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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2 February 2026 has been entered.
Claims 8, 13, and 16 have undergone amendments. Claims 1, 2, 4-6, 8-11, and 13-16, submitted on 2 February 2026, represent all claims currently under consideration.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 2 February 2026, is acknowledged and has been considered.
Response to Amendment
The 35 U.S.C. § 112(b) and 35 U.S.C. § 112(d) rejections of Claim 8 are each withdrawn. Applicant has deleted reference to S-methyl 4-methyl-4-[methyl(2-phenoxycyclopentyl)amino]pent-2-ynethioate, obviating the antecedent basis and issues regarding further limitation of Claim 1.
The 35 U.S.C. § 112(a) rejection of Claims 13 and 16 is maintained. Applicant has amended the claims to delete reference to the prevention of cancers, and has specified certain cancers that can be treated with compounds of the invention. Applicant further provided several references which demonstrate that several forms of each of the claimed cancers are known to be associated with dysregulation of aldehyde dehydrogenase. However, the claim includes cancers such as “solid carcinoma”, “carcinoid tumors”, “adenocarcinomas”, and “sarcomatoid carcinomas”, which are broad forms of cancer, and not all forms of these cancers have upregulated aldehyde dehydrogenase. For example, several forms of the claimed cancers do not overexpress ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and ALDH2, which are demonstrated in the specification to be inhibited by compounds of the invention (See 112(a) rejection below, Protein Atlas References).
Claim Objections
Claim 13 is objected to because of the following informalities: The limitation “carcinoid tumors” is listed twice in the Markush list of cancers. 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.
Claim 13 is 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 the treatment of certain cancers, such as those which overexpress or display greater aldehyde dehydrogenase activity such as breast cancer, it does not reasonably provide enablement for all forms of the claimed cancers. 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 one of many cancers, comprising administering to a subject in need a therapeutically effective amount of a compound of Claim 1. The compounds of claim 1 are aminothiolester inhibitors of aldehyde dehydrogenase. Thus, the claims are directed to a method which can be used to treat several forms of cancer, including all forms of solid carcinoma, carcinoid tumors, sarcomatoid carcinomas, adenosquamous carcinomas, and adenocarcinomas, among other forms of cancer, using the compounds of the invention to inhibit the activity of aldehyde dehydrogenase.
The state of the prior art and the predictability or unpredictability of the art:
As described in the prior office action, aldehyde dehydrogenase is a known target in several forms of cancer, where it is upregulated and targeting this enzyme is a known therapeutic target for the treatment of these cancers which display overexpressed or overactive aldehyde dehydrogenase. However, not all forms of the claimed cancers are known in the art to overexpress aldehyde dehydrogenase, specifically, ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and ALDH2, which are demonstrated in the specification to be inhibited by compounds of the invention. ALDH1A1 is shown to be found at lower protein levels in Lung adenocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, endometrial adenocarcinoma, ovary squamous cell, and at similar levels in glioblastoma (Protein Atlas, ALDH1A1, https://web.archive.org/web/20241111045952/https://www.proteinatlas.org/ENSG00000165092-ALDH1A1/cancer). ALDH2 is shown to have lower protein levels in lower in lung squamous cell, renal cell carcinoma and head and neck squamous cell, levels not elevated in lung adenocarcinoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, lower in renal cell carcinoma, and is not significantly elevated in endometrioid adenocarcinoma, with similar levels of protein found in glioblastoma. There were few cases of malignant melanomas, lung and pancreatic cancers displayed moderate to strong cytoplasmic staining. Rare cases of malignant gliomas, colorectal, breast, ovarian and stomach cancers were moderately positive. Remaining cancer tissues were weakly stained or negative (Protein Atlas, ALDH2, https://web.archive.org/web/20160801042850/https://www.proteinatlas.org/ENSG00000111275-ALDH2/cancer). ALDH1A3 protein levels are similar in glioblastoma, lung adenocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, and lower in liver hepatocellular carcinoma and endometroid adenocarcinoma (Protein Atlas, ALDH1A3, https://web.archive.org/web/20241206171804/https://www.proteinatlas.org/ENSG00000184254-ALDH1A3/cancer). Protein levels of ALDH3A1 were similar in glioblastoma, lung adenocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and endometroid adenocarcinoma, lower in head and neck squamous cell carcinoma, liver hepatocellular carcinoma, and renal cell carcinoma (Protein Atlas, ALDH3A1, https://web.archive.org/web/20250808104410/https://www.proteinatlas.org/ENSG00000108602-ALDH3A1/cancer). Protein levels of ALDH1A2 were similar in glioblastoma, lower in lung adenocarcinoma, lung squamous cell carcinoma, head and neck squamous cell carcinoma, liver hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, and endometrioid adenocarcinoma (Protein Atlas, ALDH1A2, https://web.archive.org/web/20250120212731/https://www.proteinatlas.org/ENSG00000128918-ALDH1A2/cancer). Thus, not all forms of the cancers which are claimed overexpress the five isoforms of aldehyde dehydrogenase which the specification shows are capable of being inhibited by the compounds of the invention.
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 each form of cancer as claimed, as every form of cancer which is claimed does not overexpress the isoforms of aldehyde dehydrogenase which are shown to be inhibited using the compounds of the invention.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification demonstrates that the compounds of the invention are potent inhibitors of ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and ALDH2 (Table 4, Page 53). Thus, the specification enables the treatment of cancers which overexpress or have aberrant activity associated with these enzymes. However, the specification does not provide examples demonstrating the successful treatment of each form of the cancers which are claimed.
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.
Allowable Subject Matter
Claims 1, 2, 4-6, 8-11, and 14-15 are allowed.
Claim 16 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: A search of the prior art retrieved no art which anticipates or renders obvious newly amended Claim 1 (See Updated STN Search, Search Notes, Prior Office Action). The closest prior art comes from Ceylan (WO 2017/064247; Publication Date: 20 April 2017). As described in the prior office action, Ceylan discloses aldehyde dehydrogenase inhibitors of formula (I)
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wherein variables X1 and X2 are selected from C1-C7 alkyl group, phenyl, benzyl, or X1 and X2 come together with the nitrogen atom to which they are linked to form a heterocycle, or a pharmaceutically acceptable salt thereof (Page 3, Line 33- Page 4, Line 5). However, there are no teachings, suggestions, or motivations to replace one of variables X1 or X2 (analogous to variables R1 and R2 of the examined application) with a -CH2CH2O- group which has a terminal -CONR7R8 group, wherein R7 is methyl and R8 is NRR’ with R and R’ being selected from methyl, propenyl, benzyl, pyridyl, benzyloxybutyl, methyl-cyclohexenyl, or substituted benzyl. There is also no motivation to replace the alkyl group which is bound to the sulfur with a –(C1-C7)-CO2Z or branched –(C1-C7)alkyl-NY1Y2 group as described in the examined application. These groups are not described in the disclosure, and the artisan would not have any motivation to incorporate these groups in place of the methyl group as they are structurally distinct from the methyl group, and would not be expected to predictably result in a compound which has similar properties as DIMATE. The compounds
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and
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are disclosed, but do not contain an OR4 moiety attached to this ring system, and there is no teaching, suggestion, or motivation provided that would guide the artisan to modify these compounds to arrive at the compounds of Claim 1 of the examined application. Quash (European Journal of Medicinal Chemistry, 43, 2008, 906-916) discloses aminothiolester aldehyde dehydrogenase inhibitors of general structure
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, including compounds wherein
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are
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(Compound 2g) and
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(2j). However, there is no teaching, suggestion, or motivation provided to modify these compounds to contain the OR4 moiety of the compounds of the examined application. As these compounds are novel, the methods of producing these compounds are similarly found to be novel and non-obvious. Moreover, there is no prior art which teaches antibody-drug conjugates of these compounds linked to an antibody..
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, 2, 4-6, 8-11, and 14-15 are allowed.
Claim 13 is rejected.
Claim 16 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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