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 .
DETAILED ACTION
This Office Action is responsive to the Response to Election/Restriction and Amendment filed 09/19/2025, wherein the Amendment cancelled claims 1-22, 37-46, 48-54, and 58-59, amended claims 22-36, 47, 55-57, and added claim 60.
Claims 22-36, 47, 55-57, and 60 are pending.
Priority
This application claims the following priority:
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Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See, for examples, pgs. 53 and 54.
Election/Restrictions
Applicant’s election without traverse of Group II, the method of use, cancer as the disease and fluvoxamine as the CYP1A2 inhibitor, in the reply filed on 09/19/2025, is acknowledged.
Applicant’s comments regarding the Restriction Requirement on pgs. 8-9 Remarks, 09/19/2025, are acknowledged.
Claims 24-31, 33-36, 47 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Claims 22, 23, 32, 55, 57 and 60 are examined on the merits herein.
Claim Objections
Claim 55 is objected to because of the following informalities:
-Claim 55 recites both “Gastric (Stomach) Cancer” and “Stomach (Gastric) Cancer, in the same Markush group. Since these are synonyms, one of these phrases should be deleted.
-In claim 55, “Kidney (Renal) Cancer” is recited twice in the same Markush group. The second iteration of the phrase should be deleted.
-In claim 55, the “and” between “Childhood Cancers” and “Non-Hodgkin Lymphoma” should be replaced with a comma. See MPEP 2173.05(h) for guidance on proper Markush language.
Appropriate correction is required.
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 22, 23, 32, 55, 57, and 60 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 term “moderate or strong” in claim 22, line 7, and claim 60, line 4, is a relative term which renders the claim indefinite. The term “moderate or strong” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Since the instant specification and prior art does not teach a baseline of CYP1A2 inhibitor activity or teach what defines moderate or strong in reference to this baseline, this phrase is indefinite.
In view of compact prosecution, for the purpose of applying prior art, any CYP1A2 inhibitor is interpreted as meeting this limitation.
-Claim 55 is indefinite because it is not clear if the cancers recited following the term “optionally” in line 3, are examples of the solid and haematological cancers recited in lines 2-3 of the claim, or if they are cancer in addition to solid and haematological cancers that can be treated by the method of claim 23.
In view of compact prosecution, for the purpose of applying prior art, the cancers recited following “optionally” are interpreted as exemplary of solid and haematological cancers, and as not further limiting the claims.
-Further regarding claim 55, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 55 recites the phrases Hepatocellular (Liver) Cancer,” “Gastric (Stomach) Cancer,” “Pancreatic Neuroendocrine Tumors (Islet Cell Tumors),” and “Osteosarcoma (Bone Cancer),” wherein the broad limitations are “Liver,” “Gastric Cancer,” “Pancreatic Neuroendocrine Tumors,” and “Bone Cancer,” and the narrow limitations are “Hepatocellular Cancer,” “Stomach Cancer,” “Islet Cell Tumors,” and “Osteosarcoma,” respectively.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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 22, 23, 32, 55, 57, and 60 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 treating leukemia, lymphoma, or myeloma in a subject by administering a combination of flubendazole and genistein or fluvoxamine, does not reasonably provide enablement for a method of treatment, in general, or a method of treating a disease treatable by inhibition and/or disruption of microtubule structure and function or by impairment or reversion of EMT, or of treating a neurodegenerative disease, liver disease, a spinal cord injury, or myopathy, by administering flubendazole or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof, and further comprising concurrent, separate, or sequential administration of any moderate or strong cytochrome P450 IA2 isoenzyme (CYP1A2) inhibitor. 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.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 22 is directed toward a method of treating any disease treatable by inhibition and/or disruption of microtubule structure and function, or by impairment or reversion of EMT, or of treating any neurodegenerative disease, any liver disease, any spinal cord injury, or any myopathy, by administering flubendazole or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof, and further comprising concurrent, separate, or sequential administration of any moderate or strong cytochrome P450 IA2 isoenzyme (CYP1A2) inhibitor.
Independent claim 60 is directed toward a method of treatment comprising administering to a human or animal subject flubendazole or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof, and which further comprises concurrent, separate, or sequential administration of any moderate or strong cytochrome P450 IA2 isoenzyme (CYP1A2) inhibitor.
As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Prior Art
Shimmer (US 2012/0202840, published 2012, PTO-892) teaches a method of treating a hematological malignancy in a subject in need thereof comprising administering an effective amount of flubendazole and/or a pharmaceutically acceptable solvate and/or prodrug thereof (pg. 19, claim 1).
Shimmer teaches the hematological malignancy as leukemia, such as AML, ALL or CML, lymphoma or myeloma 9pg. 19, claims 7-8).
Yu (IDS of 01/20/2023) teaches flubendazole as improving locomotor function after contusion spinal cord injury (abstract).
Nixon (IDS of 01/20/2023) teaches repurposing and formulating flubendazole, a known antiparasitic agent, for the treatment of the fungal disease, cryptococcal meningoencephalitis (title, abstract).
Hou (IDS of 01/20/2023) teaches flubendazole as targeting breast cancer stem-like cells.
Thus, while the prior art teaches flubendazole for treating diseases, the prior art teaches flubendazole as treating specific diseases, and is silent regarding combining it with another CYP1A2 inhibitor.
Predictability in the Art
The instant specification teaches that “Despite the potential therapeutic uses for flubendazole, its application in the clinic has been severely hampered by a number of pharmacokinetic and tolerability challenges and limitations. Low systemic bioavailability, unsuitable pharmacokinetic or unsuitable safety profiles of flubendazole formulations have limited the development of systemic clinical/therapeutic treatment based on flubendazole. . .Prior attempts to improve the therapeutic utility of flubendazole have been unsuccessful” (pg. 3, Specification).
The instant specification further teaches that “Either unacceptable local adverse effects or systemic effects due to the dose of flubendazole plus its toxic metabolites have terminated development for various therapeutic systemic uses,” and that “Flubendazole drug development activities over the last >40 years have, to a greater extend, not been able to overcome issues of extend and variability of systemic exposure to flubendazole and its metabolites to allow development of better and/or acceptable benefit: risk scenarios for therapeutic uses of flubendazole” (pg. 5, Specification).
As such, treatment of diseases and/or disorders with flubendazole is unpredictable.
Working Examples
Example 1, beginning on pg. 40, investigates cytochrome P450 reaction phenotyping of flubendazole using recombinant enzymes, and concludes that “flubendazole was very rapidly metabolized by the CYP1A2 recombinant enzyme.”
Example 2, beginning on pg. 42, investigates the stability of flubendazole in human liver microsomes in the absence and presence of furafylline, a CYP1A2 inhibitor, and concludes that flubendazole intrinsic clearance in human liver microsomes was strongly decreased in the presence of the strong CYP1A2 inhibitor, flufylline.
Example 3, beginning on pg. 45, investigates the stability of flubendazole in human hepatocytes, the absence and presence of cimetidine, mexiletine, thianbendazole, fluvoxamine, and furafylline, and concludes that furafylline, thiabendazole, fluvoxamine, and mexiletine behaved as strong CYP1A2 inhibitors of flubendazole, and cimetidine behaved as a moderate CYP1A2 inhibitor of flubendazole.
None of these examples provide data from in vivo studies.
None of these examples show a method of treating an instantly claimed disease, as recited in instant claim 22.
Direction and Guidance
In view the prior art teaching flubendazole as treating specific diseases, the unpredictably in the art regarding administering flubendazole to treat diseases/disorders, and the lack of working examples, the specification does not provide sufficient direction or guidance to make or use the instantly claimed methods.
Quantity of Experimentation
In view of the great number of diseases encompassed by a disease treatable by inhibition and/or disruption of microtubule structure and function or by impairment or reversion of EMT, or of treating a neurodegenerative disease, liver disease, a spinal cord injury, or myopathy, in view of the great number of combinations of flubendazole and moderate or strong CYP1A2 inhibitors, and in view of the great number of possible combinations of diseases and combinations of flubendazole and CYP1A2 inhibitors, the amount of experimentation would be astronomical. This amount of experimentation amounts to invention and not development; it is an undue amount of experimentation.
Thus, while being enabling for a method of treating leukemia, lymphoma, or myeloma in a subject by administering a combination of flubendazole and genistein or fluvoxamine, the specification does not reasonably provide enablement for a method of treatment, in general, or a method of treating a disease treatable by inhibition and/or disruption of microtubule structure and function or by impairment or reversion of EMT, or of treating a neurodegenerative disease, liver disease, a spinal cord injury, or myopathy, by administering flubendazole or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof, and further comprising concurrent, separate, or sequential administration of any moderate or strong cytochrome P450 IA2 isoenzyme (CYP1A2) inhibitor.
Claim Rejections - 35 USC § 103
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 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.
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 22, 23, 32, 55, 57 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0202840 to Shimmer (published 2012, PTO-892) in view of Narasimhan (Genistein exerts anti-leukemic effects on genetically different acute myeloid leukemia cell lines by inhibiting protein synthesis and cell proliferation while inducing apoptosis – molecular insights from an iTRAQ™ quantitative proteomics study, Oncoscience, published 2015, PTO-892), as evidenced by Burnett (Evaluation of CYP450 inhibitory effects and steady-state pharmacokinetics of genistein in combination with cholecalciferol and citrated zinc bisglycinate in postmenopausal women, Int J Womens Health, published 2011, PTO-892).
Shimmer teaches a method of treating a hematological malignancy in a subject in need thereof comprising administering an effective amount of flubendazole and/or a pharmaceutically acceptable solvate and/or prodrug thereof (pg. 19, claim 1).
Shimmer teaches the hematological malignancy as leukemia, such as AML, ALL or CML, lymphoma or myeloma (pg. 19, claims 7-8).
Regarding claims 22 and 60, while Shimmer teaches a method of treating a hematological malignancy in a subject by administering flubendazole, it differs from that of instant claims 22 and 60 in that it does not teach a CYP1A2 inhibitor.
Narashimhan teaches genistein as exerting anti-leukemic effects on AML cell lines by inhibiting protein synthesis and cell proliferation while inducing apoptosis (title, abstract).
Narashimhan teaches that genistein exerts cytotoxicity on AML cell lines, is a FLT3 inhibitor, wherein FLT3 inhibitors have efficacy in treating AML patients, regulates crucial pathways in MV4-11 and HL-60 cells, and induces apoptosis via caspase activation, (last paragraph pg. 111-1st full paragraph on pg. 112; pgs. 112-116, “Results”).
As evidenced by Burnett, genistein is a moderate CYP1A2 inhibitor (“Results”).
Regarding claims 22 and 60, it would have been prima facie obvious to one ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the genistein of Narashimhan, to the methods of Shimmer, to arrive at instant claims 22 and 60. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-both Shimmer and Narashimhan teach a method of treating leukemia, and specifically AML,
-Narashimhan teaches genistein as exerting cytotoxicity on AML cell lines, as a FLT3 inhibitor, wherein FLT3 inhibitors have efficacy in treating AML patients, as regulating crucial pathways in MV4-11 and HL-60 cells, and as inducing apoptosis via caspase activation, and
-"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), MPEP 2144.06.
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a more potent and therapeutically effective method of treating leukemia.
Regarding the recitation of “concurrent, separate, or sequential administration,” in claims 22 and 60, Shimmer teaches combining flubendazole and another active ingredient together in a single composition. As such, an ordinary skilled artisan would have been motivated to concurrently, separately, or sequentially, administer flubendazole and genistein, to predictably arrive at a dosage regimen that is optimized for therapeutic effect of the active ingredients on the treatment of leukemia.
Regarding claims 23, 32, and 55, the combined method of Shimmer and Narashimhan teaches a method of treating leukemia, a haematological cancer.
Regarding claim 57, Shimmer teaches its methods for administration to humans ([0067], [0076], [0100]).
Claims 22, 23, 32, 55, 57 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0202840 to Shimmer (published 2012, PTO-892) in view of Ballin (The Antidepressant fluvoxamine increases natural killer cell counts in cancer patients, published 2007, PTO-892) and Chouaib (Improving the outcome of leukemia by natural killer cell-based immunotherapeutic strategies, published 2014, Frontiers in Immunolog, PTO-829).
Shimmer is applied as discussed above.
Regarding claims 22 and 60, while Shimmer teaches a method of treating a hematological malignancy in a subject by administering a flubendazole, it differs from that of instant claims 22 and 60 in that it does not teach a CYP1A2 inhibitor.
Ballin teaches that fluvoxamine increases natural killer cell counts in cancer patients (title, abstract).
Regarding claims 22 and 60, it would have been prima facie obvious to one ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add the fluvoxamine of Ballin, to the methods of Shimmer, to arrive at instant claims 22 and 60. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-both and Shimmer Ballin teach a method of treating cancer,
- Ballin teaches that fluvoxamine increases natural killer cell counts in cancer patients,
-Chouaib teaches that natural killer cells are widely recognized as potent anti-leukemia mediators (abstract), and
-"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), MPEP 2144.06.
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a more potent and therapeutically effective method of treating leukemia that increases natural killer cell counts.
Regarding the recitation of “concurrent, separate, or sequential administration,” in claims 22 and 60, Shimmer teaches combining flubendazole and another active ingredient together in a single composition. As such, an ordinary skilled artisan would have been motivated to concurrently, separately, or sequentially, administer flubendazole and fluvoxamine, to predictably arrive at a dosage regimen that is optimized for therapeutic effect of the active ingredients on the leukemia.
Regarding claims 23, 32, and 55, the combined method of Shimmer, Ballin, and Chouaib teaches a method of treating leukemia, a haematological cancer.
Regarding claim 57, Shimmer teaches its methods for administration to humans ([0067], [0076], [0100]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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/LAUREN WELLS/Examiner, Art Unit 1622