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 .
Receipt of claim amendments and arguments filed on December 30, 2025 is acknowledged. Claim 3 was canceled. Claims 1-2 and 4-20 are currently pending.
Claims 1-2 and 4-5 have been amended to require that the composition additionally comprises an oil.
Claims 6-9 have been amended to recite that the compound is included in a pharmaceutical composition with a surfactant.
Claims 10-20 have been amended to require that R1 is a nitro group, R is a methyl group and that the pharmaceutical composition comprises less than 10% water.
Rejections and objections not reiterated herein have been withdrawn in view of the claim amendments.
Examination
Search and examination have not been expanded. The compounds of claims 1-2, 4-5 and 10-20 have been fully searched. The entire scope of claims 6-9 has not yet been examined in accordance with Markush search practice. See MPEP 803.02. Not every piece of prior art found in the search has been applied against the instant claims. See MPEP 904.03.
Subject matter outside of the examined scope are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions there being no allowable generic or linking claim.
Claims 1-2 and 4-20 are the subject of this Final Office Action.
The claim amendments have necessitated the new grounds of rejection presented in this action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 6-10 remain rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Li et al. (Org. Lett. 2009, 11, 18, 4036-4039). Singh (Journal of Controlled Release 252 (2017) 28-49-previously provided in 17/202,951) is evidence that ethanol is used as co-surfactant, and Bjorn Kvamme (Fluids 2021, 6, 345) is evidence that ethanol is a surfactant.
Li teaches the claimed compound of formula
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(trans-α-methyl-o-nitrocinnamaldehyde) in an ethanol solution, as described at page 18 of the supporting information:
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. Water was not present.
With regards to the intended use and the purpose of the product (“pharmaceutical composition for reducing a rate at which nicotine is metabolized.…”, “for reducing a rate of nicotine metabolism”, “wherein the rate is reduced based on the pharmaceutical composition inhibiting an enzyme that metabolizes nicotine in a time-dependent manner”, “wherein the compound inhibits cytochrome p450 2A6…”), nothing precludes the use of the composition of Li as instantly claimed (see MPEP 2112.02(II)), nor does the recitation impart any structural characteristic that would distinguish it from the prior art composition.
See MPEP 2111.02 (II) regarding preamble statements reciting purpose or intended use: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”.
In the instant case, the body of the claims intrinsically set forth all of the limitations of the composition of claims 6-10 (that is, the compound and the surfactant or co-surfactant). Accordingly, any composition disclosed in the prior art having the elements recited in the body of the instant claims is considered to be capable of the intended use and purpose recited in the claims.
Applicant’s arguments were carefully considered but were found unpersuasive. Applicant argues that in Li, the nitro-cinnamaldehyde compound was prepared as an intermediate and not the final product. Applicant also argues that the compound was also subjected to chromatography in other solvents that are not pharmaceutically acceptable solvents, and that also sodium borohydride and lithium perchlorate were added to the ethanol solution of the compound. Applicant further argues that the compound is only very transiently present.
In response, the claims require a compound of formula
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or, with an additional interpretation, a pharmaceutical composition comprising a surfactant. Li taught that a solution of compound of formula
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(trans-α-methyl-o-nitrocinnamaldehyde) in ethanol was made. That is a pharmaceutical composition of the claimed compound in a surfactant. In the context of anticipation, what the author of the reference wanted to do with the composition, or what happened to it next, does not matter. All elements of the claimed invention were disclosed by Li. In addition, regarding the argument that the compound is only very transiently present, Li prepared a solution of the aldehyde in ethanol.
New grounds of rejection necessitated by amendments
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 2 and 6-9 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.
Claims 2 is drawn to a product (pharmaceutical composition) but also recites method steps (wherein metabolism is measured by monitoring nicotine metabolites or a genetic profile of…). Is the claim directed to a specific product dose that is defined by the process step? Because a single claim which claims both a product and the method steps of using the product is indefinite (see MPEP 2173.05(p)II). If the claim is re-written as a product made by a process (product-by-process claim), it would be proper. The claim could be amended to recite “The pharmaceutical composition of claim 1, produced by selecting a dose of the compound based on a nicotine metabolism rate of an individual to whom the pharmaceutical composition is administered, wherein the nicotine metabolism rate is measured by monitoring nicotine metabolites or a genetic profile of CYP2A6 or CYP2A13 for the individual.”
Claim 6 is drawn to “a compound” and it also recites the method step “wherein the compound is included in a pharmaceutical composition with a surfactant”. It appears that the claim is drawn to a compound with a method of use (that of including it in a pharmaceutical composition with a surfactant). A single claim which claims both a product and the method steps of using the product is indefinite (see MPEP 2173.05(p)II). If claim 6 is to be directed to a pharmaceutical composition comprising the compound and a surfactant, the claim should be amended to recite that.
Claims 7-9 are rejected for containing the issues of claim 6.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gasha et al. (Yakugaku Zasshi (1972), 92(4), 490-497), in view of Faikoh et al. (Fish & Shellfish Immunology 38 (2014) 15-24-previously cited), and Li et al. (Macromolecules 2015, 20, 6022-6032-previously cited) and further in view of Salimi (Jundishapur J. Nat Pharm Prod., 2014 August: 9(3);e16125), Nikam et al. (Advance Pharmaceutical Journal 2018; 3(2): 43-54- published online on 29 July 2018-previously cited) and Singh (Journal of Controlled Release 252 (2017) 28-49-previusly cited) and Grossen (J. Controlled Release (2017) 260, 46-60-previously cited).
Gasha taught that α-methyl-m-nitrocinnamaldehyde
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and α-methyl-p-nitrocinnamaldehyde
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have antifungal activity against Trichophyton mentagrophytes and Trichophyton rubrum. See Table I, compounds I-j and I-k, and results. Trichophyton mentagrophytes and Trichophyton rubrum cause tinea infections in humans, which are treated with topical and oral antifungals.
The art knows that cinnamaldehyde and its derivatives are hydrophobic and have poor water solubility. This problem has been solved by Faikoh through the preparation of “liposome-encapsulated cinnamaldehyde (LEC)”. See page 16, left column, last four lines. Cinnamaldehyde was encapsulated in liposomes by mixing cinnamaldehyde, lecithin and alpha-tocopherol in ethanol. See section 2.2 at page 16. No water was present in the liposome-encapsulated product. Additionally, to increase water solubility of poorly-soluble cinnamaldehyde, Li taught the preparation of nanocapsular dispersions of cinnamaldehyde by first adding and mixing Tween-80 surfactant, followed by ethanol cosurfactant, 1,2-propanediol, extra virgin olive oil and cinnamaldehyde. The antifungal activity was improved. See page 6028. No water was present in the making of this product.
Salimi disclosed that the oral route is one of the most preferred ways for chronic drug therapy; but the drug dissolution is usually a rate-determining step of the absorption processes for poorly water-soluble drugs. Poorly soluble or lipophilic compounds lead to restricted oral bioavailability, high intra and inter subject variability and a possible increase in dose. Salimi disclosed various types of lipid base formulations that are utilized to solve this problem, and taught that “self-emulsifying drug delivery system (SEDDs) is an isotropic mixture of natural and synthetic oils, non-ionic surfactants or, ore or more hydrophilic solvent and co-solvents/surfactant and polymer that improve bioavailability and increase solubility of poorly-soluble drugs.”
Nikam and Singh are evidence of commonly used nanoemulsion ingredients in drug delivery. Castor oil, olive oil or other oils are used. Surfactants, co-surfactants and enhancers used are PEG300, PEG400 and Poloxamers (triblock copolymers formed by poly-ethylene oxide and poly- propylene oxide). Grossen is evidence that PEG-PCL triblock copolymers is a well-known biodegradable drug delivery in nanomedicine. No water is present in the making of this product.
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
Gasha teaches antifungal compounds α-methyl-m-nitrocinnamaldehyde and α-methyl-p-nitrocinnamaldehyde, but does not teach a composition comprising an oil, a surfactant, a co-surfactant, or a co-solvent all-together or encapsulation as claimed.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
One of ordinary skill in the art is a chemist practitioner with the knowledge and skills of the authors of the references cited to support the examiner's position. It would have been prima facie obvious to one of ordinary skill to make nano-dispersions (nano-emulsions) as in Li of liposome-encapsulated α-methyl-m-nitrocinnamaldehyde or α-methyl-p-nitrocinnamaldehyde, in the interest of improving their water solubility and thereby, improving their bioavailability and antifungal activities. In addition, one of ordinary skill in the art would have been motivated to make a self-emulsifying drug delivery system (SEDDs) of α-methyl-m-nitrocinnamaldehyde or α-methyl-p-nitrocinnamaldehyde as they were described by Salimi to improve bioavailability and increase solubility of poorly-soluble drugs.
Castor oil, polysorbate 80,PEG-300, and the triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO) and PEG-PCL, are ingredients commonly used in nano-emulsions for encapsulation of therapeutics in drug delivery. Thus, the ordinary skilled artisan would have been motivated to use these known ingredients in making the nano-emulsions, and the SEDDs, and in encapsulating the active cinnamaldehyde derivatives of the Gasha reference.
Regarding the compound of claim 8, one of ordinary skill in the art would have been motivated to make the o-nitro position isomer of the nitro-cinnamaldehyde compounds of Gasha with the expectation that additional nitro-cinnamaldehyde derivatives useful as antifungals would be obtained. It is well established that position isomers are prima facie structurally obvious even in the absence of a teaching to modify. The isomer is expected to be preparable by the same method and to have generally the same properties. This expectation is then deemed the motivation for preparing the position isomers. Note MPEP2144.09, second paragraph: “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.”
Under the Supreme Court rationales in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007), here at least exemplary rationales (A) and (C) apply:
(A) Combining prior art elements according to known methods to yield predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way.
With regards to the intended use and the purpose of the product (“pharmaceutical composition for reducing a rate at which nicotine is metabolized.…”, “for reducing a rate of nicotine metabolism”, “wherein the rate is reduced based on the pharmaceutical composition inhibiting an enzyme that metabolizes nicotine in a time-dependent manner”, “wherein the compound inhibits cytochrome p450 2A6…”), nothing precludes the use of the composition of Li as instantly claimed (see MPEP 2112.02(II)), nor does the recitation impart any structural characteristic that would distinguish it from the prior art composition.
See MPEP 2111.02 (II) regarding preamble statements reciting purpose or intended use: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”.
In the instant case, the body of the claims intrinsically set forth all of the limitations of the composition claimed. Accordingly, any composition disclosed in the prior art having the elements recited in the body of the instant claims is considered to be capable of the intended use and purpose recited in the claims.
In regards to claim 18 with the recitation “the one or more tri-block copolymers enhances oil bioavailability of the compound”, the composition disclosed by the prior art recites all of the structural limitations required in the claims, therefore it would have been expected that the same properties would be present. This is because an identical composition must necessarily produce the same effects, since products of identical chemical composition cannot have mutually exclusive properties when used in an identical manner MPEP § 2112.
Claim 20 is a product-by-process claim, however, patentability is based on the product itself. If the product is the same as a product from the prior art, the claim is unpatentable. See MPEP 2113:
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Conclusion
Claims 1-2 and 6-20 are rejected.
Claims 1, 4 and 5 appear allowable.
Not every piece of prior art found in the search has been applied against the instant claims. See MPEP 904.03.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621