DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group (I) in the reply filed on 10/27/2025 is acknowledged.
Applicant’s election without traverse of monoethanolamine in the reply filed on 10/27/2025 is acknowledged.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
This application is a Continuation of U.S. application Ser. No. 16/279,289, filed Feb. 19, 2019, now Patent No. 11,607,742, which is a Continuation of U.S. application Ser. No. 15/468,815, filed Mar. 24, 2017, now Patent No. 10,213,448, which claims priority to U.S. Provisional Patent Application Ser. No. 62/313,417, filed Mar. 25, 2016. However, it is noted U.S. application Ser. No. 16/279,289, filed Feb. 19, 2019, now Patent No. 11,607,742, should be a Divisional of U.S. application Ser. No. 15/468,815, filed Mar. 24, 2017, now Patent No. 10,213,448
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/11/2023 has been considered by the examiner.
Status of Claims
Claims 1 and 4-20 are pending. Claims 2 and 3 are canceled. Claims 11-20 are withdrawn. Claims 1 and 4-10 are examined in accordance to the elected species.
Claim Objections
Claim 1 and 4-10 are objected to because of the following informalities: the recitation of “ofEtn” in line 5 of claim 1 should be “of Etn.” Additionally, with respect to claim 5, the recitation of “in capsules” (plural) should be changed to “in the form of a capsule” because a single composition (singular) cannot be appeared to be contained or formulated in multiple capsules. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 and 4-10 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.
Claim 1 recites a monoethanolamine (Etn)-related compound selected from the group consisting of Etn, an Etn pro-drug, an Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, and a pharmaceutically acceptable salt thereof. It is not clear if Etn hybrid molecule is the only molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond or if Etn and an Etn pro-drug are also comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond. The election of Etn (monoethanolamine) which is a molecule that does not comprise Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, establishes the fact that only the Etn prodrug and the Etn hybrid molecule are the only molecules that can comprise Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond.
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, claims 4-6 and 9-10 recite the broad recitation composition, and claim 1 also recites pharmaceutical composition which is the narrower statement of the range/limitation. 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. The same situation applies to claim 7 as being dependent to claim 6 and claim 8 as being dependent to claim 7.
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 1-10 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are several guidelines when determining if the specification of an application allows the skilled artisan to practice the invention without undue experimentation. The factors to be considered in determining what constitutes undue experimentation were affirmed by the court in re Wands (8 USPQ2d 1400 (CAFC 1986)). These factors are (1) nature of the invention; (2) state of the prior art; (3) level of one of ordinary skill in the art; (4) level of predictability in the art; (5) amount of direction and guidance provided by the inventor; (6) existence of working examples; (7) breadth of claims; and (8) quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(1) Nature of the invention
The claims are directed to a method of treating ovarian cancer comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition comprising:
a monoethanolamine (Etn)-related compound selected from the group consisting of Etn (elected compound), an Etn pro-drug, an Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, and a pharmaceutically acceptable salt thereof; and
a pharmaceutically effective carrier,
(2) State of the prior art
The state of the art is that oral formulation of ethanolamine with phosphoric acid at a pH 5 was effective inhibiting tumor growth and antiproliferation in ovarian cancer line in vitro. (See first paragraph of the left column of page 3785 of Saxena et al, Clin Cancer Res (2017) 23 (14): 3781–3793.) However, Saxena also teaches unfortunately, formulations with pH 7.4 and/or containing PhosE were either not as effective in inhibiting tumor growth as Etn at pH 5 or in some cases even accelerated tumor growth. Moreover, Etn absorption was independent of pH (5/7.4) or acid (H3PO4/HCl/H2SO4) employed to adjust formulation pH. These data generated compelling grounds to exclusively pursue the Etn-containing formulation at pH 5 adjusted using phosphoric acid. (See first paragraph of the left column of page 3785 and Supplementary Table S4.) Thus, one cannot ascertain whether the instant invention is of use of Etn, phosphoethanolamine or any Etn pro-drug/Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, or a pharmaceutically acceptable salt thereof can be expected for treating ovarian cancer.
(3) Level of one of ordinary skill in the art
The level of skill in the art is deemed to be high, generally that of a medical Doctor specializing in the field of oncology.
(4) Level of predictability in the art
The art pertaining to the use of inhalation of Etn, phosphoethanolamine, any Etn pro-drug, or any Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, or a pharmaceutically acceptable salt thereof for treating ovarian cancer is highly unpredictable. Specifically, namely Fact Sheet (Texas Commission on Environmental quality, September 2015) teaches although monoethanolamine (MEA) has not been classified as causing cancer when inhaled by the International Agency for Research on Cancer or the USEPA, MEA has the potential to cause cancer in human. (See first paragraph of page 2.)
In Sum, Fact Sheet shows ethanolamine cannot be expected to treat ovarian cancer via any route including the inhalation route. In fact, ethanolamine has never been recognized for the treatment of ovarian cancer as a standalone treatment. Ovarian cancer treatment involves surgery, chemotherapy, targeted therapy, and sometimes hormone therapy. Monoethanolamine has not been administered directly to humans as a therapeutic agent.
Anvisa (Anvisa, July 29, 2024) teaches the use of products not registered by Anvisa for cancer treatment is extremely risky. These products can negatively interfere with conventional therapies and pose a risk of contamination. Patients must not abandon established medical treatments in favor of unauthorized therapies of unknown efficacy, such as phosphoethanolamine. (See Risks of Using Unregistered Products.) Moreover, Anvisa teaches
without adequate clinical research and proper registration, phosphoethanolamine cannot be considered safe or effective for treating cancer. Medical science is based on rigorous data and evidence, and criteria for approving new treatments are established to protect the health of patients. (See Importance of Clinical Research.)
In sum, Anvisa demonstrates phosphoethanolamine has not been considered for treating cancer.
Jiang et al (Front Oncol. 2022 Nov 21;12: 1004978, pages 1-16) teaches niclosamide- ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the preclinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet. (See Abstract.) Moreover, Jiang teaches a potential solution to the bioavailability challenge of niclosamide is niclosamide ethanolamine (NEN), a salt form of niclosamide that also functions as a mitochondrial uncoupler with a superior safety profile and enhanced bioavailability. (See second paragraph of the right column of page 3.) Additionally, Jiang teaches the efficacy of niclosamide in targeting Wnt/β-catenin pathway in a wide spectrum of cancer types including prostate, ovarian, breast, colorectal, pancreatic, and neuroblastoma. (See second paragraph of the left column of page 5.)
In sum, Jiang highlights ethanolamine can conjugate other molecules via ester, carbonate, urethane or anhydride bond to form a prodrug or a hybrid molecule, However, its role in this situation involves creating a stable salt, conjugate or derivative to boost drug delivery and bioavailability of the molecule (niclosamide). In other words, the efficacy of niclosamide ethanolamine (NEN) is attributed to the niclosamide and not the ethanolamine.
Hartshorne et al (GB2446801A) teaches a water-based wellbore treatment fluid contains: one or more viscoelastic-gelling carboxylic acids and/or alkali metal salts thereof; and one or more solubilizing alkylolamines. The alkylolamines solubilise a sufficient portion of the carboxylic acids and/or alkali metal salts to render the fluid viscoelastic. (See Abstract.) Hartshorne teaches a number of examples are now presented to illustrate the formulation of viscoelastjc surfactant solutions with the alkylolamine salts of fatty acids for use at elevated temperatures includes, but not limited to stearic-ethanolamine and behenic-ethanolamine (also known as N-docosanoyl-ethanolamine. (See examples.)
In sum, stearic-ethanolamine and behenic-ethanolamine (also known as N-docosanoyl-ethanolamine are known in the art as viscoelastjc surfactants and not for the claimed treatment.
Chua et al (“Advanced Ovarian Cancer: What You Need to Know” December, 29, 2025) teaches ovarian cancer is not one single disease — it’s a type of gynecologic cancer (cancer of the female reproductive system). Cancers that fall under this umbrella include tumors that grow in the ovaries, fallopian tubes, and peritoneum (tissue that lines the inside of your abdomen). Some ovarian cancers are caught early, when the tumor is still small. Others are more advanced, meaning the tumors have grown larger or spread to other organs. Advanced ovarian cancer is usually harder to treat and has a worse outlook. (See first and second paragraphs.)
In sum, not all ovarian cancer can be expected to be treated. For instance, a person of ordinary skill in the art cannot expect the claimed compounds to treat advanced ovarian cancer without undue experimentation.
Mak et al (Am J Transl Res. 2014 Jan 15;6(2):114–118) teaches the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore, the safety and efficacy identified in animal studies is generally not translated to human trials. (See Abstract.)
Agadjanian et al (Sci Rep 15, 34969 (2025)) teaches ovarian cancer is a heterogeneous disease characterized by late-stage diagnosis and poor survival rates. Research efforts are hindered by the complexity of the tumor microenvironment and the lack of suitable preclinical models. While immortal human cell lines and patient-derived xenograft (PDX) models have contributed significantly to understanding tumor biology, they are limited by their immunodeficient nature, which precludes the study of immune-mediated mechanisms. Genetically modified mouse models of ovarian cancer address this limitation but the long and unpredictable tumor latency is impractical for testing therapies. (See second paragraph of page 1.) Moreover, Agadjianian teaches with the plethora of syngeneic ovarian cancer cell lines to choose from, is there a need for additional cell lines? The effectiveness of currently available therapies for treating ovarian carcinomas remains limited, largely due to the heterogeneous nature of these tumors. Ovarian carcinomas encompass a variety of distinct mutant genotypes, each of which exerts diverse and often poorly understood influences on tumor phenotypes. These influences extend to critical factors such as the tumor’s microenvironment and its response to treatment. This complexity poses significant challenges, particularly in developing and evaluating new immunotherapies. Our limited understanding of the mechanisms by which cancer genotypes shape both immunophenotypes and therapeutic responses further complicates efforts to improve outcomes in this disease. (See fifth paragraph of page 2.)
In sum, the lack of animal model for ovarian cancer would reasonably hinder treatment of ovarian cancer. A person of ordinary skill in the art cannot expect the claimed method to be effective for treating ovarian cancer in a human or any subject.
(5) Amount of direction and guidance provided by the inventor
The claims encompass a vast number of Eth-related compound. Applicant’s limited guidance does not enable the public to use the claimed Etn-related compounds for treating ovarian cancer. There is no directional guidance for the treatment of ovarian cancer with all Etn-related compounds in every subject and in every route of administration and treatment of ovarian cancer and advanced ovarian with ethanolamine in a human subject. Hence, there is no enablement for all Etn-related compounds claimed to effectively treat ovarian cancer.
(6) Existence of working examples
The claims encompass a vast number of ETn-related compounds that lacks pharmacological utility. Applicant’s limited working examples do not enable the public to use all Etn-related compounds claimed for treating ovarian cancer. While Applicant’s claims encompass a plethora of possible Etn-related compound for treating ovarian cancer, the specification only provides guidance of a particular in vitro assay for inhibiting or reducing ovarian tumor growth. The in vivo assay was used for prostate cancer. The specification appears to be silent on (1) any correlation between the in vitro testing and in vivo success and (2) any in vivo models suggestive of treatment of ovarian caner with any of the claim Etn-related compounds.
(7) Breadth of claims
The claims are extremely broad due to the vast number of possible Etn-related compounds, route of administrations, and subject.
(8) Quantity of experimentation needed to make or use the invention based on the content of the disclosure
The specification does not enable any person skilled in the art to which it pertains to make and use the invention commensurate in scope with the claims because using an oral formulation comprising phosphoethanolamine as an Etn conjugated with a phosphate group via an ester bond and phosphoric acid buffer at pH 7.4 was shown to be ineffective in inhibiting tumor growth and in some cases even accelerated tumor growth as taught by the instant specification. The specification fails to enable the skilled artisan to practice the invention without undue experimentation to use a monoethanolamine (Etn)-related compound selected from the group consisting of Etn, an Etn pro-drug, an Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, and a pharmaceutically acceptable salt thereof; and a pharmaceutically effective carrier for treating ovarian cancer. Furthermore, based on the unpredictable nature of the invention, the state of the prior art, and the extreme breadth of the claims, one skilled in the art could not perform the claimed invention without undue experimentation.
Improper Markush Grouping Rejection
Claims 1 and 4-10 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of Etn (monoethanolamine), an Etn prodrug comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond, and an Etn hybrid molecule comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Specifically, monoethanolamide
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a naturally occurring organic chemical compound with the formula HOCH2CH2NH2 or C2H7NO. The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid with an odor reminiscent of ammonia used in pharmaceuticals as a versatile ingredient for pH adjustment, solubilizing acidic drugs (forming salts to improve absorption), creating emulsions, and as a sclerosing agent (ethanolamine oleate) for esophageal varices, improving formulation stability, texture, and drug delivery, while also serving as a reference standard in quality control.
Etn prodrug comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond is described in the specification at paragraph [0042] as carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Etn prodrugs undergo a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life. An example of the Etn-prodrug includes 2 aminoethyl 4-hydroxy-3-methoxy- benzoate
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an ester linking an aminoethyl group to the carboxylic acid of Vanillic Acid (4-hydroxy-3-methoxybenzoic acid), a derivative of vanillin. it's more likely a synthesized research chemical or intermediate, perhaps related to flavor/fragrance.
Etn hybrid comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond is described in the specification at paragraph [0043] as a hybrid molecule of Etn and another chemotherapeutic drug. For example, Etn hybrids of belinostat, where ethanolamine forms an hybrid molecule by the conjugation with belinostat.
Belinostat ethanolamine salt
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refers to the pharmaceutical form of belinostat, a histone deacetylase (HDAC) inhibitor drug used primarily for treating relapsed/refractory peripheral T-cell lymphoma (PTCL), often formulated as a salt for better solubility and delivery, such as with ethanolamine. It works by targeting HDAC enzymes, affecting gene expression to fight cancer, and is known to cause side effects like fatigue, nausea, and low blood counts, requiring careful monitoring.
Etn hybrid comprising Etn conjugated to another compound through an ester, carbonate, urethane or anhydride bond is described in the specification at Table 2 includes
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. 2-aminoethyl docosanoate is the same as behenic-ethanolamine is known as a viscoelastic surfactant for water-based wellbore treatment fluid.
Therefore, the members of the Markush grouping are not considered to share a “single structural similarity” and common use where the alternatives do not share both a substantial structural feature and a common use because the ethanolamine does not constitute a significant portion of the Etn-related compound.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
Claims 1 and 4-10 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628