DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Preliminary amendment filed on 10/24/2022 has been entered. Claims 1-16 are pending in this application. Claims 2, 4-10, and 13-16 are withdrawn. Claims 1, 3, 11, and 12 are currently under examination.
Priority
This application is a 371 of PCT/IB2021/053378 filed on 04/23/2021, which claims benefit of US PRO 63/014,838 filed on 04/24/2020.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/014,838, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 1, 3, 11, and 12 recite “obtaining a biological sample of a cancer from the patient… comparing the determined level to a threshold level for the at least one biomarker; and administering a pharmaceutically effective amount of at least one mitochondrial biogenesis inhibitor if the determined level exceeds the threshold level”, and/or “the mitochondrial biogenesis inhibitor is… tigecycline, minocycline… clarithromycin, pyrvinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline… an mDIVI-1 derivative, caffeic acid phenyl ester, an antimitoscin, and a repurposcin”, which are not disclosed or supported by the prior-filed Application No. 63/014,838. Thus, the priority date of claims 1, 3, 11, and 12 is 04/23/2021.
Election/Restrictions
Applicant's election without traverse of Group I invention (claims 1-3 and 10-12) and species (A. the gene signature recited in claim 3, each of ACLY, VDAC3, HADH2, and COX6B1, and B. azithromycin as the specific inhibitor) in the reply filed on 08/21/2025 is acknowledged. Claims 2, 4-10, and 13-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 1, 3, 11, and 12 are currently under examination.
Information Disclosure Statement
Two information disclosure statements (IDS) filed on 10/24/2022 and 11/19/2024 have been considered.
Claim Objections
Claims 1 and 12 are objected to because of the following informalities: In claim 1, change the recitation “a cancer” (line 3) to “a tumor” to be consistent with “tumor” in the preamble; spell out the abbreviated “CSC-based” (line 5) to “cancer stem cell (CSC)-based”; and insert the missing phrase “at least one of” immediately before the recitation “ACLY” because the conjunction “and” indicates combination of all recited 13 biomarkers. In claim 12, insert the missing phrase “the group consisting of” immediately after the recitation “selected from” (line 2) to comply with Markush group format ending with conjunction “and” before the last species; change the misspelled “erythromycin” (line 3) to “erythromycin”; and spell out the abbreviated “TPP-” (line 5) and “mDIVI1-1” (line 6) to “triphenyi-phosphonium (TPP)” and “mitochondrial division inhibitor-1 (mDIVI-1)”, respectively. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 11, and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing the likelihood of tumor metastasis and tumor recurrence in a patient, , does not reasonably provide enablement for preventing the likelihood of tumor metastasis and tumor recurrence in a patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or to use the invention commensurate in scope with these claims. Claims 3, 11, and 12 depend from claim 1.
Applicants claim a method for preventing the likelihood of tumor metastasis and tumor recurrence in a patient, recited in claim 1. However, no limiting definition of “preventing" or “prevention” is given in the instant Specification. In the absence of a limiting definition by the Applicants, "prevention" as described according to the Institute for International Medical Education (pages 15 and 16), is a preventive measure, such as preserving physical fitness in primary prevention and effective intervention to correct departures from good health in secondary prevention. More specifically, tertiary prevention, which is most relevant as used in the context of the instant invention, "consists of the measures available to reduce or eliminate long-term impairments and disabilities, [and to] minimize suffering caused by existing departures from good health". Thus, the claimed method for preventing the likelihood of tumor metastasis and tumor recurrence in a patient as interpreted by a skilled practitioner of the medical or pharmaceutical arts would be to reduce for long-term the occurrence of or to eliminate the likelihood of tumor metastasis and tumor recurrence in a patient by the method.
The Applicant's attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The rejected invention is drawn to A method for preventing and/or reducing the likelihood of tumor metastasis and tumor recurrence in a patient, the method comprising: obtaining a biological sample of a tumor from the patient; determining, or having determined, the level of at least one mitochondrial biomarker… comparing the determined level to a threshold level for the at least one biomarker; and administering a pharmaceutically effective amount of at least one mitochondrial biogenesis inhibitor if the determined level exceeds the threshold level.
Relative skill of those in the art: The relative skill of those in the art is from biomedical field (see the cited reference below).
Breadth of claims: The claim is extremely broad in that it encompasses the prevention of the likelihood of tumor metastasis and tumor recurrence in a patient using the instantly claimed method.
State of the prior art/Predictability or unpredictability of the art: There is no teaching or suggestion in the state of the prior art that application of certain pharmaceutical method can prevent the likelihood of tumor metastasis and tumor recurrence in a patient. Sotgia et al. (CELL CYCLE VOL. 17, NO. 17, 2091–2100, 2018, also listed in IDS filed on 10/24/2022) disclosed a short mitochondrial gene signature predicts tumor recurrence and distant metastasis, in high-risk breast cancer patients, receiving endocrine therapy. Note that high expression of this Mito-Signature predicts treatment failure on Tamoxifen (Tam). These represent ER-positive patients, with the luminal A sub-type of breast cancer, who showed local lymph node metastasis at diagnosis, with 10–15 y of follow-up data. RFS, recurrence-free survival; DMFS, distant metastasis-free survival.
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(page 2097, right column, Figure 10). One of skilled artisan would understand that contemporary treatment or management of tumor metastasis and tumor recurrence is to reduce the likelihood, not to prevent or to eliminate the likelihood.
Amount of guidance/Existence of working examples: It is worth noting that there are no working examples in the instant application to show that the claimed method is effective for preventing the likelihood of tumor metastasis and tumor recurrence in a patient as recited in the claim. The exemplary embodiments of the Specification merely present: (i) an open-access online survival analysis tool to interrogate publicly available microarray data from up to 3,951 breast cancer patients; and (ii) Assays for Tumor Growth, Metastasis using fertilized White Leghorn eggs (para. [0070-0072]).
Quantity of experimentation: In order to practice the full scope of the invention, one skilled in the art would need to undertake a novel and extensive research program to show that a preventive measure can be achieved after applying the claimed method. Furthermore, one of ordinary skill in the art would need to test a representative number of animals before one of ordinary skill in the art would be able to conclude that any method can be used to prevent the likelihood of tumor metastasis and tumor recurrence. Because this research would have to be exhaustive, and because it would involve such a wide and unpredictable scope of use in prevention of the likelihood of tumor metastasis and tumor recurrence in a patient, it would constitute an undue and unpredictable experimental burden.
Lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP § 2164. Genetech, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors as discussed above, including the amount of guidance provided and the predictability of the art and the lack of working examples to practice the full scope of the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 11, and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Claim 11 depends from claim 1.
Claim 1 recites “threshold level” (lines 8 and 10), which is not specifically defined, but is also called control. The “control” is broadly defined as “a sample, reference, or standard that is used as a basis for comparison with one or more experimental or test samples” (para. [0033]). Thus, the “threshold level” is not a defined cutoff value and thus the scope of the level is unclear. Applicant is advised to insert the clause “that is an expression level of a suitable non-tumor sample taken from the same individual or from a population”, supported by para. [0033], immediately after the recitation “a threshold level” (line 8).
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: Claim 3 recites “comprises each of ACLY, VDAC3, HADH2, and COX6B1”, which means comprising of one of these 4 biomarkers. Since the “comprises” is open-ended, claim 3, requiring only one of 4 biomarkers with opening for additional biomarkers, would be broader than the independent claim 1 which comprises at least one of 13 biomarkers. Applicant is advised to change the recitation “each of” (line 2) to “a combination of” for indicating that the gene signature requires all 4 biomarkers, which is also supported by Table 3 in the Specification.
Claim 12 recites “derivative” (lines 5 and 6), which is not specifically defined and thus the scope is unclear. Applicant is advised to insert the compound word “moiety-containing”, supported by the Specification, immediately before the recitation “derivative” (lines 5 and 6).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 11, and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon or a product of nature without significantly more. The 2019 Revised Patent Subject Matter Eligibility Guidance (issued January 7, 2019)” (https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf) and “October 2019 Update: Subject Matter Eligibility (issued October 17, 2019)” (https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf), are followed here. The claim is directed to a statutory category, e.g., a process (Step 1: YES). The claim is then analyzed in Step 2A (Prong one) to determine whether it is directed to any judicial exception. The claims 1 and 3 recite a method comprising obtaining a biological sample of a cancer from the patient; determining, or having determined, the level of at least one mitochondrial biomarker in the biological sample of a CSC-based mitochondrial-related gene signature comprising at least one of ACLY, VDAC3, HADH2, COX6B1, ATP5B, MCCC1, SLC25A10, TIMM8A, ECH1, ACACA, HSPA9, CHCHD2, and CCDC47; comparing the determined level to a threshold level for the at least one biomarker; and administering a pharmaceutically effective amount of at least one mitochondrial biogenesis inhibitor if the determined level exceeds the threshold level, which encompass a process of mentally looking up a chart that is documented with increased expression levels of listed biomarkers in cancer sample compared with a control, followed by administering to the cancer patient an inhibitor of the corresponding biomarker or mentally identifying from the chart the benefit of an inhibitor of the corresponding biomarker that has been previously administered to the cancer patient. Accordingly, the claim is directed to at least one exception (Step 2A, prong one: YES). The claim is then analyzed in Step 2A (Prong two) and is deemed that this judicial exception is not integrated into a practical application because there is no indication that the obtaining a biological sample, determining, or having determined, the level of at least one mitochondrial biomarker, comparing the determined level to a threshold level for the at least one biomarker; and administering an inhibitor steps are in any marked way. Instead, those steps are mental steps or are routine, well-known, and well-understood. Thus, the claimed process as a whole does not display markedly different characteristics compared to the closest naturally occurring process. Accordingly, the Step 2A (Prong two) is NO because this judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because prior to applicant’s invention and at the time of filing the application, administering of a pharmaceutically effective amount of at least one mitochondrial biogenesis inhibitor if the determined level exceeds the threshold level, as evidenced by the references under the 102/103 rejection below. The recitation of specific biomarkers does not affect this analysis, because it was also well-understood, routine and conventional. Thus, the claimed method, when recited at this high level of generality, does not meaningfully limit the claim, and the claim as a whole does not amount to significantly more than each “natural phenomenon” by itself (Step 2B: NO). The claim does not qualify as eligible subject matter.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 11, and 12 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Lisanti et al. (WO 2018/195434, October 25, 2018, hereinafter referred to as Lisanti ‘434) incorporated by Lamb et al. (Oncotarget, Vol. 5, No. 22, p. 11029-11037, 2014, hereinafter referred to as Lamb ‘2014, also listed in IDS filed on 10/24/2022).
With regard to structurally limitations “a method comprising obtaining a biological sample of a tumor (or breast cancer) from the patient; determining, or having determined, the level of at least one mitochondrial biomarker in the biological sample of a CSC-based mitochondrial-related gene signature comprising at least one of ACLY, VDAC3, HADH2, COX6B1, ATP5B, MCCC1, SLC25A10, TIMM8A, ECH1, ACACA, HSPA9, CHCHD2, and CCDC47 (or a combination of ACLY, VDAC3, HADH2, and COX6B1, elected); and administering a pharmaceutically effective amount of at least one mitochondrial biogenesis inhibitor (or azithromycin, elected) if the determined level exceeds a threshold level that is an expression level of a suitable non-tumor sample taken from the same individual or from a population” (claims 1, 3, 11, and 12):
Lisanti ‘434 disclosed methods of treating cancer by administering to a patient in need thereof of a pharmaceutically effective amount of an inhibitor of oxidative metabolism. Inhibitors of oxidative metabolism may include members of tetracycline family and the erythromycin family. Members of the erythromycin family include erythromycin, azithromycin, and clarithromycin. It is an objective of this disclosure to demonstrate that mitochondrial biogenesis plays a critical role in the propagation and maintenance of many cancers. It is also an objective of this disclosure to demonstrate that the combination of mitochondrial-targeting compounds and glycolysis-targeting compounds may be used to eradicate cancer stem cells (CSCs) by metabolically "starving" the CSCs (page 4/52, [0008]; page 3/52, [0006]). Targeting the metabolic differences between tumor and normal cells holds promise as a novel cancer treatment strategy. Proteomic analysis of human breast cancer stem cells likewise revealed the significant overexpression of several mitoribosomal proteins as well as other proteins associated with mitochondrial biogenesis, Lamb et al., Oncotarget, 5(22): 11029-11037 (2014). Functional inhibition of mitochondrial biogenesis using the off-target effects of certain bacteriostatic antibiotics or OXPHOS inhibitors provides additional evidence that functional mitochondria are required for the propagation of cancer stem cells (pages 2/52 to 3/52, [0004]). Lamb ‘2014 (incorporated by reference here) disclosed a published clinical data set of N=28 breast cancer patients in which their tumor samples were subjected to laser-capture microdissection, to physically separate epithelial cancer cells from their adjacent tumor stroma. Table 3 presents a summary of these findings. Overall, 39 of the “metabolic targets” that we identified in mammospheres (Tables 1 & 2) were also transcriptionally elevated in human breast cancer cells in vivo (Table 3).
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. Quantitative proteomics or transcriptional analysis was conducted to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. Inhibition of MCT1/2 function effectively reduces mammosphere formation in both ER-positive and ER-negative breast cancer cell lines. Very similar results were obtained with oligomycin A, an inhibitor of the mitochondrial ATP synthase. These findings have important clinical implications for exploiting mitochondrial metabolism to eradicate cancer stem cells and to prevent recurrence, metastasis and drug resistance in cancer patients (page 11034, left col., para. 2 and Table 3; page 11029, Abstract).
Thus, these teachings of Lisanti ‘434 incorporated by Lamb ‘2014 anticipate Applicant’s claims 1, 3, 11, and 12 because (a) the method of Lisanti ‘434 administered inhibitors of oxidative metabolism, specifically including erythromycin or azithromycin, to target cancer stem cell for treating cancer, especially in selected patients having upregulated mitochondrial biogenesis biomarkers, and (b) Lamb ‘2014 provides such upregulated mitochondrial biogenesis biomarkers in Table 3, which comprises the claimed biomarkers, or, in an alternative, skilled artisan would be motivated to combine the method of Lisanti ‘434 with differential gene expression profile of Lamb ‘2014 to treat selected cancer patients by targeting cancer stem cells having upregulated mitochondrial biogenesis biomarkers.
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691