DETAILED ACTION
Status of Claims
The amendment submitted November 3, 2025 has been entered.
Claims 1-15 and 18 are pending and under consideration.
Claims 16-17 are cancelled by Applicant.
Claims 1-15 and 18 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 of AZD6738 as a species of an inhibitor of ATRi and colorectal cancer (CRC) as species of cancer in the reply filed on November 3, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-15 and 18 read on the elected species.
Claims 1-15 and 18 are under consideration and the subject of this Office Action.
Information Disclosure Statement
Two information disclosure statements (IDS) submitted on October 21, 2024 and May 3, 2024 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.
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 1-15 and 18 are 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 1-15 and 18 are directed towards “A method for treating a cancer in a human patient in need thereof, comprising administering an effective amount of sodium trans-[tetrachloridobis(1H-indazole)ruthenate(II)] and an effective amount of an inhibitor of ataxia-telangiectasia mutated and Rad3-related protein kinase (ATRi).”
Claim 2 is specifically directed towards where the effective amounts of BOLD-100 and ATRi are synergistically effective.
Claims 3-10 are directed towards types of cancers, particularly colorectal cancer (CRC) and myeloma.
Claims 14-15 are directed towards administration of BOLD-100 and ATRi (i.e: sequentially, in combination, or separately).
Claim 18 comprises further assaying a sample from the patient for a mutation.
Applicant has defined synergy on page 26, paragraph [00106] as “In therapeutic applications, synergy between active ingredients occurs when an observed combined therapeutic effect is greater than the sum of therapeutic effects of individual active ingredients, or a new therapeutic effect is produced that the active ingredients could not produce alone. Accordingly, when components of a formulation are present in synergistically effective amounts, the formulation yields a therapeutic effect that is greater than would be achieved by the individual active ingredients administered alone at comparable dosages. In this context, the enhancement of therapeutic effect may take the form of increased efficacy or potency and/or decreased adverse effects. The synergistic effect may be mediated in whole or in part by the pharmacokinetics and/or pharmacodynamics of the active ingredients in a subject, so that the amount and proportion of the ingredients in the formulation may be synergistic in vivo. This in vivo synergy may be effected with a formulation that includes the active ingredients in amounts and proportions that are also synergistic in in vitro assays of efficacy. As used herein, the term "synergistically effective amounts" accordingly refers to amounts that are synergistic in vivo and/or in vitro. A numeric quantification of synergy is often expressed as a fractional inhibitory concentration index (FICI), which represents the sum of the fractional inhibitory concentrations (FICs) of each drug tested, where the FIC is determined for each drug by dividing the minimum inhibitory concentration (MIC, the lowest concentration of the drug which prevents visible growth of the bacterium in a standard in vitro assay - standard colorometric assay based on resazurin) of each drug when used in combination by the MIC of each drug when used alone. In very general terms, a FICI lower or higher than 1 indicates positively correlated activity (at least additive synergy) or an absence of positive interactions, respectively. More definitively, synergy of two compounds may be conservatively defined as a FICI of <0.5 (see Odds, 2003; with additivity or additive synergy corresponding to a FICI of >0.5 to ≤1; no interaction (indifference) corresponding to a FICI of >1 to ≤4; and antagonism corresponding to a FICI of >>4). Synergy of three compounds has been defined as a FICI of <1.0. (Berenbaum, 1978; Yu et al., 1980).”
Applicant has not specifically defined “cancer”, or “treating,” and has very few definitions in the specification in this regard.
Pages 2-3, paragraph [0005] of Applicant’s specification explain that: “The cancer may be a cancer that is resistant to treatment with BOLD-100 alone, or is a cancer that is resistant to treatment with the ATRi alone, or a cancer that is resistant to another chemotherapy agent or chemotherapy regimen, and may for example be a metastatic cancer. The cancer may be a colorectal cancer (CRC), such as a CRC adenocarcinoma. The cancer may be characterized by a BRAF mutation (BRAFMT). The cancer may further be characterized by microsatellite stability (MSS).”
It is well-known in the art that metastatic cancer is a broad term. The National Foundation for Cancer Research explains that “Metastatic cancer (also known as Stage 4 cancer) is not a single type of cancer, but rather a term used to describe any cancer that has spread from the area it started to other areas of the body. Although cancer can spread to any part of the body, the most common sites of metastasis are the bones, liver, and lungs (The National Foundation for Cancer Research, “Metastatic Cancer,” https://nfcr.org/cancer-types/cancer-types-metastatic-cancer/#:~:text=(metastatic%20breast%2C%20prostate%2C%20lung,treatment%2C%20most%20cannot%20right%20now, Accessed: March 2, 2026).”
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.”
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).
In terms of ATRi, this is also a broad class of therapeutic agents that are structurally diverse. Hu notes that “In the combination strategy, an ATRi is typically combined with a radiation or a targeted drug such as chemotherapy agent poly (ADP-ribose) polymerase (PARP) inhibitor, etc. Diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl to macrocycle are capable of achieving good ATR inhibitory activity and good ATR selectivity over other closely related enzymes (Hu, S., Hui, Z., Duan, J., Garrido, C., Xie, T. and Ye, X.Y., 2022. Discovery of small-molecule ATR inhibitors for potential cancer treatment: A patent review from 2014 to present. Expert Opinion on Therapeutic Patents, 32(4), pp.401-421).”
Hu further notes that “With eight ATR inhibitors currently being evaluated in clinical stages, the drug discovery in this field is more furious than ever full with a lot of completion. Since 2014, there are 33 patent applications published, mostly by pharmaceutical companies. Analyses of these patents have revealed that various structurally diverse scaffolds are capable of achieving good to excellent inhibitory activity against ATR kinase with good selectivity over other closely related family members. Based on the scaffold type, those inhibitors can be classified into four groups: (1) monocyclic heteroaryl cores such as pyrimidine (patents by Univ. Texas, Kelun, Bluevalley, etc.), pyrazine (patents by Vertex), and pyridine (patents by Univ. Texas); (2) bicyclic heteroaryl cores: 5,6-fused or 6,6-fused heteroaryl. Examples are pyrazolo[1,5-a]pyrimidine (patents by Merck KGaA), pyrazolopyridine (patents by Repare and Betta Pharma Co. Ltd.), tetrahydropyrido[4,3-d]pyrimidine (patents by Univ. Texas, Table 2), imidazo[1,2-b]pyridazine (patents by Shanghai Yingpai), pyrido[3,4-b]pyrazine-2-(1H)-one (patent by Kelun), and naphthyridine (patents by Bayer Pharma AG); (3) tricyclic heteroaryl core such as oxazino[4,3-d]pyrimido[5,4-b][1,4]oxazine (patents by Merck KGaA and Fundación) and bridged polycyclic core (patent by Shanghai De Novo Pharma Co. Ltd.); and (4) macrocycles (patents by Atrin Pharma LLC) .”
Consequently, it is reasonable to conclude that the claims are broad with respect to cancer, ATR inhibitor, 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 cancer in a human patient using an ATR inhibitor and BOLD-100.
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).”
For metastatic colorectal cancer, Biller explains that “Metastatic CRC remains incurable for most patients. Based on population-based data from the National Cancer Institute, 5-year survival for metastatic CRC is 14%.”
Biller further explains that “Survival depends on the molecular subtype, which informs prognosis by identifying both a tumor’s natural history as well as therapies that are and are not likely to be effective. For the 50% of patients with KRAS/NRAS/BRAF wild-type metastatic CRC, median survival with treatment is approximately 30 months (Figure),18,19 with survival rates of 80% at 1 year, 40% at 3 years and 20% at 5 years after start of first-line chemotherapy (Biller, L.H. and Schrag, D., 2021. Diagnosis and treatment of metastatic colorectal cancer: a review. Jama, 325(7), pp.669-685).”
Biller further explains “There is no approved or recommended immunotherapy regimen or combination therapy for microsatellite stable/MMR-proficient metastatic CRC.”
Biller finally explains that “While overall prognosis for metastatic CRC remains poor, with fewer than 20% of patients surviving beyond 5 years, advances in the diagnosis and treatment of unresectable metastatic CRC have enabled personalized care based on the tumor’s molecular profile with improved outcomes for some subtypes. Since 2014, targeted biologic therapies and immune checkpoint inhibition have changed the approach to management of uncommon molecularly defined subsets of metastatic CRC, although further research is required to optimize the sequencing of treatments and combat mechanisms of resistance. Research priorities include developing approaches to treat KRAS/NRAS–variant tumors and overcome the resistance of most metastatic CRC to immunotherapy.”
Applicant has not demonstrated any studies showing the claimed invention can overcome drug resistance as claimed or is generalizable across the subtypes of CRC.
De Falco further teaches for CRC that “In order to optimise treatment strategy, the institution of a multidisciplinary team (MDT) is crucial to determine the goal to achieve. In fact, treatment algorithm has been tailored according to three major points: (1) patient characteristics (performance status (PS), comorbidities, age and previous adjuvant treatment) and preferences (quality of life (QoL), acceptance of toxicities and expectations); (2) tumour features (tumour burden, pattern of progression, sites of metastasis, potential resectable metastases and primary tumour location); (3) molecular profile (RAS/BRAF status, microsatellite instability (MSI), and—eventually—human epidermal growth factor receptor (HER2 overexpression and NTRK (neurotrophic tyrosine receptor kinase) rearrangement)( De Falco, V., Napolitano, S., Rosello, S., Huerta, M., Cervantes, A., Ciardiello, F. and Troiani, T., 2019. How we treat metastatic colorectal cancer. ESMO open, 4, p.e000813).”
Particularly, De Falco emphasizes that “CRC is an heterogeneous entity for which therapeutic algorithm need to be chosen upfront by a multidisciplinary tumour board in order to ensure the ‘continuum of care’ for the patients. Finally, the advent of genomic analysis has generated new possibilities for evaluating off-label targeted therapies in refractory cancers and for enrolment in clinical trial with matched targeted therapeutics. Above all, physicians should personalise the treatment, considering several factors, including molecular profile, tumour location, achievable goals, patient characteristics and preference.”
Consequently, De Falco teaches that in human patients, a highly individualized strategy based on optimizing various parameters is required. Therefore, such treatment is not generalizable across CRC.
For metastatic breast cancer, Lin explains that “Regardless of the advances in our ability to detect early and treat breast cancer, it is still one of the common types of malignancy worldwide, with the majority of patients decease upon metastatic disease (Lin, P.H. and Laliotis, G., 2022. The present and future of clinical management in metastatic breast cancer. Journal of clinical medicine, 11(19), p.5891).”
Particularly, Lin teaches that “Despite the recent advances in treatment, follow-up and targeted therapies, around 30% of breast cancer patients still eventually relapse with distant metastasis [5], which develops approximately 5–20 years after the initial diagnosis [6].”
Lin further teaches that “Breast cancer is an intrinsically heterogeneous and complex disease with various molecular subtypes, histological features, and clinical characteristics [2,13].”
Regarding metastatic cancer, Ganesh teaches that “To date, no drugs have been approved exclusively for use in the adjuvant setting and not for macrometastatic disease, although some dormancy-specific trials in the adjuvant setting are in progress (reviewed in ref. 104). Indeed, several drugs that have been demonstrated to provide a survival benefit in treating macrometastasis fail to show benefit in the adjuvant setting against micrometastasis. In colon, breast and non-small-cell lung (NSCLC) cancers, only one in three agents approved to treat macrometastatic cancer have been approved for perioperative treatment when no visible metastases are present105. While such attrition could be due to inadequate trial sample size or insufficient depth of pathway inhibition, it could also be due to the intrinsic differences in the biology of dormant and indolent micrometastases in the adjuvant setting versus growing, radiologically apparent macrometastases”(Ganesh, K. and Massagué, J., 2021. Targeting metastatic cancer. Nature medicine, 27(1), pp.34-44).
In terms of preclinical studies, Ganesh teaches that “Most preclinical studies assessing novel therapeutic approaches aim to prevent metastasis or slow tumor growth in animal models, not to shrink large tumors. Thus, there is a disconnect between preclinical studies, which aim to control micrometastases, and first-in-human clinical studies, which assess shrinkage of macrometastases. This disconnect may explain why several drugs that showed promise in controlling micrometastatic tumor growth in preclinical studies failed to achieve shrinkage of macrometastatic tumors in human clinical trials.”
Applicant has performed no studies specifically geared towards the study of metastasis. Only cell viability studies were done, which fail to model metastatic cancer.
Finally, Ganesh teaches that “Effective therapeutic targeting of metastatic cancer must address not only the dynamic plasticity of the cancer cells themselves as they progress through the metastatic cascade but also the mechanisms used by dormant and growing metastases to corrupt and co-opt their niches and evade immune surveillance. Converging lines of evidence from close observation of patient phenotypes, analysis of clinical samples and experimental studies in improved preclinical models are illuminating the properties of metastatic cancers as regenerative states distinct from primary tumors.”
Regarding multiple myeloma, Dima teaches that “Multiple myeloma (MM) is a frequent hematological malignancy characterized by the uncontrolled growth of clonal plasma cells, primarily in the bone marrow. Over the past years, novel therapies have been discovered and introduced into clinical practice that have dramatically changed the treatment landscape of MM. Despite the tremendous advances, MM remains incurable, with poor outcomes particularly in patients with relapsed/refractory disease, emphasizing the need for new therapeutic approaches (Dima, D., Jiang, D., Singh, D.J., Hasipek, M., Shah, H.S., Ullah, F., Khouri, J., Maciejewski, J.P. and Jha, B.K., 2022. Multiple myeloma therapy: emerging trends and challenges. Cancers, 14(17), p.4082).
Dima further teaches that “Recently, there has been an increasing interest in unraveling the underlying genomics of MM in an effort to better understand the clinical heterogeneity of this complex disease, characterize its precursor states, and elucidate the significant cytogenetic and molecular events leading to active myeloma.”
Dima further teaches that “Several patient-related, disease-related, and treatment-related factors should be considered when selecting therapy for MM. The most important patient-related factors include age, frailty, and performance status. Disease-related parameters include the nature of the disease, for example risk status, and extent of organ damage. Treatment-related factors refer to drug availability and drug adverse events; in the case of relapsed/refractory disease the number and type of prior treatments, as well as depth and duration of previous responses, should also be taken into consideration.”
Consequently, treatment is also highly personalized, requiring optimization of various parameters in human patients for multiple myeloma and not generalizable.
Additionally, although Applicant has provided support for limited drug combinations, Applicant has not demonstrated such data can be extrapolated across the broad and chemically diverse pharmacological agents and cancers 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 cancer 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, cancers 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, as cited above. Many of the cancers claimed require highly personalized strategies requiring optimization of various parameters and are incurable, particularly for many metastatic cancers.
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 it is not well-supported that simply combining such pharmacological agents would necessarily result in treating the cancers as claimed. As aforementioned, many of the agents are not effective for all cancers 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:
In vitro studies with BRAFTMT ,MSS CRC cells demonstrating sensitivity to treatment with BOLD-100 (page 27, Example 2, Figure 2) using Western blot and cell viability studies.
In vitro studies with BRAFMT and BRAFWT CRC cells with BOLD-100 for cell viability, and also BOLD-100 in combination with Vemurafenib, with calculation of CI values (Example 3, page 28).
In vitro studies using BRAFTMT HT-29, and VACO432 cells and treatment with BOLD-100 and 60 FDA approved drugs alone or in combination for cell viability (Example 6, page 29).
In vitro studies with HT-29 and VACO432 CRC cells with BOLD-100 and ATRi ZED6738, M4344 or Berzosertib to assess apoptosis (Example 7, page 30).
In vitro studies with 20 colon cancer cell lines using BOLD-100 (Example 9, page 30)
In vitro studies with myeloma cell lines using BOLD-100 and ATR inhibitor BAY1895344 to determine cell viability. CI was calculated (Example 10, page 31).
Consequently, Applicant has provided in vitro studies on cell survival on human CRC and myeloma cell lines. However, Applicant has provided no in vivo studies or demonstrated the results would transfer into human patients as recited in claim 1.
Furthermore, 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 cancer in human patients as claimed beyond in vitro into the clinic, nor does such data take into account the challenges for metastatic cancers for various cancer types, many of which are untreatable and require personalized, complex development for treatment regiments.
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 cancers as claimed on this basis. Applicant has also not demonstrated that such synergies would be extrapolated across the structurally diverse ATR inhibitor family 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 cancer, 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 cancer or studies across a broad range of cancers, including the diverse range of metastatic cancers and resistant cancers.
Studies for efficacy for the different classes of cancer agents/combination therapies claimed.
Studies exemplifying the diversity across the broad class of ATR inhibitors as claimed, and supporting that the synergism is actually effective.
Demonstration that the methods can actually be used to treat cancer in human patients as claimed 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 and additionally, as metastatic cancer can emerge years after initial cancer treatments.
Actual preclinical models that translate into the clinic for metastasis. Applicant has provided no examples suggesting the claimed invention can broadly treat metastatic cancers.
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 1-15 and 18.
Therefore, claims 1-15 and 18 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. Wernitznig (Information Disclosure Statement, May 3, 2024, Non-Patent Literature No. 14) teaches KP1339/IT-139/BOLD-100 is effective in treating colon adenocarcinoma based a highly predictive colon cancer model and suggest combination therapies to increase effectiveness.
Conclusion
Claims 1-15 and 18 are under consideration and are rejected.
No claims are 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.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622