DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group 1 in the reply filed on 1/29/2026 is acknowledged. Applicants amended of claim 5 and withdrawing of claim 2 is acknowledged. There are no new claims.
Claims 1 and 3-8 are pending in the application and will be examined on the merits.
Priority
3. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 202310018497.9, filed on 1/06/2023.
Drawings
4. The drawings are objected to because FIG 1C has overlapping lines within the graph. The layout of the overlapping lines makes it difficult to understand the graph and the delineation of the lines. Applicant is advised to utilize varying line styles (solid, dashed, dotted), line widths and adjust marker sizes and spacing to differentiate overlapping lines visually which would make the lines in FIG. 1C discernable. 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.
Claim Objections
5. Independent claim 1 and dependent claim 3, are objected to because of the following informalities:
Applicant should consider amending independent claim 1 at lines 2, 4, and 5 to recite “salts thereof” instead of “salts” (line 2) or ‘the salts” (line 4 and 5). As best understood, applicant’s intent was to refer to salts of methylaminocolchicine or salts of C-10 methyl substituted colchicine instead of salts generically. Applicant should also consider amending subsequent dependent claims to be consistent with any amendments made to independent claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
6. 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 and 3-8 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 a method of using methylaminocolchicine for tumor growth inhibition effect in BALB/c-nu mice (FIG. 1A-1C and [0086]), does not reasonably provide enablement for “antagonizing tumors” and/or “overcoming microtubule inhibitor resistance” and/or for “combination therapy for antagonizing tumors and overcoming microtubule inhibitor resistance” using a “methylamino-substituted colchicine at C10 position and salts”. 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.
Breadth versus disclosure (MPEP 2164.06; Amgen v. Sanofi):
The specification asserts efficacy “for various hematological malignancies and solid tumors” (e.g., leukemia, lymphoma, breast, lung, prostate, liver, renal, colon, gastric, skin [0013]) and for “antagonizing microtubule inhibitor resistance” to taxanes and vinca alkaloids [0003].
Working data are limited to:
In vitro GI50 measurements on a subset of cell lines (HL-60, K562, MOLM-13, PC-3, HepG-2, HCT-116, HeLa [0073], [0008]) and four resistant/parental pairs (A549/A549-T, MCF-7/MCF-7-T, MX-1/MX-1-T, KB/KB-V [0010]) as depicted in Table 1. below:
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One xenograft model (A549/T in BALB/c-nu mice) comparing methylaminocolchicine with paclitaxel and colchicine [0027].
Selected salt forms, such as hydrochloric acid, hydrobromic acid. nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, trifluoroacetic acid, acetic acid, benzoic acid, methanesulfonic acid. phenylacetic acid, salicylic acid, oxalic acid, maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, gluconic acid, hydroxymaleic acid and 1,4-butanedisulfonic acid, evaluated only in A549/A549-T in vitro [0020].
There is no enabling disclosure across the full universe of claimed tumor types, disease contexts (hematologic vs. solid), resistance mechanisms, patient populations, or clinical routes/dose regimens, nor across the full genus of salts and dosage forms.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the 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.
Nature of the invention:
The instant invention relates to systemic chemotherapeutic treatment of a wide array of tumors, including resistant malignancies, and to combination therapy with apoptosis-modulating agents.
Antitumor chemotherapy and overcoming drug resistance are complex, unpredictable arts, where small changes in structure, tumor type, genetic background, microenvironment, and co-medications can dramatically affect efficacy and toxicity.
The claimed methods encompass use of methylaminocolchicine and all pharmaceutically acceptable salts in multiple dosage forms (tablets, capsules, granules, injections) for both hematologic and solid tumors, with and without microtubule inhibitor resistance, and in combination with broadly defined Bcl-2/Bcl-xL inhibitors.
No human clinical data are provided, and in vivo data are limited to a single xenograft model; the translation from such limited preclinical data to reliable, routine treatment regimens across all claimed indications is highly uncertain. There are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs (Hanahan et al. “The Hallmarks of Cancer.” Cell, Vol. 100 (January 7, 2000): An Enumeration of the Traits).
Given the inherent unpredictability in oncology and drug resistance therapy, the breadth of the claimed methods far exceeds what can be reliably enabled by the narrow disclosure. Hanahan D et al. teaches “several lines of evidence indicate that tumorigenesis in humans is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives (Hanahan et al. “The Hallmarks of Cancer.” Cell, Vol. 100 (January 7, 2000): paragraph 4). Hanahan D et al further notes that the advent of powerful technologies for profiling cells in tumors at the single-cell level has collectively revealed the widespread existence of intertumoral heterogeneity (Hanahan et al. “The Hallmarks of Cancer.” Cell, Vol. 100 (January 7, 2000): Unlocking phenotypic plasticity (and consequent functional heterogeneity).
The state of the prior art:
The background section acknowledges prior art on microtubule inhibitors and resistance mechanisms.
The specification describes taxane-site inhibitors (paclitaxel, docetaxel) and vinca-site inhibitors (vincristine, vinblastine) as established chemotherapeutics and notes known resistance mechanisms such as P-glycoprotein-mediated-efflux, altered β-tubulin expression, mutation, and apoptosis evasion.
Colchicine is described as an FDA-approved drug for gout and FMF, with “strong inhibitory activity in tumor cell lines,” but “weak in vivo efficacy and narrow toxicity index” and no approval for tumor therapy [0004].
Structurally modified colchicine derivatives are said to have been reported, but none approved for tumor therapy, and the specification states that methylaminocolchicine’s activity against paclitaxel- and vincristine-resistant tumors and its combinations with Bcl-2/Bcl-xL inhibitors “have not been reported yet” [0005]. Yang et al. teaches “microtubule inhibitors are widely used in first line cancer therapy, though drug resistance often develops and causes treatment failure. Colchicine binds to tubulins and inhibits tumor growth, but is not approved for cancer therapy due to systemic toxicity” (abstract). Furthermore, this study investigated structural modifications of colchicine to improve its therapeutic potential for cancer treatment. Researchers replaced the methoxyl group in colchicine's tropolonic ring with amino groups, particularly focusing on methylaminocolchicine (compound 1b). One of the key findings was that “Methylaminocolchicine showed superior antiproliferative effects compared to colchicine, paclitaxel, and vincristine across multiple cancer cell lines, as depicted in Table 1 above (Yang et al. “Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance” Vol. 68, 100951 (May 2023)).
Thus, the applicant’s post-filing peer-reviewed publication clarifies a few of the missing teachings in this application regarding safe and effective use of methylaminocolchicine and its salts, it doesn’t particularly teach within combination therapy across the claimed breadth. The art would not render the extensive additional experimentation routine.
The relative skill of those in the art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The predictability or lack thereof in the art:
Oncology and anti-microtubule therapies are unpredictable; response and resistance vary by tumor type, genotype, microenvironment, transporter expression (e.g., P-gp), and co-medications. “Among the most important unsolved questions about the antitumor activities of microtubule-targeted drugs concern the basis of their tissue specificities and the basis for the development of drug resistance to these agents. For example, it is not known why paclitaxel is so effective against ovarian, mammary and lung tumors, but essentially ineffective against many other solid tumors, such as kidney or colon carcinomas and various sarcomas. Similarly, for the Vinca alkaloids, it is unclear why they are frequently most effective against hematological cancers, but often ineffective against many solid tumors. There are clearly many determinants of sensitivity and resistance to antimitotic drugs, both at the level of the cells themselves and at the level of the pharmacological accessibility of the drugs to the tumor cells” (Jordan, M., Wilson, L. “Microtubules as a target for anticancer drugs”. Nat Rev Cancer 4, 253–265 (2004). Tumor sensitivity and resistance, lines 1-10). Many results here are not routine or predictable: small modifications to tubulin ligands can change binding mode (inhibitory vs. polymerizing), alter cell-type activity, change P-gp susceptibility, and alter systemic toxicity. Achieving and controlling combination synergy clinically involves PK/PD matching and toxicity balancing that is not routine.
To practice the claims across all recited cancers and resistance states, a skilled artisan would need to perform extensive experimentation to determine:
Effective and safe dose ranges, schedules, and routes (e.g., for tablets vs. injections) for methylaminocolchicine and each salt in humans.
Pharmacokinetics, bioavailability, and toxicity profiles for each dosage form and salt.
Clinical efficacy and resistance reversal across each claimed tumor indication.
Synergy parameters and optimal ratios with each Bcl-2/Bcl-xL inhibitor across different tumors and resistance backgrounds.
Jordan MA & Wilson L, “Microtubules as a target for anticancer drugs,” Nat Rev Cancer. 2004;4(4):253–265 supports the notion that clinical and biological variability among microtubule targeting drugs that supports broad tumor claims will likely require extensive dosing/efficacy testing.
The breadth of the claims:
The breadth of the claims: Claim 1 recites methods of using methylamino-substituted colchicine at C10 and its salts “for antagonizing tumors”, “for overcoming microtubule inhibitor resistance”, and for “combination therapy for antagonizing tumors and overcoming microtubule inhibitor resistance” without limiting tumor type, patient population, resistance mechanism, specific microtubule inhibitor, or route of administration.
Claim 3 covers the use of methylaminocolchicine and its salts “in combination with an anti-apoptotic protein Bcl-2/Bcl-xL inhibitor as an anti-tumor drug”, where the specification lists venetoclax, navitoclax, A1331252, and A1155463 merely as examples but does not limit the claims to these agents [0100-0103].
Claim 4 encompasses “hematological malignancies and solid tumors”, including but not limited to “leukemia, lymphoma”, and the solid tumors include breast cancer, lung cancer, prostate cancer, liver cancer, renal cancer, colon cancer, gastric cancer, and skin cancer “[0012-0013].
Claim 5 recites a broad genus of salts formed with numerous inorganic and organic acids; yet only 5 salt forms are actually exemplified within the specification [0035, 0042, 0048, 0055, and 0060].
Claim 6 covers multiple dosage forms (tablets, capsules, granules, injections), with no specific formulations, excipients, stability data, or dosing ranges disclosed.
Claims 7 and 8 broadly claim concomitant or sequential use of methylaminocolchicine (or its salts) with Bcl/Bcl-xL inhibitor compositions and pharmaceutically acceptable carriers in a “clinically acceptable compound preparation”, without teaching how to achieve clinically acceptable safety and efficacy across the entire claimed range.
The breadth of these claims far exceeds the limited examples and data actually provided, which focus on tumor growth inhibition effect of methylaminocolchicine provided by an example in BALB/c-nu mice (FIG. 1A), tumor weights at the end of test (FIG. 1B), mouse weights after medication (FIG. 1C) and effects of methylaminocolchicine, paclitaxel, vincristine, and colchicine on microtubule polymerization force (FIG. 2). The examples of particular tumor cell lines disclosed within the specification include human leukemia cells HL-60, K562, MOLM-13, prostate cancer cells PC-3, hepatoma cells HepG-2, colon cancer cells HCT-116, and cancer cells Hela, [0008, 0068].
As such, the breadth of the claims is great.
The amount of direction or guidance presented:
Salts and dosage forms are not enabled across claimed scope.
The salt genus recites numerous acids (e.g., hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, trifluoroacetic, benzoic, oxalic, maleic, fumaric, succinic, tartaric, lactic, gluconic, 1,4-butanedisulfonic), but only a few salts are synthesized and characterized, and only in vitro A549/A549-T GI50 data are shown for five salts [0020].
There is no teaching enabling stability, purity, polymorph control, pharmaceutical acceptability, solubility, and in vivo performance for the entire salt genus. Certain acids (e.g., nitric acid) may yield salts with poor stability or safety profiles not suitable for pharmaceutical use.
Tablets, capsules, granules, and injections are mentioned [0021] without enabling manufacturing guidance (e.g., excipients, release profiles, solvent systems, lyophilization, sterilization, osmolality, pH control), nor dose ranges or routes (IV vs. IP vs. oral) tied to efficacy/safety across the scope (ALZA v. Andrx).
The presence or absence of working examples:
Combination therapy enablement not commensurate with breadth.
The specification claims synergy with multiple Bcl-2/Bcl-xL inhibitors and a broad molar ratio range (1:250 to 1:1000), but provides synergy data only in one resistant cell line (A549/T) and only for selected concentration windows (20–80 nM methylaminocolchicine; 5–20 µM inhibitor).
No in vivo data for combinations, no tumor-type breadth, no PK/PD or toxicity for combinations, and no teaching covering how to achieve and maintain the asserted ratios clinically across dosage forms and patient variability (Wyeth v. Abbott).
The spec contains multiple working examples (synthesis, five salts prepared, in vitro GI50 on various lines, one in vivo xenograft, tubulin polymerization assay, combination indices in A549/T). However, these examples are limited in breadth: most in vitro work is limited to certain lines; in vivo evidence is one xenograft model and single dosing regimen; salts are tested only in A549/A549 T. The examples are not representative of the entire claimed genus (all tumors, all salts, all formulations, clinical use).
Mechanistic assertions and functional results across full scope:
The disclosure reports methylaminocolchicine promoting tubulin polymerization, in contrast to colchicine (Example 10), and asserts “more active than paclitaxel, vincristine, and colchicine” and “no cross resistance” broadly. These are functional results spanning many tumors and resistance mechanisms with limited supporting data, and are not enabled across the full claim scope (MPEP 2164.08(a); CFMT, Inc. v. Yieldup).
Absence of human dosing and clinical enablement:
No human dosage ranges, titration protocols, contraindications, or safety envelope are provided for any indication, salt, dosage form, or combination therapy. In this unpredictable field, extrapolation from limited in vitro and one murine model is insufficient to enable clinical methods across the breadth claimed (MPEP 2164.08(a)).
Note that 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. Genentech, Inc. v. Novo Nordisk, 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, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 1, and 3-8.
Consequently, claims 1 and 3-8 are rejected for lacking scope of enablement.
Claim Rejections - 35 USC § 112
7. 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, 5-6 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Evidence that claim 1 fail(s) to correspond in scope with that which the inventor or a joint inventor, or for pre-AIA applications the applicant regards as the invention can be found in the wording of claim 1. Specifically, the claim is directed towards multiple purported inventions including a method for using a methylaminocolchicine and salts for antagonizing tumors, a method for using the methylamino-substituted colchicine for overcoming microtubule inhibitor resistance, or a method for using the methylamino-substituted colchicine for combination therapy for antagonizing tumors and overcoming microtubule inhibitor resistance. Furthermore, the claim is missing a transitional phrase followed by steps for the method being claimed. Hence, the steps for performing the methods are missing and the claim is improperly drafted. For the purposes of examination, the examiner will read the claim as three separate clauses written in the alternate without any further steps. It should be noted that claims 3 and 8 do disclose at least one step for the method of claim 1 and therefore do not inherit the deficiencies noted above.
Dependent claim 5, recites in part, “...wherein HX comprises, but is not limited to, one selected from the group consisting of…”. This phrasing makes the metes and bounds of the claim ambiguous. It is unclear what the actual scope of HX is intended to be due to the broad recitation of “HX comprises, but is not limited to” and the narrower recitation of a closed Markush grouping of acids that form the basis of the HX salt form.
Claim 6 recites the limitation "the pharmaceutical dosage form" in line 2. There is insufficient antecedent basis for this limitation in the claim, as neither dependent claim 4 nor any of its parents claims recite “a pharmaceutical dosage form”.
Claim 8 recites the limitation "the pharmaceutical formulation" in line 2. There is insufficient antecedent basis for this limitation in the claim, because there is no mention of “a pharmaceutical formulation” earlier in claim 8 or in its parent claim, independent claim 1.
Claim Rejections - 35 USC § 102
8. 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.
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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krzywik et al. (New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking; Published: August 2, 2020 in Pub Med Central) herein referred as Krzywik.
Krzywik discloses use of colchicine which is a plant-based alkaloid extracted from Colchicum autumnale and Gloriosa superba that shows antimitotic effects on a number of cancer cell lines (see Introduction). The disclosure is directed towards synthesizing colchicine, a well-known anticancer compound by structurally modifying the C10 (methylamino group) position (see abstract).
Figure 1 of Krzywik further shows a comparison of selectivity index values of the tested compounds showing efficacy against tumor cells greater than toxicity against normal cells. There was also a notable difference between the modified colchicine and unmodified colchicine. The introduction of methylamino group at position C10 significantly increased the cytotoxicity of a relevant derivative in comparison to that of unmodified colchicine (see paragraph 2 of Conclusion). Clinical usefulness of many microtubule disrupting agents has been reduced due to drug resistance. However, the current modification of colchicine allows for binding to beta-tubulin thereby overcoming microtubule inhibitor resistance (introduction and section 2.3). Thus, Krzywik teaches the limitations of claim 1.
Therefore, claim 1 is rejected as being anticipated by Krzywik.
Claim Rejections - 35 USC § 103
9. 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.
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 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Kryzwik et al. (New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking; Published: August 2, 2020 in Pub Med Central) in view of Chen et al. (Enhancement of Light Activated Drug Therapy Through Combination with Other Therapeutic Agents (US Publication US 2011/0008372 A1) Published: January 13 2011) herein referred as Chen.
As mentioned above in the rejection of claim 1, Kryzwik discloses synthesizing colchicine, a well-known anticancer compound by structurally modifying the C10 (methylamino group) position (see abstract). In addition, scheme 1 illustrates synthesis of double-modified colchicine derivatives with changes at the C7 and C10 positions.
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Thus, Kryzwik discloses the methylaminocolchicine represented by Formula 1 as show in in claim 5.
Chen discloses combining known anti-cancer drug therapy with additional therapeutic agents including agents for reducing the anti-apoptotic effects of Bcl-2 or Bcl-xL (see abstract, and claim 12). The therapeutic agents can be delivered via injections (0041). Combination therapy has broad therapeutic potential for patients with “solid and hematological tumors” (see paragraph [0032]). Thus, Chen’s teachings disclose instant claims 3, 4 and 6-8.
Although, Kryzwik discloses the modified colchicine of claim 1, it does not disclose a combination therapy. Chen discloses combination therapy of anti-cancer drugs and therapeutic agents, it does not specifically disclose the anti-cancer drug being the modified Colchicine as taught by Krzywik.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine Chen’s anti-cancer drug therapy (with additional therapeutic agents including agents for reducing the anti-apoptotic effects of Bcl-2 or Bcl-xL) with the methylaminocolchicine of Kryzwik to make the treatment more effective. One of ordinary skill in the art would have been motivated to do so because using Bcl-2/Bcl-Xl-modulating agents as chemosensitizers in combination therapy would enhance antitumor efficacy.
Therefore, claims 3-8 are rejected as being obvious over Krzywik in view of Chen.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gazard et al. (Synthesis of Colchicine C-10-amino -Acid Derivatives, published 10 November 2015 in Chemistry of Natural Compounds, Volume 51, pages 1138-1141) is directed towards synthesizing colchicine derivatives and salts by modifying on C-10 by natural and synthetic amino acids.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622