DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 7-12, 14, 16, 18, 19, 21, 23, 25-27, 29 and 30, submitted on 26 July 2023, represent all claims currently under consideration.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
This application is a 371 of PCT/US/2022/013896, filed 26 January 2022, which claims priority to provisional US 63/141,802, filed 26 January 2021. The effective filing date is 26 January 2021.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 12 February 2025, are acknowledged and have been considered.
Drawings
The drawings are objected to because Figures 1, 2, 4, 5, 11, and 16 are of low image quality and are difficult to interpret. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term INCUCYTE (Page 34, 35, 49) and SYTOX (Pages 35, 49) which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 14 is objected to because of the following informalities: There is a superfluous comma in the limitation “in order to inhibit, mitochondrial complex I, III, or both in a subject” (Emphasis Added). Appropriate correction is required.
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 9-12, 23, 25, and 26 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 treatment of cancers which are sensitive to inhibition of mitochondrial complexes I and/or III, does not reasonably provide enablement for the treatment of all forms of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of a compound of Claim 1. These compounds are inhibitors of mitochondrial complex (I) and complex (III). Thus, the claims are directed to a method which can be used to treat all forms of cancer using the compounds of the invention to inhibit the activity of mitochondrial complexes (I) and/or (III).
The state of the prior art and the predictability or unpredictability of the art:
Wang (Journal of Biomedical Science, 2023, 30:61) provides a review of mitochondrial alterations in human cancer. Dysregulation of cellular metabolism is one of the emerging cancer hallmarks. How mitochondrial dysfunction contributes to cancer progression remains unclear. The authors findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients, providing precise and personalized medicine against cancer (Abstract). Deregulation of cellular energetics has been recognized as a cancer characteristic, with cancer cells preferentially utilizing glycolysis over mitochondrial OXPHOS even in aerobic circumstances, referred to as the Warburg effect. Further studies have proposed that rather than impaired mitochondria, respiration in cancer cells might not be sufficient. Decreased cellular respiration might not be essential for cancer cell proliferation, and the tumor microenvironment might be another critical factor for cancer progression. The regulatory mechanisms leading to decreased cellular respiration in cancer cells are complicated and depend on tumor type (Page 2). Mutations in mtDNA and in the nuclear genes for the TCA cycle are commonly observed in cancer cells and are involved in metabolic remodeling. Additionally, mutations in oncogenes and tumor suppressor genes might contribute to cancer metabolism remodeling via altered mitochondrial pathways such as OXPHOS and fatty acid, glutamine, and one-carbon metabolisms (Page 2). The Warburg effect leads to cancer cells preferring the generation of 2 ATP via aerobic glycolysis instead of OXPHOS. To compensate for ATP production, glycolysis is upregulated by glucose transporters and glycolytic enzymes. Proliferative cancer cells exhaust all nutrients and oxygen very quickly, resulting in nutrient deprivation and hypoxia. In addition, lactate, a glycolytic product of cancer cells, contributes to acidic conditions. Although the Warburg effect proposes a preference for aerobic glycolysis, most cancer cells have intact mitochondria and an energetic shift between glycolysis and OXPHOS can occur in cancer cells (Page 2). Antioxidants, such as N-acetylcysteine, can suppress mitochondrial dysfunction-induced cell migration in human gastric cancer cells. Recent evidence proposed that mitochondria-targeted antioxidants such as MitoQ and MitoTEMPO could not significantly alter the progression of v-raf murine sarcoma viral oncogene homolog B-1 induced melanoma and KRAS-induced lung cancer in endogenous animal models (Page 8). Mitochondrial dysfunction has been suggested to contribute to a variety of human diseases such as cancer. Changes in energy metabolism or mitochondria might suppress the anticancer function of immune cells and enhance the immune escape of cancer cells in the tumor microenvironment. These findings suggest that targeting mitochondrial retrograde signaling in cancer cells and modulating metabolism and mitochondria might be promising therapeutic strategies against cancer progression to malignancy. The cancer-specific differences in mitochondrial alterations, mitochondrial retrograde signaling pathways, and response to immunotherapy need further investigation to develop precise and personalized medicine against cancer (Conclusion). However, not every cancer would be expected to be successfully treated by administering an inhibitor of mitochondrial complex I and/or III. Expression of NDUFAF1 is found to be variable among cancers, with some cancers showing high levels of this protein such as certain liver, cervical, and urothelial carcinomas. However, other cancers such as lymphoma and skin cancers were negative for this protein (Human Protein Atlas, https://web.archive.org/web/20241104004121/https://www.proteinatlas.org/ENSG00000137806-NDUFAF1/cancer). Thus, the artisan would not expect this method to predictably treat each and every form of cancer due to the lack of evidence of overexpression of mitochondrial complex I in all forms of cancer, as well as the conflicting roles that mitochondrial metabolism play in cancers, with the Warburg effect indicating that inhibition of this enzyme may not be sufficient to treat all cancers. Moreover, there is no evidence in the pharmaceutical arts for a panacea that can be used to treat each and every form of cancer.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer are sensitive to the inhibition of mitochondrial complexes (I) and/or (III), nor do all cancers overexpress these proteins.
The amount of direction or guidance presented and the presence or absence of working examples:
The compounds of the invention are inhibitors of mitochondrial complex I and complex III. Example 1 (Page 31) shows that the compounds of the invention inhibit OXPHOS and induce antiproliferative and immunomodulatory effects in human pancreatic cancer cells. Table 2 shows the IC50 value of compounds of the invention on the proliferation of HCT116 human cancer cells, showing efficacy at low µM concentrations, as well as a reduction in suppressive neutrophils. Thus, the specification enables the treatment of cancers which overexpress these proteins, or are sensitive to inhibition of mitochondrial complexes (I) and/or (III). However, the specification does not provide data demonstrating the treatment of each and every form of cancer.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim Rejections - 35 USC § 112(b)
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, 8-12, 14, 16, 18, 19, 21, 23, 25-27, and 29-30 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 defines variable X- as selected from halogen, 2,2,2-trifluroacetic acid, HO-, RCOO-, and acetic acid. Claim 1 does not define what variable R encompasses, causing the metes and bounds of claim 1 to be undefined and therefore, indefinite. Claims 2, 3, 8-12, 14, 16, 18, 19, 21, 23, 25-27, and 29-30 are rejected as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claim 7 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 7 has two lists of compounds which are separated by a “from:”, with one half of the list having Mito2-HU through Mito14-HU, and the second half having three triphenylphosphonium analogues. It is unclear which list of compounds are specifically claimed in the examined claim.
Claim 7 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 7 claims three ionic compounds
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, but these compounds lack a corresponding X- as claimed in Claim 1 which Claim 7 depends upon. There is a lack of antecedent basis for the removal of variable X- in these compounds.
Claims 25, 26, 29, and 30 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims claim an effective concentration of less than about 20 µM, or less than about 10 µM. However, the specification does not define what encompasses “about”, leading there to be uncertainty of the metes and bounds of what encompasses “about 10µM” and “about 20 µM”, causing the claims to be indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 depends on Claim 1, which states that the ionic compound must have a corresponding anion X- accompanying the compound. The final three compounds which are claimed do not have a corresponding anion X-, causing these compounds to not further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
Claims 1-3, 8, 14, 16, 18, 19, 21, 27, 29, and 30 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action.
The following is an examiner’s statement of reasons for allowance: The prior art does not teach, suggest, or provide motivation to develop the compounds of the examined application (See STN Search, Search Notes). The closest prior art is STN RN 749153-61-5 (Entered STN: 21 September 2004). STN RN 749153-61-5
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differs from the compounds of the examined application by the replacement of the -O- prior to the linking group by a -C(=O)- moiety. There is no evidence in the prior that art this compound is useful for inhibiting mitochondrial complexes I or III. Thus, the artisan would have no motivation or reasonable expectation of success, to modify this compound by replacing the -C(=O)- moiety with -O- as claimed in the examined application. The triphenylphosphonium moiety is known in the prior art to be useful for the targeting of mitochondria (See Kalyanaraman, WO 2019/136154) (IDS, 12 February 2025). However, none of the prior art teaches the utilization of the hydroxyurea moiety in these compounds, nor is there any suggestion or motivation found to modify these compounds to arrive at the compounds claimed in the examined application.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1-3, 7-12, 14, 16, 18, 19, 21, 23, 25-27, 29 and 30 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625