DETAILED ACTION
The amendment submitted September 18, 2025 has been entered.
Claims 6-8, 10-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55 remain pending and under consideration.
Claims 1-5, 9, 14-15, 19, 24, 26-27, 35-37, 47, 49, 54, and 56 were previously cancelled by Applicant.
Claims 6, 10, 21 and 55 are amended by Applicant.
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 .
Information Disclosure Statement
One additional information disclosure statements (IDS) submitted on September 18, 2025 is 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.
WITHDRAWN OBJECTIONS
The examiner withdraws objections to the abstract based on corrections made by Applicant.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to Claims 6, 7-8, 11-13, 16-18, 20-23, 25, 28-33, 38-46, 48, 50-53, and 55-56 under 35 U.S.C. 112(b) based on claim amendments by Applicant.
The examiner withdraws rejections to 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, and 55-56 on the ground of nonstatutory double patenting as being unpatentable over claims 93-113 of copending Application No. 18/403,027 (reference application), claims 1-7, and 11-22 of U.S. Patent No. 11865094B2, claims 1-9 of U.S. Patent No. 10945978B2, claims 1, 5-28, 32-36, 40-53 of U.S. Patent No.10543183B2, claims 1-13, 17-28 of U.S. Patent No. 9962348B2, claims 1-19, 23-28 of U.S. Patent No. 9707195B2, claims 1-15 of U.S. Patent No. 9399028B2 and claims 1-2, 6-14 of U.S. Patent No. 9526710B2 based on arguments presented by Applicant.
MAINTAINED/MODIFIED REJECTIONS
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 6-9, 10-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, and 55-56 remain 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 non-small cell lung cancer, does not reasonably provide enablement for all the cancers and cancer treatments claimed across the subjects claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
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 6-9, 10-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, and 55-56 are directed to “a method of treating ApoE-related cancer selected from breast cancer, colon cancer, renal cell cancer, lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, bladder cancer, neuroendocrine cancer, lymphoma, squamous cell carcinoma of the head and neck, and melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of 2-[3-[(3R)-3-[[2-chloro-3- (trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]butoxy]phenyl]acetic acid, or a pharmaceutically acceptable salt thereof.”
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).
Applicant has defined patient as “The term "subject," as used herein, refers to a human or non-human animal (e.g., a mammal such as a non-human primate, horse, cow, or dog) (page 17, lines 40-41).”
Applicant has also defined cancers as “The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas (page 13, lines 10-14).”
Applicant has also defined treatment as “The term "treatment" (also "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or are established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition” (page 18, lines 8-19).
Consequently, it is reasonable to conclude that the claims are broad with respect to the patient population, cancer and treatment.
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).
Instant claims are directed towards ApoE-related cancers, and specifically, breast cancer, colon cancer, renal cell cancer, lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, bladder cancer, neuroendocrine cancer, lymphoma, squamous cell carcinoma of the head and neck, or melanoma as per claim 9.
However, the state of the art suggests that the role of ApoE is controversial in many cancer types, including cancers claimed by Applicant.
Darwish explains that “Even though the function of APOE in cancer progression is unclear, it can inhibit proliferation due to its high-affinity interaction with proteoglycan and heparin in the cancer tissue [47]. The association between breast cancer and APOE was controversial in the beginning due to a lack of associations between them; however, research has revealed that patients with one or two copies of the e4 allele along with elevated triglyceride levels were at a fourfold risk of developing breast cancer in comparison to those with low triglyceride concentrations [48,49]. Additionally, researchers have documented contradicting reports between APOE polymorphisms and breast cancer risk; while some studies have reported an association [48,50,51,52,53,54], other studies did not report any link between APOE polymorphism and breast cancer risk [55,56]. A meta-analysis concluded that, among Asians, carriers of the E4E4, E4E3, and E4E2 genotypes were associated with a high breast cancer risk, compared to the E3E3 genotype [57]. Likewise, in Taiwan, studies reported a risk of breast cancer in females with the APOE genotype; neither the APOE2 nor APOE4 alleles showed a notable correlation with markers of cell growth [51,52,58]. On the other hand, Caucasians had no association between breast cancer and APOE2, APOE3, or APOE4 [57]. Moreover, has been APOE positively correlated with breast cancer progression and invasion [47] (Darwish, Nour M., Mooza Kh Al-Hail, Youssef Mohamed, Rafif Al Saady, Sara Mohsen, Amna Zar, Layla Al-Mansoori, and Shona Pedersen. "The Role of Apolipoproteins in the Commonest Cancers: A Review." Cancers 15, no. 23 (2023): 5565).”
Consequently, Darwish demonstrates conflicting reports on the role of APOE in breast cancer that varies based on patient population.
Darwish further explains that “ApoE, known to be implicated in cardiovascular and neurological diseases, is involved in tumorigenesis, cancer cell proliferation, and metastasis, and is associated with amplified oxidative stress [105,106]. However, its role in lung cancer remains unclear. In one study, ApoE was found to be upregulated in patients diagnosed with NSCLC by 1.6-fold; however, the use of APOE as a candidate biomarker remains insignificant [107]. This finding was supported by an in vivo study in which APOE knockdown inhibited the proliferation and metastasis of lung cancer cells [108]. In addition to the correlation between APOE upregulation and increased lung adenocarcinoma frequency, APOE is associated with a higher incidence of malignant pleural effusions (MPEs), a complication of lung adenocarcinoma, compared to lung cancers without MPEs [109].
Consequently, Darwish demonstrates the role of ApoE in lung cancer is equally not well-understood or clear.
Darwish further explains issues pertaining colorectal cancer (CRC): “APOE function has been seen to be highly controversial between studies. Whilst some studies associate ApoE with tumor progression, another study proposes ApoE as a potential protective factor. The study which proposed ApoE as a protective factor associated the ApoE gene being silenced with an increased susceptibility to inflammation-related tumorigenesis [116]. On the other hand, a different study suggested that ApoE activation was seen to restrict the immune system suppression of cancer cell proliferation, thus promoting cancer growth and metastasis. Nevertheless, these studies all showed a significant ApoE level upregulation in CRC. Further patterns have also been identified, like ApoE levels being significantly higher when a tumor has metastasized to the liver. One study specified that this upregulation occurs only in primary CRC, not in stage II of CRC [116]. A murine model using wild-type mice showed that ApoE upregulation was also associated with enlarged tumor sizes. The proposed mechanisms through which ApoE accelerated cancer is in relation with intracellular adhesion and junctions, thereby decreasing cell contact inhibition and polarizing normal cells to tumor cells through the PI3K/Akt/mTOR pathway [118]. ApoE’s polymorphism has also been studied. There are three different ApoE alleles— ApoE -ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158)—that differ only due to two amino acids. ApoE -ε4 is associated with reduced proximal colorectal neoplasia in the forms of adenoma and carcinoma; however, investigation into distal neoplasms have shown no significant difference [31]. Yet these findings still need further investigation, as another study involving Japanese males could not identify these correlations between ApoE-ε4 and proximal adenomas, suggesting that ApoE is affected by other factors other than genes, for example, ethnicity in this case. Other factors that may determine the potential association between the genotypes of ApoE and colonic cancer include racial variation, genetic background, diet, and physical training, which have likely led to a discrepancy in findings on the carcinogenicity of the allele ε4. ApoE-ε3 has also shown an inverse correlation between concentration and colon cancer; a deficiency in ApoE-ε3 leads to colon cancer, which has been especially observed populations over 50 years of age [116]. ApoE serum levels have been proposed as a diagnostic marker for metastatic CRC under chemotherapy and bevacizumab treatment. However, further research is needed to fully understand the potential of APOE as a biomarker for clinical outcomes.”
Consequently, Darwish demonstrates that patient population is critical in determination the role of APOE in colorectal cancer (CRC) and conflicting role of ApoE as promoting tumor progression versus a protective element.
Pertaining pancreatic cancer, Darwish explains that “ApoE was found to contribute to immunosuppression and inhibiting the apoptosis of malignant cells in pancreatic cancer. ApoE contributes to immune suppression in pancreatic cancer by activating the NF-κB signaling pathway. This triggers the production of CXCL1, which is a protein that plays a role in immune suppression by recruiting immune cells that hinder the immune response to the tumor. It was concluded that blocking the production of CXCL1 may reverse ApoE-mediated immune suppression. Furthermore, ApoE expression was found to be higher in pancreatic cancer tissue than in normal pancreatic tissue, and that elevated ApoE levels are linked to worse outcomes for pancreatic cancer patients [128,129]. In addition, ApoE2 has been found to aid pancreatic cancer cells in avoiding mitochondrial apoptosis by regulating the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade [130]. A study found that pancreatic cancer cell proliferation is associated with increased expression of ApoE2-LRP8, a ligand–receptor pair that promotes tumor progression. The ApoE2-LRP8 axis appears to be a dominant biological cascade in this process, inducing the expression of p-ERK1/2 and c-Myc, both of which are involved in the cell cycle and promote tumor growth. The study suggests that targeting the ApoE2-LRP8 axis could be a promising therapeutic strategy for pancreatic cancer [131]. These findings suggest that ApoE2 could be a useful prognostic marker and a potential target for developing novel therapies against pancreatic cancer, yet further research is needed.”
Darwish demonstrates that although targeting APOE2 could be a promising strategy for pancreatic cancer, more research is required.
In summary, Darwish explains that “The role of apolipoproteins in the context of cancer has recently emerged as a subject of increasing interest within the scientific community. Nonetheless, it is imperative to acknowledge that notable gaps persist within the existing literature concerning the precise roles and impacts of apolipoproteins in different cancers. The available data often exhibit discrepancies, particularly with regard to the upregulation or downregulation of specific apolipoproteins, thus warranting further investigation and clarification. A substantial portion of the research dedicated to exploring the involvement of apolipoproteins in cancer has been conducted, utilizing murine models or non-human cell lines. Moving forward, a more informative and clinically relevant approach would entail a shift towards investigating the role of apolipoproteins in human cell lines.”
Consequently, Darwish illustrates that there is a dearth of studies studying actual human cell lines and actual clinical data in addition to many unknowns and gaps pertaining the role of APO in different cancers, and conflicting findings in terms of ApoE’s role.
Furthermore, aside from the variable role of ApoE in the heterogenous and diverse cancers claimed, to the best of the Examiner’s knowledge and what is known in the prior art, there remains no general monotherapy for treating all types of ApoE-related cancers as claimed.
Therefore, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for treatment of cancers as 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, veterinary medicine, 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.
Additionally, the role of APOE is also controversial and unclear for all types of cancers claimed, including a lack of data on human cell lines and/or clinical data. Particularly, the role of ApoE can vary significantly based on the cancer type and patient population, supporting lack of predictability in the art.
Based on these cumulative factors, it is reasonable to conclude that predictability in the art is 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: Adverse event profile using combination therapy consisting of Abequolixron and docetaxel. No details were provided on what type of subject was actually tested, if they had cancer, and if so what type of cancer.
Efficacy studies on Xenograft A549 mice: Group 1 was a control using corn oil, group 2 was administered cisplatin, group 3 was administered Abequolixron, Group 4 and Group 5 were administered varying amounts of cisplatin and Abequolixron.
Applicant has failed to provide working examples and key details encompassing the subjects and cancers tested, including providing working examples representative for the diversity of cancers, subjects/patient populations and treatment regimens claimed.
Applicant has provided no examples of monotherapy using Abequolixron alone to support effectiveness based on the alleged novel dosing regimen.
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, particularly in terms of cancer, patient population and combination therapies claimed.
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 across the many heterogenous types of cancer and tumors claimed and disease progression, particularly for cancers that do not translate from in vivo to clinical models. Each the cancers recited are broad classes of cancers, many of which have conflicting reports regarding APOE in the literature. Only A549 was tested which is known in the art as human non-small lung cancer cells and also a cell-line known to correlate well from in vivo to clinical models.
Studies in animal and human populations as claimed encompassing the diversity of subjects and patients (i.e.: cancers that are resistant to the chemotherapies recited in claim 39 and per claim 43 and 44)
Studies exemplifying the diversity in combination therapies claimed (i.e.: administration of a statin as per claim 31 and agents listed in claim 33).
Guidelines for dosing, timing, and administration regimen for mono- and combination therapies depending on cancer, disease progression and patient population. Applicant has recited many different combination therapies; however, only adverse event profiles were exemplified for docetaxel and Abequolixron, despite the large diversity of additional therapeutic agents recited. As aforementioned, Applicant has omitted key details regarding the adverse event profiles. Examples 1 and 2 do not use the same subjects, or combination therapies.
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 6-9, 10-13,16-18,20-23,25,28-34,38-46,48,50-53 and 55-56.
Therefore, claims 6-9, 10-13,16-18,20-23,25,28-34,38-46,48,50-53 and 55-56 are rejected for lacking enablement commensurate with the scope of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55-56 remain rejected under 35 U.S.C. 103 as being unpatentable over Tavazoie et al. (USPN 9,399,028 B2) as evidenced by PubChem ( National Center for Biotechnology Information. PubChem Compound Summary for CID 10218693, RGX-104 free Acid. https://pubchem.ncbi.nlm.nih.gov/compound/RGX-104-free-Acid. Accessed June 11, 2025)(“PubChem”), Childs et al. (Childs, Daniel S., and Aminah Jatoi. "A hunger for hunger: a review of palliative therapies for cancer-associated anorexia." Annals of palliative medicine 8, no. 1 (2018): 50)(“Childs”), National Cancer Institute (National Center Institute. NCI Dictionary of Cancer Terms. “Neuroendocrine Tumor. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neuroendocrine-tumor. Accessed June 11, 2025)(“National Cancer Institute”), Teixidó et al. (Teixidó, Cristina, Noelia Vilariño, Roxana Reyes, and Noemí Reguart. "PD-L1 expression testing in non-small cell lung cancer." Therapeutic Advances in Medical Oncology 10 (2018): 1758835918763493)(“ Teixidó”), and Dana Farber Cancer Institute (Dana Farber Cancer Institute. “Inoperable Cancer: What Does it Mean? https://blog.dana-farber.org/insight/2017/12/inoperable-cancer-meaning/#:~:text=%E2%80%9CLiquid%20cancers%2C%E2%80%9D%20such%20as,material%20within%20the%20body%27s%20bones. Accessed June 11, 2025)(“Dana Farber Cancer Institute”).
Applicant recites a method administering the compound “2-[3-[(3R)-3-[[2-chloro-3- (trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]butoxy]phenyl]acetic acid, or a pharmaceutically acceptable salt thereof,” which is also known as RGX-104 or Abequolixron or SB742881 as evidenced by PubChem and shown below.
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Using broadest reasonable interpretation, “a pharmaceutically acceptable salt,” is also interpreted to include any and all salt forms, including Abequolixron hydrochloride and metal salts.
Regarding claim 6, Tavazoie teaches similar “methods of treating ApoE-related cancer in a subject in need thereof, the method comprising administering to the subject” the identical compound known as RGX-104 or Abequolixron or SB742881 as evidenced by PubChem.
Tavazoie specifically teaches ApoE-related cancers: “In another aspect, the invention features a method for treating melanoma (e.g., metastatic melanoma) in a subject in need thereof. The method includes (a) increasing in the subject the expression level or activity level of a metastasis suppressor factor selected from the group consisting of DNAJA4, Apolipoprotein E (ApoE), LRP1, LRP8, Liver X Receptor (LXR, e.g., both LXR-alpha and LXR-beta), and miR-7 (column 4, lines 10-19).”
Tavazoie also teaches “In one aspect, the invention features a method for treating cancer, including administering to a subject in need thereof, a LXR agonist, wherein the LXR agonist is administered in an amount sufficient to increase the expression level or activity level of ApoE to a level sufficient to slow the spread of metastasis of the cancer (column 1, lines 58-63).” Abequolixron is known in the art to be an LXR agonist.
Tavazoie also teaches other cancers including ApoE cancers recited in instant claims 6, 34 and 56 such as “In other embodiments, the cancer is breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, or melanoma. In some embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer. In certain embodiments, the cancer is renal cell cancer. In further embodiments, the cancer is pancreatic cancer. In other embodiments, the cancer is non-small cell lung cancer. In some embodiments the cancer is colon cancer. In further embodiments, the cancer is ovarian cancer (column 2, lines 53-63).”
Consequently, Tavazoie teaches methods similar to claims 6-10, 34, 55 and 56.
Tavazoie teaches methods similar to claim 11 where the dosing amount is “about 80 mg to about 160 mg per administration.”
Tavazoie specifically teaches a working example where “The mice were palpated daily for tumor formation and after detection of tumors measuring 5-10 m3 in volume, the mice were assigned to a control chow or a chow containing each respective LXR agonist: LXR-623 (20 mg/kg/day), WO-2007-002563 Ex. 19 (100 mg/kg/day), WO-2010-0138598 Ex. 9 (10 mg/kg/day or 100 mg/kg/day), or SB742881 (100 mg/kg/day),” which meets the limitation of claim 11 (Example 25, column 148, lines 22-32).
Tavazoie does not specifically teach administering about 80 mg as per claim 12; however, regarding dosage, Tavazoie teaches that “The expression “effective amount” as used herein, refers to a sufficient amount of the compound of the invention to exhibit the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular therapeutic agent and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the anticancer activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (column 91, lines 31-55).”
Regarding claims 13 and 20, Tavazoie teaches combination therapies such as “chemotherapy and/or immunotherapy.”
Specifically, Tavazoie teaches “In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. The additional compound having antiproliferative activity can be selected from a group of antiproliferative agents including those shown in Table 2 (column 96, lines 1-6).”
Table 2 of Tavazoie lists anti-cancer agents including docetaxel as per claim 16.
Table 2 also lists platinum agents such as “carboplatin and cisplatin” as per claim 21, and additionally “pemetrexed.”
Table 2 also includes “immunomodulators” which constitutes immunotherapy, meeting the limitations of claim 21 (see also claim 1 of Tavazoie)
Tavazoie also teaches that “It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects)(column 96, lines 7-19).”
Regarding claim 29, Tavazoie teaches further administering corticosteroids.
Tavazoie specifically teaches that: “The method may further include administering a antiproliferative compound selected from the group consisting of alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists/antagonists, endothelin A receptor antagonist, retinoic acid receptor agonists, immuno-modulators, hormonal and antihormonal agents, photodynamic agents, tyrosine kinase inhibitors, antisense compounds, corticosteroids, HSP90 inhibitors, proteosome inhibitors (for example, NPI-0052), CD40 inhibitors, anti-CSI antibodies, FGFR3 inhibitors, VEGF inhibitors, MEK inhibitors, cyclin D1 inhibitors, NF-kB inhibitors, anthracyclines, histone deacetylases, kinesin inhibitors, phosphatase inhibitors, COX2 inhibitors, mTOR inhibitors, calcineurin antagonists, IMiDs, or other agents used to treat proliferative diseases. Examples of such compounds are provided in Tables 1(column 4, line 1).”
Regarding claim 33, Tavazoie teaches methods similar that include further administering an appetite stimulant. As aforementioned, Tavazoie teaches administration of corticosteroids, which are known to be appetite stimulants for cancer-related anorexia as evidenced by Childs.
Childs explains that “A subgroup of cancer patients who struggle with appetite loss will find an appetite stimulant helpful. Importantly, as far as we know, although appetite stimulants might improve appetite, they do not appear to improve global quality of life or survival; hence, their role should be clearly defined prior to prescribing them to patients. For practical purposes, the two classes of agents that have been most extensively and successfully studied are progestational agents and corticosteroids.”
Regarding claim 38, Tavazoie teaches methods where the cancer is a neuroendocrine tumor. Tavazoie teaches the methods can be used to treat thyroid cancer which includes medullary thyroid cancer, which is a neuroendocrine tumor as evidenced by the National Cancer Institute.
Specifically, Tavazoie teaches: “Typical vascularized tumors that can be treated with the method include solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients. Exemplary solid tumors include, but are not limited to, carcinomas of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, glioblastomas, neuroblastomas, Kaposi's sarcoma, and sarcomas (column 80, lines 48-58).”
Additionally, Tavazoie explains that “The term “cancer” refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like (column 6, lines 50-53).”
Regarding claims 39-41, Tavazoie teaches “In other embodiments, the cancer is a drug resistant cancer. In further embodiments, the cancer is resistant to vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, or a PDLL inhibitor (column 2, lines 64-67),” which meets the limitations of claim 39-41.
Tavazoie defines “drug resistant cancer” as “any cancer that is resistant to an antiproliferative in Table 2.
Tavazoie additionally discloses working examples studying drug-resistant melanoma in mice and human in vitro and in vivo studies (column 123, lines 10 to 54), meeting the limitations of claims 39-41.
Claims 1-15 of Tavazoie are additionally directed towards treating drug-resistant cancer using the identical drug and combination therapies.
Regarding claims 42, Tavazoie teaches “the PDL-1 expression level of less than 1% when tested in an immunohistochemistry assay.”
Specifically, Tavazoie teaches ““A method of treating drug resistant cancer in a subject in need thereof, comprising administering to the subject an effective amount of an LXRβ agonist, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor, wherein said inhibitor is nivolumab or atezolizumab (MPDL3280A), wherein said drug resistant cancer is breast cancer, non-small cell lung cancer, or ovarian cancer, and wherein said LXRβ agonist is” identical to instant invention (claim 1 of Tavazoie).
It is known in that art that an assay is routine practice in screening cancer patients prior to administration of checkpoint inhibitors as evidenced by Teixidó.
Teixidó explains that “There is consensus that PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors in several tumor types. Hence PD-L1 expression evaluated by immunohistochemistry (IHC) is currently used as a clinical decision-making tool to support the use of checkpoint inhibitors in NSCLC patients.”
Regarding claim 43, Tavazoie teaches cancers that are metastatic.
Specifically, “Although some conventional cancer therapies have been used in treating metastatic melanoma, they are not effective. Metastatic melanoma therefore remains one of the most difficult cancers to treat and one of the most feared neoplasms. Accordingly, there is a need for new agents and methods for diagnosis and treatment of melanoma (column 1, lines 42-47).” Additionally, Tavazoie teaches “In some embodiments the migrating cancer is metastatic cancer. The metastatic cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer (column 2, lines 19-25),” and additional methods of treatments as per claims 1-2 of Tavazoie.
Regarding claim 44, Tavazoie teaches cancers that are unresectable.
Tavozie teaches “Examples of cancers that can be defined as metastatic include but are not limited to non-small cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medullablastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, multiple myeloma, leukemia, intraepithelial neoplasms, liver cancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer,” and it is known in the art that “leukemia, lymphoma and multiple myeloma” are inherently unresectable as evidenced by Dana Farber Cancer Institute.
As Dana-Farber Cancer Institute explains, “Liquid cancers,” such as leukemia, lymphoma, and multiple myeloma, are considered inoperable by nature, because they involve cells or tissues that are dispersed throughout the body. Leukemia and multiple myeloma, for example, originate in abnormal cells of the bone marrow, the spongy material within the body’s bones.”
Dana-Farber Cancer Institute additionally explains that “The other major type of inoperable cancer involves metastatic tumors. A single, isolated tumor may, over time, seed the growth of multiple secondary tumors elsewhere in the body. In some cases, the original tumor as well as secondary tumors can be removed. But in many instances, the secondary tumors are too numerous to remove safely.” Consequently, metastatic cancers also known in the art as unresectable.
Regarding claims 45-46 and adverse effects, Tavazoie teaches that “The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).”
Instant claim 48 recites outcomes resulting from administration of an effective amount of the compound. As both Tavazoie and claim 6 recite the identical process step of administering an effective amount for the identical condition and using the identical drug, it is reasonable to conclude that the outcome will be the same. Consequently, Tavazoie meets the limitations of claim 48.
As per MPEP 2112: “The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995).
Furthermore, as per MPEP 2112.I: "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
Finally, MPEP 2112.II: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
Regarding claims 50, Tavazoie teaches that: “The dosage required depends on the choice of the route of administration; the nature of the formulation; the nature of the patient's illness; the subject's size, weight, surface area, age, and sex; other drugs being administered; and the judgment of the attending physician. Suitable dosages are in the range of 0.01-100 mg/kg. Variations in the needed dosage are to be expected in view of the variety of compounds available and the different efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by i.v. injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization as is well understood in the art. Encapsulation of the compound in a suitable delivery vehicle (e.g., polymeric microparticles or implantable devices) can increase the efficiency of delivery, particularly for oral delivery (column 92, lines 12-27).”
Tavazoie additionally teaches that “A pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally (column 94, lines 24-26).”
Regarding claim 51-52 , Tavazoie teaches working example 25 where SB742881 is administered daily (Example 25, column 148, lines 22-28).
Specifically, SB742881 is administered in a dose of 100 mg/kg/day.
Tavazoie does not explicitly teach the specific treatment durations as instant invention for SB742881 alone or as part of combination therapy regimens.
Tavazoie does not explicitly teach the effective amount of docetaxel as per claim 18, for pembrolizumab as per claim 22-23, carboplatin or cisplatin as per claim 25, or pemetrexed as per claim 28. However, such parameters would be routine for a person of ordinary skill in the field of oncology to develop as a result of routine optimization to deliver a personalized plan based on a patient’s age, weight, cancer type, etc. as aforementioned by Tavazoie.
Therefore, it would have been prima facie obvious before the effective filing date to modify Tavazoie’s methods to access the claimed invention because Tavazoie teaches identical subject matter as instant invention, including the identical compound, subject, cancers and amount administered to a subject, and combination therapies recited in instant claims.
As aforementioned, the difference between Tavazoie and instant invention is the specific amounts and treatment durations. However, a person of ordinary skill in the art would be motivated to optimize Tavazoie’s method to access the specific amounts and treatment duration as result of routine optimization in personalizing treatments for specific subjects, patient populations, disease type and other known parameters in the medicinal arts as explained by Tavazoie in a manner to avoid adverse effects and optimize effectiveness of the treatment plan.
As per MPEP 2144.05, II, A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, one would arrive at the claimed invention as a highly predictable result with a reasonable expectation of success based on the beneficial teachings of Tavazoie.
Therefore, claims 6-13, 16-18, 20-23, 25, 28-30, 33-34, 38-46, 48, 50-53, 55-56 are rejected on grounds of being obvious.
Claims 6 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Tavazoie et al (US9399028B2)(“Tavazoie”) in view of Jones et al (Jones, Hannah M., Ziwei Fang, Wenchuan Sun, Leslie H. Clark, Jessica E. Stine, Arthur-Quan Tran, Stephanie A. Sullivan, Timothy P. Gilliam, Chunxiao Zhou, and Victoria L. Bae-Jump. "Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro." American journal of cancer research 7, no. 12 (2017): 2478) (“Jones”).
The teachings of Tavazoie are set forth as relied up on above.
Tavazoie does not teach combination therapy using statins.
However, Jones teaches that “Statins have been shown to have promising anti-tumorigenic activity in many types of cancers.”
Jones also teaches that “ In the present study, our results indicate that ATO (atorvastatin), similar to simvastatin, exhibits anti-tumorigenic activity in ovarian cancer cells through induction of apoptosis, cell cycle G1 arrest and autophagy.”
Finally, Jones explains that “Currently, statins are being studied clinically for use in the prevention and treatment of cancer and as an adjuvant treatment in combination with chemotherapeutic agents… These findings indicate that ATO is a potential novel and well-tolerated chemotherapeutic agent for use in the prevention and treatment of cancers including ovarian cancer and warrants further investigation in clinical trials for ovarian cancer.
Consequently, Jones teaches statins alone and in combination with other chemotherapeutic can be used in treating cancers such as ovarian cancer.
As per MPEP 2144.06: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Both Tavazoie and Jones teach compositions and methods useful for the same purpose of treating identical diseases, and additionally, combination therapy. Consequently, as re Kerkhoven, the idea of combining Tavazoie’s administration of Abequolixron with Jones’s administration of atorvastatin logically flows from their individual teachings in the prior art.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have combined Tavazoie’s invention with Jones’s invention to access the instant invention as per claims 31-32. A person of ordinary skill in the art would have arrived at the dosing regimen as a result of routine optimization in developing combination therapy treatment regimens based on the individual subject and other common parameters well-known in the pharmaceutical arts tailored towards a patient’s cancer needs.
As per MPEP 2144.05, II, A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claims 6, and 31-32 are rejected on grounds of being obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55-56 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-10 of U.S. Patent No. 11878956B2 in view of Tavazoie et al (US9399028B2)(“Tavazoie”), Jones et al (Jones, Hannah M., Ziwei Fang, Wenchuan Sun, Leslie H. Clark, Jessica E. Stine, Arthur-Quan Tran, Stephanie A. Sullivan, Timothy P. Gilliam, Chunxiao Zhou, and Victoria L. Bae-Jump. "Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro." American journal of cancer research 7, no. 12 (2017): 2478) (“Jones”) and as evidenced by PubChem ( National Center for Biotechnology Information. PubChem Compound Summary for CID 10218693, RGX-104 free Acid. https://pubchem.ncbi.nlm.nih.gov/compound/RGX-104-free-Acid. Accessed June 11, 2025)(“PubChem”), Childs et al (Childs, Daniel S., and Aminah Jatoi. "A hunger for hunger: a review of palliative therapies for cancer-associated anorexia." Annals of palliative medicine 8, no. 1 (2018): 50)(“Childs”), National Cancer Institute (National Center Institute. NCI Dictionary of Cancer Terms. “Neuroendocrine Tumor. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neuroendocrine-tumor. Accessed June 11, 2025)(“National Cancer Institute”), Teixidó et al (Teixidó, Cristina, Noelia Vilariño, Roxana Reyes, and Noemí Reguart. "PD-L1 expression testing in non-small cell lung cancer." Therapeutic Advances in Medical Oncology 10 (2018): 1758835918763493)(“ Teixidó”), and Dana Farber Cancer Institute (Dana Farber Cancer Institute. “Inoperable Cancer: What Does it Mean? https://blog.dana-farber.org/insight/2017/12/inoperable-cancer-meaning/#:~:text=%E2%80%9CLiquid%20cancers%2C%E2%80%9D%20such%20as,material%20within%20the%20body%27s%20bones. Accessed June 11, 2025)(“Dana Farber Cancer Institute”).
The teachings of Tavazoie, Jones, PubChem, Childs, National Cancer Institute, Teixidó, and Dana Farber Cancer Institute are set forth as relied upon above.
Claims 1, 7-10 of ‘956 are directed towards methods of treating metastatic cancer in a subject comprising administering to the subject an effective amount of the zinc salt of Abequolixron (compound 25), “wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, colon cancer, renal cell cancer, lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, bladder cancer, head and neck cancer, glioblastoma, diffuse large B-cell lymphoma, leukemia, and melanoma,” including drug-resistant metastatic cancer. Instant claims recite administering a pharmaceutically acceptable salt as an alternative, which is inclusive of the zinc salt as claimed in ‘956.
Additionally, Applicant utilizes the term “comprising.” As per MPEP 2111.03, I: The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to modified the claims of ‘956 to arrive at the instant claims as ‘956 teaches identical cancers, drug, and combination therapies as instant claims, because instant claims are directed towards pharmaceutically acceptable salts of Abequolixron inclusive of the zinc salt, Jones teaches the use of statins in combination therapy, PubChem teaches that Compound 25 is Abequolixron and identical to instant claim set, Childs teaches that corticosteroids are appetite stimulants commonly used in cancer treatments, Teixidó teaches PD-L1 assays are routine in the practice of utilizing checkpoint inhibitors, and Dana Farber Cancer institute teaches that metastatic cancers are inoperable or unresectable cancers. Additionally, the transitional term “comprising,” is inclusive of additional unrecited elements and method steps.
Consequently, a person of ordinary skill in the medicinal arts would arrive at the instant claim set as a highly predicable result with a reasonable expectation of success based on routine optimization as part of developing a personalized cancer treatment plan based on cancer type, patient population, and other common parameters in the art of oncology.
Consequently, Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55-56 are rejected on grounds of obviousness-type nonstatutory double patenting.
Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55-56 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-19 of U.S. Patent No. 12258303B2 in view of Tavazoie et al (US9399028B2)(“Tavazoie”), Jones et al (Jones, Hannah M., Ziwei Fang, Wenchuan Sun, Leslie H. Clark, Jessica E. Stine, Arthur-Quan Tran, Stephanie A. Sullivan, Timothy P. Gilliam, Chunxiao Zhou, and Victoria L. Bae-Jump. "Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro." American journal of cancer research 7, no. 12 (2017): 2478) (“Jones”) and as evidenced by PubChem ( National Center for Biotechnology Information. PubChem Compound Summary for CID 10218693, RGX-104 free Acid. https://pubchem.ncbi.nlm.nih.gov/compound/RGX-104-free-Acid. Accessed June 11, 2025)(“PubChem”), Childs et al (Childs, Daniel S., and Aminah Jatoi. "A hunger for hunger: a review of palliative therapies for cancer-associated anorexia." Annals of palliative medicine 8, no. 1 (2018): 50)(“Childs”), National Cancer Institute (National Center Institute. NCI Dictionary of Cancer Terms. “Neuroendocrine Tumor. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neuroendocrine-tumor. Accessed June 11, 2025)(“National Cancer Institute”), Teixidó et al (Teixidó, Cristina, Noelia Vilariño, Roxana Reyes, and Noemí Reguart. "PD-L1 expression testing in non-small cell lung cancer." Therapeutic Advances in Medical Oncology 10 (2018): 1758835918763493)(“ Teixidó”), and Dana Farber Cancer Institute (Dana Farber Cancer Institute. “Inoperable Cancer: What Does it Mean? https://blog.dana-farber.org/insight/2017/12/inoperable-cancer-meaning/#:~:text=%E2%80%9CLiquid%20cancers%2C%E2%80%9D%20such%20as,material%20within%20the%20body%27s%20bones. Accessed June 11, 2025)(“Dana Farber Cancer Institute”).
The teachings of Tavazoie, Jones, PubChem, Childs, National Cancer Institute, Teixidó, and Dana Farber Cancer Institute are set forth as relied upon above.
Claims 1, 7-10 of ‘303 are directed towards methods of treating cancer in a subject comprising administering to the subject an effective amount of the zinc salt of Abequolixron (compound 25), “wherein the cancer is lung cancer or endometrial cancer” including drug-resistant metastatic cancer. Instant claims recite administering a pharmaceutically acceptable salt as an alternative, which is inclusive of the zinc salt as claimed in ‘303.
Claims 14-19 of ‘303 are directed towards combination therapies similar and/or identical in subject matter to instant invention, which is overlapping in scope with instant claims.
Additionally, Applicant utilizes the term “comprising.” As per MPEP 2111.03, I: The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to modified the claims of ‘303 to arrive at the instant claims as ‘303teaches identical cancers, drug, and combination therapies as instant claims, because instant claims are directed towards pharmaceutically acceptable salts of Abequolixron inclusive of the zinc salt, because Jones teaches the use of statins in combination therapy, PubChem teaches that Compound 25 is Abequolixron and identical to instant claim set, Childs teaches that corticosteroids are appetite stimulants commonly used in cancer treatments, Teixidó teaches PD-L1 assays are routine in the practice of utilizing checkpoint inhibitors, and Dana Farber Cancer institute teaches that metastatic cancers are inoperable or unresectable cancers. Additionally, the transitional term “comprising,” is inclusive of additional unrecited elements and method steps.
Consequently, a person of ordinary skill in the medicinal arts would arrive at the instant claim set as a highly predicable result with a reasonable expectation of success based on routine optimization as part of developing a personalized cancer treatment plan based on cancer type, patient population, and other common parameters in the art of oncology.
Consequently, Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, 55-56 are rejected on grounds of obviousness-type nonstatutory double patenting.
Response to Arguments
The Remarks of August 8, 2025 have been fully considered but are not fully persuasive for the reasons below.
35 USC 112(a)
Applicant’s Arguments:
“The Office rejects all claims for lacking enablement and suggests that only non-small cell lung cancer is enabled. The Office reasons that the claims are “broad with respect to the patient population, cancer, and treatment,” that the state of the art is “highly unpredictable,” and the level of predictability is low. Applicant respectfully disagrees. First, Applicant respectfully disagrees that the scope of the claims is broad. The claims are limited to a single compound, a specific subset of cancer (namely, ApoE-related cancer), and a specific dosing regimen that is exemplified in the application.”
Examiner’s Response:
The Examiner respectfully disagrees. The cancers listed by Applicant are broad, and heterogenous in terms of etiology, origin, heterogeneity within the specific tumors, environmental vs genetic drivers, drug resistance and treatment options. As aforementioned, the subject as claimed by Applicant is equally broad. Applicant has failed to provide sufficient data and/or support that the instant invention is enabled for the full scope of the claims as outlined previously and restated above.
Based on Applicant’s working examples and what is known in the prior art, Applicant has failed to demonstrated the specific dosing regimen is effective for other cancers besides lung cancer in mice. Applicant has not demonstrated effectiveness of the dosing regiment in any actual human cancer patients or across the full scope of subjects as claimed. In fact, there is a lack of details supporting the effectiveness of the claimed dosing regimen for treating cancer, which was previously emphasized to Applicant. Applicant has failed to provide a response as requested previously to address these significant and critical gaps in data and working examples to support an enabled disclosure.
Applicant is reminded that as per MPEP 2164.05 “To overcome a prima facie case of lack of enablement, applicant must present argument and/or evidence that the disclosure would have enabled one of ordinary skill in the art to make and use the claimed invention at the time of filing. This does not preclude applicant from providing a declaration after the filing date which demonstrates that the claimed invention works. However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art at the time of filing. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must reasonably enable the full scope of the claimed invention. See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
Consequently, the Examiner once more invites Applicant to appropriately respond to the scope of enablement rejection, particularly regarding the details omitted from the working examples provided and absence of experimental data supporting the claimed dosing regimen and methods of treatment.
Applicant’s Arguments:
“Second, Applicant disagrees that the art is highly unpredictable. In reaching the conclusion that the art is highly unpredictable, the Office relies heavily on a single reference, Darwish, in finding this alleged unpredictability. Applicant submits that this is a selective reading of Darwish and that Darwish actually confirms the role of ApoE in cancer is very well understood… Thus, Applicant submits that Darwish serves to confirm that ApoE-related cancer is a well- understood, well-defined term to one of skill in the art. Indeed, a review of the various tables provided in Darwish reveals the immense amount of knowledge that is available to one of skill in the art regarding ApoE’s role in various cancers. The presence of a single reference questioning a narrow, the possible inability of ApoE to be used as a biomarker in certain cases, and the need for more research to better understand the role of ApoE in cancer does not mean the instant claims lack enablement.”
Examiner’s Response:
The Examiner respectfully disagrees. Applicant has misinterpreted the Examiner’s arguments. Firstly, Darwish is not relied on as a singular reference to determine predictability. The Examiner also cites to Hanahan, which supports the unpredictable and heterogenous nature of cancer as a disease containing a multitude of subtypes. As aforementioned, Applicant’s claims are directed towards broad classes of cancers that are diverse in terms of etiology, origin, treatment options, tumor heterogeneity and more. It is not reasonable to conclude that the single compound as claimed is enabled to treat all types of these cancers across the broad subjects as claimed nor is it reasonable to conclude the identical dosing regimen would be equally effective.
Darwish supports that there is variability regarding the role and significance of ApoE in the cancer types claimed and that there is variability depending on patient population, in addition to conflicting reports about the use of ApoE as a biomarker. In summary, Darwish is a literature review that highlights the state of the art for ApoE in cancers, which demonstrates ApoE is not consistent across all cancer types and patient populations as claimed: it is variable, therefore contributes to unpredictability in the art. As aforementioned, Applicant has failed to provide information on the patient populations and cancers tested as per Example 1.
Additionally, it is well-known in oncology that monotherapy is not effective for many of the cancers claimed; therefore, unreasonable to claim Abequolixron can be effectively used as monotherapy using the treatment regimen as claimed by Applicant. Applicant has provided no working examples and/or supporting in favor of such a claim.
Applicant is reminded as per MPEP 2164.03 regarding predictability, “In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).”
Therefore, Applicant’s claim that “In reaching the conclusion that the art is highly unpredictable, the Office relies heavily on a single reference, Darwish, in finding this alleged unpredictability,” is not accurate.
Applicant is further reminded as per MPEP 2164.03, “ 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. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).”
Applicant is singularly focused on ApoE as a biomarker based on the comments: “The presence of a single reference questioning a narrow, the possible inability of ApoE to be used as a biomarker in certain cases, and the need for more research to better understand the role of ApoE in cancer does not mean the instant claims lack enablement.”
However, Applicant’s claims are not directed to whether ApoE can be used as a biomarker. Instead, Applicant’s claims are directed towards treating broad classes of cancers across a broad scope for subjects using Abequolixron and Applicant has failed to demonstrate that the method of treatment is enabled through sufficient working examples and/or support suggesting that it is reasonable to extrapolate from lung cancers to the broad class of cancers claimed.
Additionally, Applicant has failed to address the prima facie case of lack of enablement as outlined by the Examiner via a comprehensive Wands factor analysis as is the standard for test of enablement.
Most critically, Applicant has failed to address the lack of critical details for working example 1 pertaining the adverse event profile using combination therapy consisting of Abequolixron and docetaxel. No details were provided on what type of subject was actually tested, if they had cancer, and if so what type of cancer.
The Examiner additionally cites to the European Search Opinion, which identified the identical issue.
Additionally, as aforementioned Applicant’s examples are both directed to combination therapies and do not provide any support where Abequolixron is administered as monotherapy.
Applicant is reminded that as per MPEP 2164.02: “A working example is based on work actually performed.”
Furthermore, “The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1310, 115 USPQ2d 2012, 2023 (Fed. Cir. 2015) ( "Only a sufficient description enabling a person of ordinary skill in the art to carry out an invention is needed."). Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”
As aforementioned, cases involving physiological activity involve unpredictable factors, and cancer itself is known to be highly heterogenous and unpredictable. Additionally, the role of ApoE varies based on the cancer and patient population. Therefore, more is required.
The Examiner once more invites Applicant to provide evidence, arguments and/or experimental data addressing the points raised the Examiner in order to provide a complete response and rebut the prima facie case for lack of enablement as previously presented.
35 USC 103
Applicant’s Arguments:
“The Cited References Tavazoie discloses the use of Compound A to treat cancer and discloses a possible range of dosages of 0.01-100 mg/kg. Tavazoie is silent with respect to the claimed dosing level and frequency of Compound A. PubChem discloses Compound A. PubChem does not disclose any information regarding dosing regimens of Compound A. Childs is an article relating to palliative therapies for cancer-associated anorexia and certain classes of drugs that can be used as appetite stimulants. Childs does not discuss the use of Compound A for any purpose, nor does it discuss ApoE-related cancers. NCI is the National Cancer Institute’s definition for neuroendocrine tumor. It does not describe the use of Compound A for any purpose, nor does it discuss ApoE-related cancers. Teixido is an article relating to PD-L1 expression testing in NSCLC. It does not describe the use of Compound A for any purpose, nor does it discuss ApoE-related cancers. Dana Farber is a blog post that describes what inoperable cancer is, why certain cancers may be inoperable, and possible treatments for inoperable cancers. It does not describe the use of Compound A for any purpose, nor does it discuss ApoE-related cancers. Finally, Jones discusses the anti-tumor properties of atorvastatin in ovarian cancer. It does not describe the use of Compound A for any purpose, nor does it discuss ApoE-related cancers.”
Examiner’s Response:
The Examiner respectfully disagrees with the assessment of prior art, and reminds Applicant as per MPEP 2145, IV. “One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).”
First and foremost, as clearly explained in the Office Action, the references cited are used as evidence for claim interpretation and to support what a person of ordinary skill in the art would have known at the effective time of filing.
Applicant is advised to consult MPEP 2173.01, I: “Under a broadest reasonable interpretation, 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 time of the invention. 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.”
Applicant is also advised to consult MPEP 2124: “In certain circumstances, references cited to show a universal fact need not be available as prior art before the effective filing date of applicant’s claimed invention. In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962). Such facts include the characteristics and properties of a material or a scientific truism. Some specific examples in which later publications showing factual evidence can be cited include situations where the facts shown in the reference are evidence "that, as of an application’s filing date, undue experimentation would have been required, In re Corneil, 347 F.2d 563, 568, 145 USPQ 702, 705 (CCPA 1965), or that a parameter absent from the claims was or was not critical, In re Rainer, 305 F.2d 505, 507 n.3, 134 USPQ 343, 345 n.3 (CCPA 1962), or that a statement in the specification was inaccurate, In re Marzocchi, 439 F.2d 220, 223 n.4, 169 USPQ 367, 370 n.4 (CCPA 1971), or that the invention was inoperative or lacked utility, In re Langer, 503 F.2d 1380, 1391, 183 USPQ 288, 297 (CCPA 1974), or that a claim was indefinite, In re Glass, 492 F.2d 1228,1232 n.6, 181 USPQ 31, 34 n.6 (CCPA 1974), or that characteristics of prior art products were known, In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962)." In re Koller, 613 F.2d 819, 824 n.5, 204 USPQ 702, 706 n.5 (CCPA 1980) (quoting In re Hogan, 559 F.2d 595, 605 n.17, 194 USPQ 527, 537 n.17 (CCPA 1977) (emphasis in original)).”
Consequently, Applicant has failed to fully respond to the Examiner’s arguments as Applicant has failed to consider what the combined teachings would have suggested to a person of ordinary skill in the art.
Applicant’s Arguments:
“The Office alleges that the claimed dosing regimen is prima facie obvious because one of skill in the art would be motivated to tailor the dosages taught by Tavazoie and that one of skill in the art would have had a reasonable expectation of success in producing the claimed invention. Applicant respectfully disagrees and addresses these rejections with the remarks below As stated in the background of the specification, LXR activation results in expression of Apolipoprotein E (ApoE), which regulates tumorigenic features. ApoE induction leads to myeloid derived suppressor cell (MSDC) depletion by binding of LRP8, an ApoE receptor on MSDCs. Collectively, activation of ApoE expression thus results in inhibition of primary tumor growth and metastatic spread.
However, Example 1 of the application as filed demonstrates that, when subjects are administered abequolixron daily, most subjects experience neutropenia, an adverse event that has the potential to become a dose limiting toxicity. Example 1 demonstrates that using the claimed dosing regimen solves this problem, by providing patients with time off from treatment. That, with nothing more, demonstrates that the claimed dose is not merely the result of routine optimization of Tavazoie, but rather a method of treating cancer that solves the previously unknown problem of unacceptable toxicity observed with daily dosing.
Example 2 serves to confirm that the claimed dose a/so effectively reduces tumor volume of a similar extent to daily dosing. This, when combined with the unambiguous demonstration that the claimed dose provides fewer adverse events, serves as strong evidence that the claimed dose provides a safer means for the treatment of cancer compared to that described in Tavazoie or any of the cited references. This new and unexpected property attributable to the claimed intermittent dosing regimen.”
Examiner’s Response:
The Examiner respectfully disagrees.
As aforementioned, Applicant has omitted key details for Example 1 regarding if the patients are healthy, type of cancer, and disease progression. Therefore, Example 1 does not demonstrate that this problem has been solved based on omission of critical details. Example 1 is also directed towards combination therapy using cisplatin and abequolixron. No data is provided for monotherapy using abequolixron or for the other methods claimed by Applicant; therefore, it is not reasonable to conclude the data presented in the application supports that the specific claimed dosing regimen results in a safer but efficient treatment of cancer.
Example 2 is performed using a completely different combination therapy regimen; therefore, it is not reasonable to equate Example 1 with Example 2, particularly based on the omission of critical details regarding cancer type and patient population.
Additionally, as aforementioned, Applicant has provided no examples using monotherapy and the dosing regimen using abequolixron.
Consequently, Applicant has failed to provide sufficient support that the claimed dose provides a safer means for cancer treatment based on intermittent dosing regimen.
As stated previously, the anticancer properties of abequolixron pertaining lung cancer were already known in the art at the effective time of filing.
Based on what is known in the prior art and as cited above, a person of ordinary skilled in the art would be motivated to optimize methods of treatment to reduce adverse events, resulting in the claimed invention. Such result would be part of routine optimization.
Applicant has failed to provide data supporting criticality of range.
As per MPEP 716.02(d), II: “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).”
Applicant is reminded as per MPEP 716.02: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
Additionally, as per MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
Applicant is further reminded as per MPEP 716.02(b) that the burden is on the applicant to establish results are unexpected and significant and that “the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) .”
Applicant’s Arguments:
“In setting forth a prima facie obviousness rejection, it is not enough simply to find the elements of an invention in the prior art and assemble those elements in the manner recited in the claims, even where the skilled artisan would have the requisite skills to make the combination proposed by the Office. There must be some identified reason or problem known to the skilled artisan at the time the application was filed that would have motivated the combination of the prior art elements in the manner being claimed. See, e.g., in re Omeprazole Ligation, 536 F.3d 1361 (Fed. Cir. 2007) (holding that the use of water soluble subcoating to prevent a previously unknown interaction between an active agent and its enteric coating was not obvious because there was no evidence suggesting a problem that would lead a skilled artisan to use the subcoating). See also M.P.E.P. § 2143. Applicant submits that none of the cited references even suggest the problem of unacceptable toxicity with daily dosing and thus the claims are not prima facie obvious over these references”
Examiner’s Response:
The examiner respectfully disagrees. Once more, the cited references are relied on as evidence to establish what is common knowledge in the prior art.
Applicant is further reminded as per MPEP 2144, I: “The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings).”
As aforementioned, a person of ordinary skill in the art would be motivated to optimize methods of treatment to avoid adverse effects as is common practice in the field of oncology and medicine regarding patient care.
Furthermore, as per MPEP 2145, II: “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)…"The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).”
Applicant’s Arguments:
“Furthermore, it was not apparent, nor could it have been predicted based on the cited references, that the claimed intermittent dosing regimen could successfully achieve the result of reduction in tumor volume. Surprisingly, this beneficial property (demonstrated in Example 2) was observed concomitantly with a decrease in the harmful side effect of neutropenia (demonstrated in Example 1). It was not clear from any of the cited references that these effects were independent of each other; that is, it was not clear that the harmful side effect could be reduced while maintaining the therapeutic effect using the claimed dosing regimen.”
Examiner’s Response:
The Examiner has already discussed the issues with the working examples presented by Applicant pertaining the omission of critical details for Example 1. Applicant is invited to provide further data and/or explanations supporting their claims regarding the dosing regimen. As aforementioned, there is no data provided for monotherapy and Examples 1 and 2 utilize different subjects and combination therapies.
Applicant’s Arguments:
“The Office has asserted that the claims 21 are obvious over Tavazoie in combination with one or more of PubChem, Childs, NCI, Teixidó, Dana Farber, and Jones. In supporting its contention that the claims are obvious, the Office states that “a person of ordinary skill in the art would be motivated to optimize Tavazoie’s method to access the specific amounts and treatment duration as result of routine optimization...as explained by Tavazoie in a manner to avoid adverse effects and optimize effectiveness of the treatment plan.” None of the cited references teach or suggest that an intermittent dosing regimen could be used that successfully treats cancer while avoiding unacceptable adverse effects, such as neutropenia. This unexpected solution to a previously unknown problem is strong evidence of nonobviousness. Given the knowledge in the art at the time of filing, one could not have predicted that the intermittent dosing regimen would be successful at treating cancer while avoiding side effects, and, consequently, one of skill in the art would not have had a reasonable expectation of success at treating cancer using the claimed dosing regimen.”
Examiner’s Response:
As aforementioned, Applicant’s working examples fail to support the claim of unexpected results. Applicant is once more reminded that the burden is on the Applicant to establish that such results are unexpected and significant.
Additionally, Applicant is reminded that as per MPEP 716.02(c): “Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)” and that “ Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).”
Applicant is reminded that as per MPEP 2145 that “Rebuttal evidence may include evidence of "secondary considerations," such as "commercial success, long felt but unsolved needs, [and] failure of others." Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 4459, 467. See also, e.g., In re Piasecki, 745 F.2d 1468, 1473, 223 USPQ 785, 788 (Fed. Cir. 1984) (commercial success). Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997).”
Consequently, the Examiner invites Applicant to provide additional arguments and/or evidence to rebut the prima facie case of obviousness and reminds Applicant as per MPEP 2145. I that arguments cannot take the place of evidence in the record.
Double Patenting
Applicant’s Arguments:
“The Office rejects the claims for nonstatutory double patenting over the ‘956 and ‘303 patents, in both cases reasoning that the instant claims encompass the zinc salt of abequolixron and that “a person of ordinary skill in the medicinal arts would arrive at the instant claim set as a highly predicable result with a reasonable expectation of success based on routine optimization...” Applicant respectfully disagrees. The claims of the ‘956 and ‘303 patents provide no guidance whatsoever as to a Suitable dose for abequolixron, nor do they provide an indication of the beneficial properties the claimed dosing regimen exhibits and the previously unknown problem they solve. For the same reasons the claims are nonobvious over Tavazoie (and the other cited references), the claims are also nonobvious over the claims of the ‘956 and ‘303 patents, and the rejections for nonstatutory double patenting may be withdrawn.”
Examiner’s Response:
Similar arguments are applied as set forth above.
For these reasons, Applicant’s arguments are not persuasive.
Conclusion
Claims 6-13, 16-18, 20-23, 25, 28-34, 38-46, 48, 50-53, and 55-56 are pending and are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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