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 in response to Applicant’s Arguments and Amendment filed, 04/02/2026, wherein the Amendment amended claims 22-24, 31-33, 36, 55, and 60, cancelled claim 57, and added claim 61.
Claims 22-36, 47, 55-56, and 60-61 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected Group II, the method of use, cancer as the disease and fluvoxamine as the CYP1A2 inhibitor, in the reply filed on 09/19/2025.
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Claims 24-31, 33-36, 47 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.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, and 60-61 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendment to claim 55 is sufficient to overcome this objection.
Specification Objections
Applicant’s amendment to the specification is sufficient-in-part to overcome these objections. See below for details.
35 U.S.C. § 112(b)
-Applicant’s arguments on pg. 13, Remarks, that “moderate” and “strong” CYP1A2 inhibitors are terms of art with a precise meaning that is well-understood by a person of skill in the art is persuasive, in view of Drug Interactions & Labelling-Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, published by the FDA, is sufficient to overcome the rejection over claim 22.
Moreover, pg. 26 of the Specification defines “moderate” and “strong” CYP1A2 inhibitors as follows:
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-Applicant’s amendment to claim 55 is sufficient to overcome the rejection over this claim.
REJECTIONS—MAINTAINED, MODIFIED & NEW
Applicant’s amendments to independent claims 22 and 60 have resulted in the below modified rejections.
Specification
(Modified) 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 pg. 53 of the 04/02/2026 Amendment to the Specification, that recites “www.”
Claim Objections
(New) Claim 61 is objected to because of the following informalities:
The claim does not end with a period. Each claim must begin with a capital letter and end with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP 608.01(m).
Appropriate correction is required.
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.
(Modified) Claims 22, 23, 32, 55, and 61 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 proliferative disease, fungal disease, and spinal cord injury in a subject by administering a combination of flubendazole and genistein, cimetidine, mexiletine, thianbendazole, fluvoxamine, or furafylline, does not reasonably provide enablement for a method of treating any infectious disease, any inflammatory disease, any fibrotic disease, any neurodegenerative disease, any liver disease, 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. 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 proliferative disease, any infectious disease, any fungal disease, any inflammatory disease, or any fibrotic disease, 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.
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 of 01/02/2026) 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).
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 proliferative diseases, fungal diseases, and spinal cord injury, the prior art does not teach flubendazole as treating any inflammatory disease, any fibrotic disease, any neurodegenerative disease, any liver disease, or any myopathy
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 extent, not been able to overcome issues of extent 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 any infectious disease, any inflammatory disease, any fibrotic disease, any neurodegenerative disease, any liver disease, or any 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 a proliferative disease, a fungal disease, or a spinal cord injury in a subject by administering a combination of flubendazole and genistein, cimetidine, mexiletine, thianbendazole, fluvoxamine, or furafylline, the specification does not reasonably provide enablement for a method of treating any infectious disease, any inflammatory disease, any fibrotic disease, any neurodegenerative disease, any liver disease, 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.
Response to Arguments
On pgs. 14-16, Remarks, Applicant summarizes the embodiments of the currently claimed invention, and states that the instant method provides increased bioavailability of flubendazole.
On pg. 17, Remarks, Applicant argues that the instant invention overcomes the poor systemic bioavailability of flubendazole, and that this is relevant to any therapy which requires systemic exposure to flubendazole, and particularly to the treatment of a proliferative disease, an infectious disease, a fungal disease, an inflammatory disease, a fibrotic disease, a neurodegenerative disease, a liver disease, a spinal cord injury, and a myopathy.
On pg. 18, Remarks, Applicant argues that the broad definition of any moderate or strong CYP1A2 inhibitor is the most appropriate way to define the CYP1A2 inhibitor and it would not be appropriate to restrict the CYP1A2 inhibitor to any list of specifically defined compounds. Applicant further argues that as any strong or moderate CYP1A2 inhibitor could reasonably be expected to have the effect on flubendazole metabolism demonstrated in the present application, the full range of combination claimed is enabled.
These arguments have been fully considered, but are not found persuasive.
As discussed in the above rejection, the instant specification provides zero examples of a method of treating any disease by administering any flubendazole and a strong or moderate CYP1A2 inhibitor. Moreover, the prior art teaches flubendazole for the treatment of specific proliferative diseases, fungal diseases, and spinal cord injuries, and not for the treatment of any infectious disease, any inflammatory disease, any fibrotic disease, any neurodegenerative disease, any liver disease, or any myopathy.
The instant specification teaches that treating diseases with flubendazole is unpredictable:
“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 extent, not been able to overcome issues of extent 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).
For these reasons, Applicant’s arguments are not persuasive to overcome the rejection.
Claim Rejections - 35 USC § 112(a)-Written Description
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.
(New) Claims 22, 23, 32, 55, and 60-61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See MPEP 2163.
Independent claims 22 and 60 recite a moderate or strong CYP1A2 inhibitor, “wherein the moderate or strong CYP1A2 inhibitor inhibits metabolism of flubendazole in the human subject.”
Independent claim 60 further recites a method of treating “a disease treatable by improved and/or sustained exposure to flubendazole.”
Regarding moderate or strong CYP1A2 inhibitors that inhibit metabolism of flubendazole in the human subject, the instant specification merely states that moderate or strong CYP1A2 inhibitors effect an inhibition of intrinsic clearance in human hepatocytes ex vivo of flubendazole of ≥2-fold, or an increase in the AUC of flubendazole in vivo by two-fold or more, and teaches eight compounds that are strong CYP1A2 inhibitors, furafylline, fluvoxamine, thiabendazole, mexiletine, 8-phenyltheophylline, ciprofloxacin, encoxacin, and zafirlukast as (pgs. 26-27, instant Specification), which have the following structures:
Furafylline
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Fluvoxamine
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thiabendazole
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Mexiletine
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8-phenyltheophylline
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Ciprofloxacin
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Encoxacin
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Zafirlukast
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.
These eight compounds do not share a single or similar core structure. As such, it is not possible to determine a structure-function relationship amongst these compounds that is critical to impart the moderate or strong CYP1A2 inhibition that inhibits metabolism of flubendazole.
Zhou (Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2, published 2009, PTO-892) teaches that a large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic, epigenetic, and environmental factors. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of them have been associated with altered drug clearance and response to drug therapy. Further studies are warranted to explore the clinical and toxicological significant of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors (abstract).
Zhou teaches that there are wide interindividual differences in CYP1A2 expression and activity, approximately 15- and 40-fold interindividual variations in CYP1A2 mRNA and protein expression levels have been observed in human livers. There is also marked racial differences in CYP1A2 activity. Environmental factors, such as cigarette smoking and oral contraceptive intake, also influence interindividual differences in CYP1A2 activity and expression. And approximately 35-75% of the interindividual variability of CYP1A2 activity is due to genetic factors (pgs. 488-489, Polymorphisms of CYP1A2 and Clinical Impact).
Zhou teaches that there is an increasing number of clinical drug interactions caused by CYP1A2 induction and/or inhibition, and the interaction may be substrate and inhibitor dependent and thus caution should be taken when conducting in vitro-in vivo extrapolation. Polymorphisms of CYP1A2 may alter drug clearance and drug response and thus dosage adjustment and therapeutic drug monitors for drugs with a narrow therapeutic index may be required. More well-designed studies are warranted to explore the genotype-phenotype relationship of CYP1A2 in terms of drug clearance and response. Personalized pharmacotherapy and individualized dosing of drugs would need incorporation of both genetic and environmental factors. The pharmaceutical industry is likely to screen drug candidates regarding their CYP1A2 binding properties early in drug development. The candidate selection might eventually lead to a less relevant role of this enzyme for newer drugs (pg. 492, Conclusions and Future Perspectives).
In view of the teachings of Zhou, it is not predictable, or well defined, whether or not a CYP1A2 inhibitor that is moderate or strong would inhibit the metabolism of flubendazole in a given disease state, based on the interindividual variations in CYP1A2.
Independent claim 60 further recites a method of treating “a disease treatable by improved and/or sustained exposure to flubendazole.”
Regarding diseases treatable by improved and/or sustained exposure to flubendazole, the instant specification does not specifically teach or describe any diseases “treatable by improved and/or sustained exposure to flubendazole.” The instant specification generically teaches that the instant methods of administering flubendazole treat cancer, infectious disease, fungal disease, proliferative disease, inflammatory disease, fibrotic disease, neurodegenerative disease, liver disease, spinal cord injury, and myopathy (pgs. 12-14, Instant Specification).
However, the specification does not teach a common etiology in these disease that is critical to impart the diseases’ abilities to be treated by “improved and/or sustained exposure to flubendazole.”
Shimmer (US 2012/0202840, published 2012, PTO-892 of 01/02/2026 ) 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 specifically 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 specific diseases, the prior art is silent regarding an etiology that is critical to the diseases and that imparts the diseases’ ability to be treated by “improved and/or sustained exposure to flubendazole.”
As such, the instant patent specification does not describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor has possession of the claimed invention. See MPEP 2163.
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(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.
(New) Claim 60 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.
-In claim 60 the term “improved” in reference to “exposure to flubendazole,” renders the claim indefinite. The term “improved” is a relative term. The term “improved” 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. For example, it is not clear if “improved exposure to flubendazole” is a dose of flubendazole that is greater than a starting dose, a dosing regimen of flubendazole that is extended, or a dose of flubendazole that is intravenous administered instead of orally administered.
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.
(Slightly modified) Claims 22, 23, 32, 55 and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0202840 to Shimmer (published 2012, PTO-892 of 01/02/2026) 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 of 01/02/2026), 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 of 01/02/2026).
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).
Shimmer teaches its methods for administration to humans ([0067], [0076], [0100]).
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 the phrase “wherein the moderate or strong CYP1A2 inhibitor inhibits metabolism of the flubendazole in the human subject,” in claims 22 and 60, MPEP 2111.04 states, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In the instant case, the wherein clause expresses the desired result of the positive step of administering flubendazole and CYP1A2 inhibitor, genistein, in an amount effective to treat cancer. As such, this limitation is met.
Regarding the phrase, “a disease treatable by improved and/or sustained exposure to flubendazole,” in claim 60, since the instant specification teaches cancer, and specifically AML ALL, CLL, lymphoma, and myeloma, as diseases treated by the instant invention, this limitation is met.
Regarding claims 23, 32, 55, and 61, the combined method of Shimmer and Narashimhan teaches a method of treating leukemia, a hematological cancer.
Response to Arguments
On pg. 19, Remarks, Applicant discusses instant examples 2 and 3, which show that the there is no significant drop in flubendazole in liver microsomes and/or hepatocytes when administered with furafylline and/or fluvoxamine, and thiabendazole, indicating that the CYP1A2 inhibitor furafylline, reduces flubendazole metabolism. Applicant then argues that Shimmer, Narasimhan, and Burnett fails to suggest that flubendazole is metabolized by CYP1A2 or that the CYP1A2 inhibitor is needed to inhibit the metabolism of flubendazole.
This argument has been fully considered, but is not found persuasive. The instant claims are directed toward a method of treating a proliferative disease, an infectious disease, a fungal disease, an inflammatory disease, a fibrotic disease, a neurodegenerative disease, a liver disease, a spinal cord injury, or a myopathy, or any disease treatable by improved and/or sustained exposure to flubendazole, 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; although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The instant claims are not limited to furafylline as the CYP1A2 inhibitor.
Regarding the phrase “wherein the moderate or strong CYP1A2 inhibitor inhibits metabolism of the flubendazole in the human subject,” in claims 22 and 60, MPEP 2111.04 states, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In the instant case, the wherein clause expresses the desired result of the positive step of administering flubendazole and CYP1A2 inhibitor, genistein, in an amount effective to treat cancer. As such, this limitation is met by the combination of Shimmer and Narashimhan.
Moreover, the combination of Shimmer and Narashimhan teach a method of treating the same disease as instantly claimed, by administering flubendazole and a moderate CYP1A2 inhibitor as instantly claimed, to the same patient population as instantly claimed. Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
On pg. 20, Remarks, Applicant argues that though In re Kerkhoven is applied in the obviousness rationale, Applicant asserts that instead, the “Obvious to Try” rationale is being utilized and that this rationale is insufficient because the prior art has not identified a finite, predictable set of options with a reasonable expectation of success.
This argument has been fully considered, but is not found persuasive. It is respectfully pointed out that the obviousness rationale does not state that an “obvious to try” standard is being utilized. As discussed above, 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.
As such, there is motivation to combine the teachings of Shimmer and Narashimhan to arrive at instant claims 22 and 60, with a reasonable expectation of success.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning on pg. 20, Remarks, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
On pg. 20, Remarks, Applicant argues that “If merely being applicable for the same disease were sufficient motivation to combine then every drug approved for that indication would be obvious to try to combine with every other—an unrealistic result that would effectively eliminate patent protection for all combination therapies.”
This argument has been fully considered, but is not found persuasive. As discussed in MPEP 2144.06, "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). In the instant case, Shimmer teaches a method of treating AML by administering flubendazole and Narashimhan teaches a method of treating AML by administering genistein. 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, and especially AML.
It is respectfully pointed out that Applicant has provided no data or evidence as to why it would not be obvious to combine flubendazole and genistein to treat AML, or why there would be no reasonable expectation of success.
(Slightly modified) Claims 22, 23, 32, 55, and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over US 2012/0202840 to Shimmer (published 2012, PTO-892 of 01/02/2026) in view of Ballin (The Antidepressant fluvoxamine increases natural killer cell counts in cancer patients, published 2007, PTO-892 of 01/02/2026) and Chouaib (Improving the outcome of leukemia by natural killer cell-based immunotherapeutic strategies, published 2014, Frontiers in Immunolog, PTO-829 of 01/02/2026).
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 the phrase “wherein the moderate or strong CYP1A2 inhibitor inhibits metabolism of the flubendazole in the human subject,” in claims 22 and 60, MPEP 2111.04 states, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In the instant case, the wherein clause expresses the desired result of the positive step of administering flubendazole and CYP1A2 inhibitor, fluvoxamine, in an amount effective to treat cancer.
Regarding the phrase, “a disease treatable by improved and/or sustained exposure to flubendazole,” in claim 60, since the instant specification teaches cancer, and specifically AML ALL, CLL, lymphoma, and myeloma, as diseases treated by the instant invention, this limitation is met.
Regarding claims 23, 32, 55, and 61 the combined method of Shimmer, Ballin, and Chouaib teaches a method of treating leukemia, a hematological cancer.
Response to Arguments
On pgs. 20-21, Remarks, Applicant’s arguments mirror the arguments over Shimmer in view of Narasimhan, which are fully addressed above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LAUREN WELLS/Examiner, Art Unit 1622
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