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 .
Priority
The present application is the U.S. National Stage Application, pursuant to 35 U.S.C.371, of PCT International Application No. PCT/US22/14379, filed January 28, 2022, which claims priority to U.S. Provisional Application No. 63/144,690, filed February 2, 2021.
Status of the Claims
Claims 1, 2, 4-9, 13-18, 26 and 29 are amended. Claims 10, 11, 27 and 33 are
canceled.
Claims 1, 2, 4-9, 13-18, 26 and 29 are pending and are examined on their merits.
Claim Objection Overcome by Amendment
Claim 29 was objected to for being a claim that depends from itself. Applicant has corrected the dependency. The objection is withdrawn.
Claim Rejections - 35 USC § 112(b) Overcome by Amendment
Applicant has amended claims 1 and 2 to define the method of administering a therapeutically effective amount of a pharmaceutical composition comprising methylenediamine (diaminomethane), or a pharmaceutically acceptable form for a condition being treated with a subject in need thereof to be a subject with lung cancer (amended claim 1) and the method for treating a subject with the same composition for treating liver cancer (amended claim 2).
Applicant has amended claim 17 to delete the phrase “a second therapeutic agent”.
Applicant has canceled claim 33.
The rejections are withdrawn.
Claim Rejections - 35 USC § 112 , first paragraph (Enablement) Reiterated and Maintained
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.
Enablement
Claim 1, 2 and 4 and their dependent claims 5-9, 13-18, 26 and 29 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 claims contain 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Response to Applicant’s Arguments:
Applicant argues to a series of Examples disclosed in the Specification, pointing to the use of methylenediamine to suppress cancer cell growth; namely Example 1, 2 (FIG. 2) and 3. Each of these examples describe the use of methylenediamine or a conjugated salt thereof against known cancer cell lines. Example 1 points to a cellular assay conducted in a microwell at 5x104/plate, Example 2 to the inhibition of cancer cells with dosage ranges from μM to mM for lung cancer lines H1229 and A549 as well as liver cancer line SNU499. Example 3 points to methylenediamine inducing apoptosis in melanoma and lung cancer cell lines detailing that the compound shows a dose dependent response.
Applicant has amended the claims 1, 2, 4 and the claims that depend from those claims (5-9, 13-18, 26 and 29) to address liver and lung cancers specifically treated with a therapeutically effective amount of methylenediamine. The ranges of the effective amount range from the μM to mM. The dose delivery as oral and the duration of 7-180 days, either with a single dose range or a rising daily dose. While the breath of claims has narrowed to lung and liver cancers, the dose, duration and “other secondary therapies” have not. Applicant has not taught anything further relating to the use of methylenediamine other than it is toxic to the selected cancer cells with a dose-dependent response; without a referencing the impact on “healthy” cells or a therapeutic amount.
The breadth of the claims
The breadth of claims are “a method for treating liver or lung cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising methylenediamine (diaminomethane).” , with a second known therapeutic for cancer treatment including with one or more of chemotherapy, hormone therapy, radiation therapy, and immunotherapy. There is no reasonable expectation that the treatment of all cancers related to the liver and lung can be accomplished by the action of a single drug and the applicant is using know anticancer therapeutics with no evidence that the compound works alone or with any other anticancer agents, thus the applicant has failed to enable the breadth of the claims.
The nature of the invention, level of one of ordinary skill, and state and predictability in the art
The invention relates to the treatment of cancer in a subject via the administration of methylenediamine (diaminomethane) and the coadministration of known anticancer drugs to treat solid tumor-related cancers and blood-related cancers. According to the MSDS, found in ChemicalBook (Revision Date:2026-01-03 Revision Number:1), the relevant identified use of the compound of methyenediamine dihydrochoride is for use as a compound for R&D use only, not for medicinal, household or other use. Further, the first aid measures of section 4 in the same document state, if inhaled, or if breathed in, move person into fresh air. If not breathing, give artificial respiration, in case of skin contact; wash off with soap and plenty of water, in case of eye contact, flush eyes with water as a precaution and, if swallowed, never give anything by mouth to an unconscious person. Rinse mouth with water. In the art of cancer medicine, one of ordinary skill in the art would be an oncologist, with several years of specialization beyond medical school. While a typical oncologist would be considered an expert in the field, this factor is outweighed by the state and unpredictable nature of the art. For example, Golub1 establishes that different cancers follow different clinical courses, and thus necessitate different therapies. Golub also shows that the boundaries between different classes of cancer are not always clear, which introduces a need for constant re-evaluation of therapies as more information is learned over the course of a treatment regimen. That is to say, by its nature the art of cancer treatment is unpredictable and constantly changing, and no one treatment option can be expected to work for all forms of cancer.
The existence of working examples
The applicant fails to provide any working examples demonstrating the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising methylenediamine (diaminomethane), (as in claim 1 and 2). The applicant only shows a lab data and a single murine model using the described methods, and does not show, either by example or reference that a pharmaceutical composition comprising methylenediamine (diaminomethane) is useful for either the treatment of cancer.
Applicant’s working examples amount to cell viability assays using a commercially available apoptosis kit purchased from the supplier Invitrogen; intended to demonstrate the ability of any compound to kill the targeted cells of the assay. According to the results listed in the specification, methylenediamine (diaminomethane) clearly kills cells. Although, they also describe a mouse model subcutaneously inoculated with liver cancer cells and treated with 120 mg/Kg and 240 mg/Kg of Methylenediamine (dihydrochloride salt) and show that the higher dose appears more effective at reducing tumor size, they do not enable it to be practiced on a related disease or condition, unless the compound kills cells indiscriminately.
The amount of direction provided and quantity of experimentation needed
The applicant has failed to describe the related disease or condition to be treated with methylenediamine (diaminomethane), but goes to great length to describe the cancers to be treated including: lung cancer, liver cancer, skin cancer, ovarian cancer, prostate cancer, breast cancer and blood cancer. Even though the applicant has “evaluated” the compound in cancer cell lines and a murine model they have not shown the cellular mechanism of action and have not performed the requisite pharmacokinetic evaluations to prove the effectiveness of the compound. For example, Brooks, et. al., Applicability of drug response metrics for cancer studies using biomaterials, Phil. Trans. R. Soc. B 374: 2018, 0226, describes the pharmacology metrics associated with the evaluation of the activity of potential drug for use as a therapeutic.
“Pharmacology metrics, such as IC50 (the inhibition concentration of a drug where the response is reduced by half), EC50 (the effective concentration of a drug that gives half-maximal response) and Emax (the drug’s maximum effect), have been used to evaluate the results of drug response assays and describe drug potency. Recently, Hafner et al. [1] defined the GR50: the concentration of a drug that reduces cell growth rate by half. The GR50 is an important contribution to the field of drug screening, because it accounts for the variable differences in growth rates between different cell lines.”
Brooks, Introduction, paragraph 1 (emphasis added).
Applicant has not performed the any of the pharmacology metrics as outlined by Brooks, to evaluate the effectiveness of the compound intended to be administered to subjects, further the quantity of experimentation necessary to establish the effectiveness of methylenediamine (diaminomethane) for use as an anticancer active compound alone or with other proven anticancer therapeutics requires significantly more experimentation to establish the IC50, EC50, Emax and GR50 of the core compound and to evaluate the interaction of the compound with other proven anticancer therapeutics interaction of the compound with other values as identified by Brooks.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL RANDALL GAUGER whose telephone number is (571)272-1325. The examiner can normally be reached M-F 7:30-5:00.
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/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Golub et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999 Oct 15;286(5439):531-7. doi: 10.1126/science.286.5439.531. PMID: 10521349
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