. This interpatient heterogeneity is often seen in the clinic and is largely attributed to differences in somatic mutations acquired in the tumor.”
El-Sayes further teaches that “There is a plethora of innovative therapeutic approaches currently being developed for the treatment of cancer. Tumor heterogeneity acts as a major hurdle for treatment and a potentiator of acquired resistance regardless of the therapeutic approach or the type of cancer. Unlike primary resistance, acquired resistance can occur in patients that initially respond to therapy, resulting in a relapse after a period of tumor regression [33]. The mechanism of resistance caused by tumor heterogeneity is the same regardless of the treatment received. In a manner similar to that of natural selection, the composition of subpopulations in the tumor changes dynamically as a result of selective pressure exerted by therapeutic intervention and changes in the TME.”
El-Sayes further teaches that “Indeed, relapse of chemoresistant tumors is frequently observed in the clinic [5,34,35]. One such example was highlighted in a study led by Kim et al. in which 20 patients with triple negative breast cancer (TNBC) were observed during neoadjuvant chemotherapy (NAC). They identified 10 patients with persistent chemoresistant clones after treatment. Upon further analysis using single-cell DNA and RNA sequencing, the data indicated that the resistant clones were pre-existing and adaptively selected by NAC [20]. A similar study involved genetic and histological analyses of tumor biopsies from 37 patients with non-small cell lung cancer (NSCLCs) that developed resistance to treatment with EGFR inhibitors. Many of these tumors acquired various mechanisms of resistance, including mutations in the PIK3CA gene and epithelial to mesenchymal transition. Furthermore, some of the tumors lost their mechanisms of resistance in the absence of further EGFR inhibitor treatment and were later responsive to a secondary challenge with EGFR inhibitors.”
By example only Marino teaches that “Molecular heterogeneity is a frequent event in cancer responsible of several critical issues in diagnosis and treatment of oncologic patients. Lung tumours are characterized by high degree of molecular heterogeneity associated to different mechanisms of origin including genetic, epigenetic and non-genetic source (Marino, Federica Zito, Roberto Bianco, Marina Accardo, Andrea Ronchi, Immacolata Cozzolino, Floriana Morgillo, Giulio Rossi, and Renato Franco. "Molecular heterogeneity in lung cancer: from mechanisms of origin to clinical implications." International journal of medical sciences 16, no. 7 (2019): 981).”
Marino further teaches that “Heterogeneity of molecular profile represents one of the most challenging issues in cancer, particularly in lung cancer, in the light of the resulting therapeutic implications. In lung cancer, different levels of molecular heterogeneity have been recognized including inter-patients, intra- and inter-tumour variability. Molecular heterogeneity between lung cancer patients with the same histotype represents a proven biological process resulting frequently in different treatment response for each individual patient.”
Marino teaches that “Tailored therapies based on the identification of molecular targets represent currently a well-established therapeutic scenario in the treatment of NSCLC patients, however short responses and development of resistance are frequently observed in daily clinical practice. Although the optimal efficacy of specific TKIs, a subset of NSCLC patients often shows a mixed response to treatment. Patient-specific response and resistance can originate not only from secondary aberrations induced by targeted therapy but also from intratumoral genetic heterogeneity.”
By example only, Iovanna teaches that “Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer characterized by extensive inter- and intra-tumoral heterogeneity (Iovanna, J., Fraunhoffer, N., Urrutia, R. and Dusetti, N., 2025. Understanding the heterogeneity of pancreatic ductal adenocarcinoma. Translational Oncology, 60, p.102479.).”
Iovanna further teaches that “Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by its high resistance to available treatments and a generally poor prognosis [1]. One of the main challenges in its clinical and therapeutic management is its marked heterogeneity among patients and within the same tumor.”
Iovanna further teaches that “PDAC is not a static disease; instead, it exhibits a continuum of phenotypic transition, driven more by epigenetic and transcriptomic regulation than by additional genetic alterations. This tumor plasticity enables PDAC to evolve into more aggressive forms over time, which has direct implications for classification and treatment.”
Therefore, it is reasonable to conclude the claims are broad with respect to tumor and/or disease of treatment.
Applicant’s claims are also broadly directed towards various pharmacological agents that are broad in structure and mechanism of action including ATR inhibitors, DNA replication stress inducting agents, E2F inhibitors, CDK 4/6 inhibitors, and PARP inhibitors.
Therefore, is reasonable to conclude that the claims are broad with respect to pharmacological agent and/or combination therapy regimen.
Applicant has not defined “treating”, “subject” or “preventing/reducing proliferation of a cell.”
Consequently, as per MPEP 2111, “the pending claims must be "given their broadest reasonable interpretation consistent with the specification."
As per MPEP 2111.01, I: “Under a broadest reasonable interpretation (BRI), words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time. The ordinary and customary meaning of a term may be evidenced by a variety of sources, including the words of the claims themselves, the specification, drawings, and prior art.”
Consequently, the subject is broadly interpreted to include any living organisms commonly used in the medicinal and veterinary arts not limited to humans, mice, mammals, cells, and biological tissues.
Consequently, it is reasonable to conclude that the claims are broad with respect to tumor, subject, pharmacological agent and treatment regimen.
The state of the prior art
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05 (a).
To the best of the examiner’s knowledge, there is no general treatment available for treating all types of tumors in a subject using an ATR inhibitor and tumor treating field.
More specifically, ATR inhibitors are not universally effective across all cancer types.
In particular, Su reports that “This meta-analysis, which included 8 randomized controlled trials and 2 non-randomized comparative studies involving 810 patients, showed that when all tumor types were pooled, ATR inhibitors did not significantly improve key efficacy outcomes compared with conventional therapies. However, stratified analysis revealed that ATR inhibitors achieved favorable objective response rates (ORR) and significantly reduced hazard ratios (HRs) for median progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). By contrast, in tumor types other than NSCLC, the efficacy was disappointing and even associated with a potential increase in adverse events. These findings suggest that the therapeutic potential of ATR inhibition may be restricted to specific tumor subtypes (Su, Y., Lu, X., Bu, Z., Yang, X. and Liu, P., 2025. The efficacy and safety of ATR inhibitors in the treatment of solid tumors: a systematic review and meta-analysis. Frontiers in Oncology, 15, p.1706837).”
Applicant has also cited using additionally DNA replication stress inducing agents such as platinum compounds.
Devarajan teaches that “Cisplatin is the most commonly used first-line drug for cancer treatment. However, many patients develop resistance to cisplatin therapy which ultimately results in therapy failure and increased mortality (Devarajan, N., Manjunathan, R. and Ganesan, S.K., 2021. Tumor hypoxia: The major culprit behind cisplatin resistance in cancer patients. Critical reviews in oncology/hematology, 162, p.103327).”
“Cisplatin acts very effectively against nonmonic tumors. However, in tumors under hypoxic stress, it becomes ineffective due to increased drug efflux, dysregulated cell signaling cascades, increased DNA damage, etc.…Since hypoxia is the most common pathological feature of tumors in cancer patients, the pharmaceutical development of potent drugs that sensitize hypoxic tumors to cisplatin therapy is of paramount importance to improve a patient's prognosis.”
Applicant has also cited using additionally an E2F inhibitor, a CDK 4/6 inhibitor and a PARP inhibitor as a combination therapy approach.
Iglesias-Ara teaches that E2F inhibition can actually induce tumors, specifically that “Thus, inhibition of E2F activity has been proposed as a therapeutic strategy for the treatment of cancer and it has been shown that small-molecule E2F inhibitors are effective against cancer cells. Our recent work raises a cautionary note on the suitability of this approach by providing evidence that loss of E2F activity has harmful effects on differentiating cells that could potentially outweigh the therapeutic benefits of E2F targeting.”
“In summary, our results show that depletion of E2f1/E2f2 can lead to apoptosis or senescence in normally differentiating p53-competent cells, but promotes tumor development upon loss of p53. These findings support the notion that cell context is critical for the outcome of E2F activity, and have important implications in the field of cancer therapy. Ongoing studies aimed to develop E2F inhibitors as anticancer agents should take into account the fact that exacerbating DNA replication rates in normal cells by depleting E2f1/E2f2 could lead to atrophy in a p53-competent context but might be oncogenic in a p53-deficient context (Iglesias-Ara, A. and Zubiaga, A.M., 2016. The stress of coping with E2F loss. Molecular & Cellular Oncology, 3(1), p.e1038423).”
Wu teaches that “CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types (Wu, X., Yang, X., Xiong, Y., Li, R., Ito, T., Ahmed, T.A., Karoulia, Z., Adamopoulos, C., Wang, H., Wang, L. and Xie, L., 2021. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nature cancer, 2(4), pp.429-443).”
Wu also teaches that “Recently, CDK4/6 inhibitors (CDK4/6i) in combination with hormonal therapy showed significant clinical activity in Rb-proficient metastatic ER positive breast cancers and three CDK4/6i, palbociclib (PB), abemaciclib and ribociclib, are now FDA-approved for this indication. Since the activity of CDK4/6 requires a functional RB protein, tumors that do not express functional Rb are resistant to these drugs. However, in many tumor types predominantly expressing wild-type RB1 (lung adenocarcinomas, melanomas, colon cancers, and others) preclinical and clinical studies have shown only modest effectiveness of CDK4/6i 10-12, suggesting that other mechanisms limit their efficacy in these tumor types.”
“We show here that the expression state of CDK6 is a critical regulator of tumor response to CDK4/6i. Cells universally express CDK4, but CDK6 expression varies significantly across tumor types as well as within the same tumor type. We found that tumors with low CDK6 expression relative to CDK4 are sensitive to CDK4/6i. Such tumor types include luminal breast cancer, Ewing sarcomas, Mantle Cell Lymphomas and others, as well as subgroups within tumor types, such as a portion of lung adenocarcinomas.”
Bhamidipati teaches that “Poly (ADP-ribose) polymerase inhibitors (PARPi) have significantly changed the treatment landscape for tumours harbouring defects in genes involved in homologous repair (HR) such as BRCA1 and BRCA2. Despite initial responsiveness to PARPi, tumours eventually develop resistance through a variety of mechanisms (Bhamidipati, D., Haro-Silerio, J.I., Yap, T.A. and Ngoi, N., 2023. PARP inhibitors: enhancing efficacy through rational combinations. British journal of cancer, 129(6), pp.904-916).”
“ While PARPis have improved outcomes for a variety of malignancies harbouring HRD, a significant proportion of HRD tumours are innately resistant to PARPi, and those with initial disease control eventually experience disease progression due to the development of a variety of resistance mechanisms…The complementary DNA-damaging effects of PARPi and chemotherapy have provided rationale for exploring their combination (Table 1). While these combinations do not directly address resistance mechanisms to PARPi, they may increase the efficacy and delay the development of resistance compared with PARPi monotherapy.”
Additionally, although Applicant has provided support for specific drug combinations, Applicant has not demonstrated such data can be extrapolated across the broad and chemically diverse pharmacological agents cited.
Additionally, Mason-Osann teaches that “Combination therapy continues to be a valuable element of cancer treatment in the era of targeted therapies (1, 19, 20). Currently, preclinical strategies to identify new drug combinations often prioritize synergy (3–5); however, this approach may have drawbacks. First, synergy metrics do not assess absolute efficacy, therefore, synergy scores can prioritize combinations of drugs with little or no monotherapy activity, resulting in technically synergistic but weak treatments. This is a significant concern because synergy is most often observed among weak drugs (10). Second, synergy metrics are generally based on short-term assays and do not reveal response durability. Therefore, including other metrics, such as overall efficacy and durability of response may enhance the translational relevance of preclinical data (Mason-Osann, E., Pomeroy, A.E., Palmer, A.C. and Mettetal, J.T., 2024. Synergistic drug combinations promote the development of resistance in acute myeloid leukemia. Blood Cancer Discovery, 5(2), pp.95-105).”
Mason-Osann furthermore teaches that “The current data, supported by prior experiments and models (7, 11, 21, 22), suggest that combination strategies depending solely on synergy may compromise durability of response. In a synergistic combination, drugs depend on each other's activity to maximize effect; small losses in sensitivity to either component drug therefore produce a larger loss in sensitivity to the combination (Fig. 1A). This means that modest resistance to a single drug produces a large fitness benefit (Fig. 3D; Supplementary Fig. S5A), speeding the emergence of drug resistance…Together, these data have important implications for how to prioritize combinations in oncology. We have shown that synergistic drug combinations, while potentially useful to achieve high efficacy, contribute to the evolutionary pressure to develop drug resistance. Therefore, to identify regimens that produce durable clinical response, preclinical assessments of drug combinations should consider metrics beyond synergy, such as monotherapy activity, overall combination activity, and durability of response.”
Therefore, based on the references provided for tumor types, pharmacological agents and combination therapy, it is reasonable to conclude that the current state of the art is unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for the broad range of subjects, tumors and conditions claimed.
(D) The level of one of ordinary skill
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP § 2141.03 (I)
The invention described pertains to medicine and pharmacology. One of ordinary skill would be a person with training in oncology, medicine, immunology, pharmacology, biochemistry or a related technical discipline.
(E) The level of predictability in the art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. 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). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. See MPEP § 2164.03.
Consequently, technologies involving physiological activity as opposed to mechanical or electrical inventions are generally regarded as being unpredictable sciences.
As aforementioned, cancer is an unpredictable, complex and heterogenous disease, and tumors are additionally well-known in the art to be complex and heterogenous as cited above.
Additionally, there is unpredictability in terms of developing combination therapy regiments, and translating from in vitro results to the clinic. Many of the pharmacological agents cited are only effective for certain cancers and/or specific tumors, and it is not well-supported that simply combining such pharmacological agents would necessarily result in treating the tumors claimed. As aforementioned, many of the agents are not effective for all tumors and in some cases synergistic combinations can accelerate drug resistance.
Based on these cumulative factors, it is reasonable to conclude that predictability in the art is extremely low.
Consequently, the applicant would need to provide more details, working examples and guidance in order for the claimed invention to be enabling based on the scope and nature of the claimed invention.
The existence of working examples
The applicants’ working examples are directed towards:
Effect of TTFields, Olaparib, radiation on pancreatic cells. Specifically, the effect of TTFields in combination with a PARP inhibitor (i.e: Olaparib) and/or IR (radiation) on Panc-1 and 04.03 cells cell survival, including synergistic effects (Figure 3, Table I and Table II).
Effect of TTFields AZD6738 (ATR inhibitor), IR (radiation) on combination of pancreatic cancer cells and non-small cell lung cancer cells (NSCLC), including synergistic effects towards H1299 and H157 cell survival and Panc-1 and 04.03 cell survival (Figures 4-5 and Tables 4-5).
Effects of TTFields, cisplatin, etoposide on NSCLC (H1299 and H157 cells) and synergistic effects (Figure 6, Tables 7-8).
Effects of TTFields, irinotecan, and IR (radiation) on NSCLC (H1299 and H157 cells) and synergistic effects (Figure 7, Tables 9-10).
Effects of TTFields, irinotecan, and IR (radiation) on pancreatic cancer cells (Panc-1) and synergistic effects (Figure 8, Tables 11).
Effects of TTFields, 5-FU, and IR (radiation) on combination of pancreatic cancer cells and non-small cell lung cancer cells (NSCLC) and synergistic effects (Figure 9-10, Tables 12-15).
Consequently, Applicant has provided in vivo studies on cell survival on human pancreatic cancer cells and NSCLC cells. Applicant has also provided support for combination therapies for the following:
TTFields in combination with PARP inhibitor, and/or radiation.
TTFields in combination with ATR inhibitor, and/or radiation.
TTFields in combination with platinum compound (cisplatin) and topoisomerase II inhibitor (etoposide) and/or radiation.
TTFields in combination with DNA topoisomerase I inhibitor (irinotecan) and/or radiation.
TTFields in combination with a thymidylate synthase inhibitor (5-FU) and/or radiation.
However, Applicant’s results are limited to supporting specific synergies between pharmacological agents in the context of killing cancer cells. Such data does not support whether such synergies would be actually effective in treating tumors in all the subjects as claimed beyond in vitro into the clinic, nor does such data take into account the complex tumor microenvironment that can complicate treatments as discussed above for various cancer types. It is uncertain whether Applicant’s methods would be able to mitigate against issues with drug resistance and if the synergies would be actually effective in treating the tumors as claimed on this basis. Applicant has also not demonstrated that such synergies would be extrapolated across such chemically and biological diverse cancer agents as claimed.
On this basis and the prior discussion, the working examples are both not commensurate with the scope of protection sought and are not enabling. One ordinarily skilled in the art would be unable to simply translate the evidence provided by the applicant without undue experimentation across the full scope of the instant invention in terms of tumor, subject, and combination therapies claimed.
(F) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As aforementioned, the quantity of experimentation depends on the prior art, the predictability of the art, and the direction provided by the inventor, which are factors that were already discussed.
In order for one ordinarily skilled in the art to practice the invention as disclosed, some attributes one would require, but are not limited to:
Studies supporting that the method is general for all tumor and cancer cells or studies across a broad range of tumor and/cancer cells.
Studies for efficacy for the different classes of cancer agents/combination therapies claimed.
Studies exemplifying the diversity in combination therapies claimed, and supporting that the synergism is actually effective.
Demonstration that the methods can actually be used to treat tumors across the wide range of subjects (i.e: humans, mice, biological tissue, etc), and are not limited to in vitro studies for cell survival.
Long-term studies verifying effectiveness of the treatment based on tendency for drug resistance to develop, especially as some synergies can actually accelerate drug resistance.
Consequently, the examiner concludes that one ordinarily skilled in the art would require undue experimentation in order to practice invention based on the details provided and scope of invention defined in Claims 1-20.
Therefore, claims 1-20 are rejected for lacking enablement.
Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Abu Khabar et al (US-PGPUB 2019/0381043 A1) discloses methods for treating cancers and tumors comprising administering protein kinase inhibitors, including AZD6738. Palti et al (USPN 8,406,870 B2) discloses methods for treating cancer involving combination approaches using TTFields and chemotherapeutic agents.
Conclusion
Claims 1-20 are pending and are rejected.
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622