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 .
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.
This office action is a response to applicant’s communication submitted May 19, 2026, wherein claims 5 and 11 were amended and claim 12 was canceled. This application claims benefit of provisional application 63/476,870 filed December 22, 2022.
Claims 1-11 and 13-20 are pending in this application.
Election
Applicant’s election of species
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wherein R1 is unsubstituted ethyl, R2 is unsubstituted methyl, and R3 is a monovalent camptothecin in the reply filed on May 19, 2026 is acknowledged. It is not clear if Applicant is traversing the election requirement or traversing any characterization that the pending claims are directed to, or limited by any particular drug moiety as described on page 1 of Applicants response (pg. 1, para. 6). Applicant argues the common inventive concept is not a specific active pharmaceutical ingredient, but rather the disulfide-based functional group chemistry and its use in biologically relevant prodrug architectures (pgs. 1-2, bridging para. 2). However, the range of disulfide moieties encompassed would present a serious search burden as they have acquired separate statuses in the art, and are not obvious variants of each other. For Example, one species of claim 18,
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and another species
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, while both possessing disulfide prodrugs and sharing the same drug moiety, the aliphatic alkyl disulfide of the first compound requires searching different fields than the latter compound comprising cyclic aromatic disulfides. There is no evidence in the prior art that the two moieties are obvious variants of each other. Thus the election requirement is found to be proper and maintained. Claims 1-8, 11, 13, 16, 18-20 are encompassed by the election. Claims 7-10, 14-15 and 17 are withdrawn as being drawn to unelected species. The elected compound was found to be free of the prior art. Additionally all compounds encompassed by claims 16 and 18 were found to be free of the prior art. The search was expanded to include the following species,
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which is encompassed by claims 1-8, 11, 13, 19-20. Additionally based on the prior art reference relied upon, the search was expanded to include any monovalent drug in order to facilitate compact prosecution.
Thus claims 1-8, 11, 13, 16, 18-20 read on the expanded species election and are examined herein.
Note regarding claim 17.
While withdrawn from consideration for the reasons described above, the Examiner notes that claim 17 includes compounds which are not encompassed by instant claim 1 and would be rejected under 112(d) for expanding, rather than limiting instant claim 1. For example, compounds
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,
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,
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recited by instant claim 17 does not possess the oxygen atom in the formula required by instant claim 1. Claim 17 also recites “formula” twice.
Drawings
The drawings are objected to because:
In the title of Figure 2A, the phrase “55 C” should read “55 °C”.
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 disclosure is objected to because of the following informalities: The phrase “MERGEFORMAT” appears throughout the specification, which is understood to be an artifact from formatting the document (pgs. 1-2, para. 0003, pg. 5, paras. 0016-0017, pg. 6, para. 0018, pgs. 11, paras. 0033, 0035, pgs. 11-12, para. 0035, pgs. 12-13, para. 0036, pg. 14, para. 0040, error continues up to page 63)
Appropriate correction is required.
Claim Objections
Claim 16 is objected to because of the following informalities:
In claim 16 the phrases “(GEM-SS)” and “(PTX-SS)” should be on the same line to avoid confusion.
Appropriate correction is required.
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.
Claims 1, 4-8, 11, 13, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Hajjaj (WO 2022/271018, cited on PTO-892, filed June 21, 2021).
Regarding claims 1, 6-8, 11, and 13: Hajjaj teaches compounds of formula I
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and relates to methods for improving the pharmacokinetic, physicochemical or pharmaceutical properties of drugs by converting the drug into a promoiety-containing I-substituted disulfanylalkyl carbonate, thiocarbamate or carbamate prodrug (abstract). In particular, the invention relates to methods for improving the solubility, permeability, stability and/or oral bioavailability of a drug by converting the drug into a pro moiety- containing I-( disulfanylalkyl) carbonate, thiocarbonate or carbamate prodrug (abstract). Hajjaj teaches compounds of formula 1 wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, and t-butyl, preferably R1 is hydrogen or methyl; wherein G is an organic structure and [C] represents a carbon atom of G; wherein OM is a drug moiety and [Z] represents a part of OM; and wherein Z is selected from the group consisting of 0, S, and N (pg. 13, lines 25-30, pg. 14, lines 1-5). In an embodiment, Z is O-C representing an oxygen and a carbon atom of drug moiety OM in which the oxygen atom O is covalently bound to the carbonyl group of the compound of Formula I and wherein the carbon atom C is covalently bound to O and to three hydrogen atoms and/or carbon atoms of OM. In this embodiment the original drug molecule (OM-ZH) comprises an alcohol function -OH that is coupled via said alcohol function to the linker. Said alcohol function may be a phenol. This type of linker will provide a ~C-O-C(=O)-O-C~ type linkage which is called a carbonate type linkage (pg. 14, lines 9-16). [ZH]DM is selected from the group consisting of from 5'-deoxy-5-fluorocytidine, Cytarabine, Lenalidomide, Thalidomide, Acyclovir, Doxorubicin, Losartan, Ciclopirox, Albendazole, Duloxetine, Mesalazine, Linagliptin, Atomoxetine, 5-Fluorouracil, Methylphenidate, Palbociclib, Azacitidine, Gabapentin, Metoprolol, Nintedanib, Carvedilol, Gemcitabine, Rasagiline, Pscilocin, Celecoxib, lbrutinib, Riluzole, Meropenem, Cinacalcet, Lapatinib, Tamiflu, Ceftriaxon, Abiraterone, Fesoterodine, Rotigotine, Orciprenaline, Acyclovir, Fulvestrant, Tenofovir, Ganciclovir, Testosterone, Kalydeco, Tizoxanide, Cannabidiol, Paliperidone, Venlafaxine, Edaravone, Paracetamol, Vorinostat, gemcitabine, Paclitaxel, Estradiol, 17-Ethynylestradiol, Propofol, Mercaptopurin, Acetylcysteine, Bucillamine, Captopril, and Zofenoprilat (pg. 30, lines 22-33). Hajjaj teaches G[C] can be
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(i.e. a substituted alkyl, pg. 20, lines 15-17). Hajjaj teaches the specific conjugate
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under formula (I) has the following variables, wherein R3 is an acetylated duloxetine (i..e monovalent drug), R1 is a substituted ethyl (ethylalcohol), R2 is H. (drawings pg. 10, table 3-2, compound 8g). Hajajj does not specifically demonstrate the compound described above wherein R1 is methyl. However, as discussed above, Hajjaj teaches R1 can alternatively be methyl instead of H (i.e. unsubstituted alkyl), as demonstrated in the following structure
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(drawings pg. 13, table 68, compound 68). Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify compound 8g of Hajjaj such that R1 is methyl instead of H as suggested by Hajjaj. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as Hajajj teaches R1 is preferably H or methyl and a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities (See MPEP 2144.09 (I)). In short, Hajajj renders obvious the following compound:
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which meets the structural limitations of claims 1, 6-8, 11, and 13.
Regarding claims 4-5: As discussed above, Hajjaj further teaches gemcitabine is an acceptable alternative drug to be used in the compounds (pg. 17, lines 7-13, 14-21). Hajjaj teaches examples using gemcitabine analogs in the disulfide conjugates (drawings, pg. 6, table 2a-2, compound 2e, drawings pg. 16, table 4-6, compound 81). According to the instant specification, gemcitabine is a chemotherapeutic drug (pg. 38, para. 0108). Taken together, it would have been prima facie obvious to further modify the compound by replacing duloxetine with gemcitabine as suggested by Hajjaj. A person of ordinary skill in the art would have the motivation to do so as Hajjaj teaches gemcitabine is a suitable alternative and it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Regarding claim 19: Hajjaj further teaches determining oral bioavailability of the compounds by dissolving them mixtures comprising water (i.e. an excipient, pg. 39, lines 22-33). Wherein it would have been obvious to arrive at the claimed compound, it similarly would have been obvious to dissolve them in water to determine oral bioavailability as taught by Hajjaj.
Claims 2-3 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hajjaj (WO 2022/271018, cited on PTO-892, filed June 21, 2021) as applied to claims 1, 4-8, 11, 13 above further in view of Zhao (J. Med. Chem., 2021, cited on PTO-892) as evidenced by Zhan (Anti-Cancer Drugs, 2017, Abstract, cited on PTO-892) and Burney (Pharm Pharmacol Int J., 2016, cited on PTO-892).
Regarding claims 2-3 and 20: As discussed above, Hajjaj teaches the prodrug of claim 1. Hajjaj teaches many conventional, nonspecific chemotherapeutic agents, such as doxorubicin, paclitaxel, camptothecan, cisplatin, and their derivatives (i.e. camptothecan is a chemotherapeutic, pg. 4, lines 1-3). Hajjaj teaches these prodrugs are unprecedented and can bring advantages with respect to solubility, permeability and/or oral bioavailability of hydroxyl, thiol and amine containing drugs. Hajjaj teaches 1(disulfanyl)methyl carbamate linkers have better results than 1-(disulfanylethyl) carbamate linkers (pg. 13, lines 5-15).
Hajjaj does not teach wherein the drug compound is camptothecin. Hajjaj does not teach wherein the compound is to be administered for the treatment of a disease.
However, Zhao teaches integration of a disulfide unit into camptothecin (abstract). Zhao teaches the preparation of CPT prodrug with the following structure
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wherein
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(pg. 17980, Scheme 3, CPT-S). Zhao teaches the prodrug molecules exhibit activity in cancer cells (pg. 17980, col. 1, para. 1, pg. 17981, table 1). Zhao teaches the activation mechanism of disulfide-based prodrugs relies on carbamate or carbonate type linkages (pg. 17980, scheme 1).
Taken together, it would have been prima facie obvious to modify the prodrug of Hajjaj such that the drug moiety is replaced with camptothecin for the purpose of treating cancer as suggested by Zhao. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as comparable disulfide prodrug moieties have been incorporated into camptothecin molecules and have activity against cancer cells, and it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)). In short the prior art render obvious the following compound
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. According to Zhan camptothecin is a BCS IV drug (abstract). According to Burney camptothecin is a substrate for CYP3A4 (pg. 475, col. 1, para. 2).
Allowable Subject Matter
Claims 16 and 18 are 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, as well as correcting minor informalities of claim 16 described above.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art are Hajjaj (WO 2022/271018, cited on PTO-892, filed June 21, 2021) in view of Zhao (J. Med. Chem., 2021, cited on PTO-892). As discussed above, the prior art renders obvious the following compound
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. While Hajjaj does not teach the drug moiety to be used is particularly limiting, the prodrugs of Hajjaj and Zhao require a carbonate/carbamate linkage between the disulfide prodrug and drug moiety wherein the drug moiety has an active amino or hydroxyl moiety. Taken together, it would be improper hindsight to suggest it would be prima facie obvious to remove the carbonate functional group and directly conjugate the disulfide linker to the drug as is demonstrated in the compounds of claims 16 and 18. A person of ordinary skill in the art would not have a reasonable expectation of success as they lack the carbonate group which plays a necessary role in the cleavage of the moieties of Hajjaj and Zhao. Thus, claims 16 and 18 would be allowable over the prior art.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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