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 amendments and arguments filed on 01/07/2026 is acknowledged. Claim 15 was canceled. Claims 1-14 and 16-20 are now pending.
Claims 1-5 have been amended to require that the orally administrable composition includes a tri-block copolymer.
Claims 17-20 have been amended to require that the orally administrable composition comprises a self-emulsifying drug delivery system (SEDDS).
Claims 6-14 and 16 have been amended to a composition comprising compounds other than the compounds previously claimed.
Election by Original Presentation
Pursuant to MPEP 821.03: Newly submitted claims 6-14 and 16 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claims to the different patentably distinct species recite the mutually exclusive characteristic of such species:
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. In addition, the newly added species will require a different search from the search performed for the aldehyde species. This will cause a search and examination burden for the examiner while the distinct aldehyde compounds are under examination and under prior art rejections.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 6-14 and 16 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Thus, claims 1-5 and 17-20 are the subject of this Final Office action.
Rejections and objections not reiterated herein have been withdrawn. The search has not been extended.
Claim interpretations
The recitation “the compound is incorporated into a formulation for oral bioavailability” does not have any specific ingredient requirements. This is interpreted to mean that the compound is in a formulation that contains one or more pharmaceutical excipients or inactive ingredients, and that is suitable for oral administration.
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 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Brackman et al. (BMC Microbiology 2008, 8:149) and Shafreen et al. (J. Mol. Recognit. 2014; 27: 106-116), in view of Faikoh et al. (Fish & Shellfish Immunology 38 (2014) 15-24), and Li et al. (Macromolecules 2015, 20, 6022-6032-previously cited) and further in view of Gursoy (Biomedicine & Pharmacotherapy 58 (2004) 173-182) or Bahloul (International Journal of Pharmaceutics 466 (2014) 341-348), and Nikam et al. (Advance Pharmaceutical Journal 2018; 3(2): 43-54- published online on 29 July 2018) and Singh (Journal of Controlled Release 252 (2017) 28-49). All references have been previously provided.
Cinnamaldehyde and analogs, such as 2-nitrocinnamaldehyde and 4-nitrocinnamaldehyde, are known to exhibit antibacterial properties. These compounds inhibit quorum sensing (QS) and biofilm formation, thereby disrupting virulence in pathogens such as Vibrio spp. (see Brackman) and Streptococcus pyogenes (See Shafreen).
Faikoh teaches that cinnamaldehyde is an effective antibacterial which has poor solubility in water. Faikoh states “liposome-encapsulated cinnamaldehyde (LEC) was developed to increase the compound’s water solubility, and its bacteriostatic and bactericidal activity against aquatic pathogens.” (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.
Li teaches that cinnamaldehyde is an effective antimicrobial ingredient widely used in food preservation. It has great antifungal activity, however, due to its hydrophobicity, it’s sparingly soluble in water and difficult to uniformly disperse in food matrices, resulting in lowered antifungal activity. See abstract and page 6023. Li teaches that nanocapsular dispersions can solve this problem, and actually improve antifungal activity (p. 6023 and Conclusions). The nanocapsular dispersion of cinnamaldehyde was made by first adding and mixing Tween-80 surfactant, followed by ethanol cosurfactant, 1,2-propanediol, extra virgin olive oil and cinnamaldehyde. See page 6028.
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).
Gursoy teaches self-emulsifying drug delivery systems (SEDDS), and necessary ingredients for improved oral delivery of lipophilic drugs: “The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids.”
Regarding co-solvents, at section “2.1.3. Co-solvents” Gursoy teaches that “the production of an optimum SEDDS requires relatively high concentrations of surfactants” and “organic solvents such as ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base.”
Bahloul teaches development and optimization for formulations of SEDDS by the selection of ingredients, including surfactants and solvents, and determination of the optimal interval of HLB for the surfactant(s).
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
Brackman and Shafreen do not teach a composition comprising a SEDDS.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
The primary references are in the same field of endeavor, i.e. antibacterial, antifungal cinnamaldehyde and derivatives. One of ordinary skill in the art is a chemist practitioner with the knowledge and skill of the authors of the references cited to support the examiner's position. As discussed above, 2-nitrocinnamaldehyde and 4-nitrocinnamaldehyde were known to have antibacterial activity at least against Streptococcus pyogenes, which is responsible for a wide range of human infections, such as strep throat and pneumonia, which are commonly treated with oral antibiotics.
It would have been prima facie obvious to one of ordinary skill in the art to make self-emulsifying drug delivery systems (SEDDS) for oral administration of the lipophilic 2-nitrocinnamaldehyde or 4-nitrocinnamaldehyde in the interest of improving their solubility in water and thereby, improving their oral absorption and antibacterial activities.
One of ordinary skill would have used the surfactants and co-solvents (co-surfactants) suggested by the references to be used in oral emulsion formulations. In view of the teachings of at least the Gursoy and Bahloul references, the ordinary artisan would have been able to optimize the HLB values of the surfactant mixture, therefore, arriving at the matching of the HLB to that of the compound, as claimed in claim 18. See at least page 346 of Bahloul.
Propylene glycol (PG) and polyethylene glycol (PEG) are taught by Gursoy to be very suitable for oral delivery. PEG-300, and the poloxamer poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO), 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 self-emulsifying drug delivery systems and encapsulating the active cinnamaldehyde derivatives of the above references.
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004).
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”, nothing precludes the use of the obvious compositions as instantly claimed (see MPEP 2112.02(II)), nor does the recitation impart any structural characteristic that would distinguish it from the prior art. “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”.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Here at least exemplary rationales (A), (C) and (D) apply.
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 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Brackman et al. (BMC Microbiology 2008, 8:149) and Shafreen et al. (J. Mol. Recognit. 2014; 27: 106-116), in view of Faikoh et al. (Fish & Shellfish Immunology 38 (2014) 15-24), and Li et al. (Macromolecules 2015, 20, 6022-6032-previously cited) and further in view of Gursoy (Biomedicine & Pharmacotherapy 58 (2004) 173-182), Nikam et al. (Advance Pharmaceutical Journal 2018; 3(2): 43-54- published online on 29 July 2018) and Singh (Journal of Controlled Release 252 (2017) 28-49). ---All references have been previously provided.
Cinnamaldehyde and analogs, such as 2-nitrocinnamaldehyde and 4-nitrocinnamaldehyde, are known to exhibit antibacterial properties. These compounds inhibit quorum sensing (QS) and biofilm formation, thereby disrupting virulence in pathogens such as Vibrio spp. (see Brackman) and Streptococcus pyogenes (See Shafreen). Streptococcus pyogenes (Group A strep bacteria) causes highly contagious infections, such as strep throat and pneumonia, which are treated with oral antibiotics.
The art knows that cinnamaldehyde and its derivatives are hydrophobic and have poor water solubility. This problem has been addressed 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. Additionally, this problem was also addressed by Li. In order to increase water solubility of poorly-soluble cinnamaldehyde, they taught the preparation of nanocapsular/nanoemulsion 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 and solubility were improved. See page 6028.
Gursoy teaches that “The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds.”
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). Particularly, see Sing: “Other common surfactants include those belonging to poloxamer family … and PEG containing block copolymers”. See also Table 3, nanoemulsions intended for oral use for the natural product curcumin. A nanoemulsion was prepared in castor oil, with Cremophor, Tween 80 and Pluronic F-68 to “increase oral bioavailability for improved anti-cancer activity”.
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
Brackman and Shafreen do not teach a composition comprising a tri-block copolymer, an oil, a surfactant which is polysorbate 80, or a co-surfactant.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
Brackman, Shafreen, Faikoh and Li are in the same field of endeavor, i.e. antibacterial, antifungal cinnamaldehyde and derivatives. 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. 2-nitrocinnamaldehyde and 4-nitrocinnamaldehyde were known to have antibacterial activity at least against Streptococcus pyogenes, which is responsible for a wide range of human infections.
It would have been prima facie obvious to one of ordinary skill in the art to make nano-dispersions or nano-emulsions for oral administration of the antibacterials 2-nitrocinnamaldehyde and 4-nitrocinnamaldehyde with the known ingredients used for making drug nano-emulsions, with the purpose of improving said nitrocinnamaldehyde’s solubility in water and thereby, improving their oral absorption and antibacterial activities.
The triblock copolymers of poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO), Castor oil, Tween-80 (polysorbate 80) surfactant, and co-surfactants, are ingredients commonly used in nano-emulsions for encapsulation of therapeutics in drug delivery, as taught by at least Singh. Thus, the ordinary skilled artisan would have been motivated to make the nano-emulsions containing a tri-block copolymer, oil, or the surfactant Tween-80 or co-surfactant.
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004).
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”, nothing precludes the use of the obvious composition as instantly claimed (see MPEP 2112.02(II)), nor does the recitation impart any structural characteristic that would distinguish it from the prior art. “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”.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Here at least exemplary rationales (A), (C) and (G) apply.
Applicant’s arguments have been considered but were found unpersuasive.
Applicants argue against the references individually. Applicants argue that neither Shafreen nor Brackmann considers that antibacterial effects would be benefited by drug delivery technology or that the bacteria are treated orally. Applicant further argues that none of Nikam, Singh and Grossen considers application of the tri-block copolymers to cinnamaldehyde or cinnamaldehyde derivatives. Additionally, Applicant argues that both Bahloul and Gursoy are directed to SEDDS for improved oral delivery but they do not teach or suggest its use with cinnamaldehyde or cinnamaldehyde derivatives. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In Addition, Applicant argues that Li and Faikoh are not concerned with administering cinnamaldehyde as a drug or it being orally administered. However, Li and Faikoh show that the artisan knew that cinnamaldehyde and derivatives are effective antibacterials which are hydrophobic and have poor water solubility. Further, Li and Faikoh are directed to solving the same particular problem of hydrophobicity of cinnamaldehyde with which the inventor was concerned.
Applicant argues that nothing in Shafreen, Brackman, Li and Faikoh suggests that cinnamaldehyde or a cinnamaldehyde derivative is a parenterally, orally, or topically administered drug. In response, Shafreen and Brackman are directed to pathogens that are proficient in causing human health-posed infections ranging from pharyngotonsillitis to life-threatening invasive infections. Strep throat and pneumonia, commonly treated with oral antibiotics, are caused by S. pyogenes (of Shafreen). The purpose of these references is not simply to test in pietri dishes, but to find treatment for S. pyogenes infections with non-toxic cinnamaldehyde derivatives that can be administered to humans through known available routes. Note that Shafreen concludes: “Currently, there are several LuxS inhibitors screened, but their toxic side effects limit their potential during disease treatment. Therefore, it is crucial to explore compounds with least toxic effects against S. pyogenes mediated QS. Cinnamaldehyde and their derivatives are well known as non-toxic and have various bioactive potential.” “Thus, from the present study, CN and their derivatives are identified as potential antibiofilm and antipathogenic inhibitor of S. pyogenes via the LuxS-mediated QS.”
In addition, cinnamaldehyde is present in cinnamon, which humans take orally. Nothing in the prior art suggested that orally administering cinnamaldehyde derivatives shouldn’t be done. The oral route is the most common and convenient method.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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).
A person of ordinary skill in the art knew about the poor water solubility problem of cinnamaldehyde and derivatives, and was also aware of solutions pertinent to the problem. Making SEDDS was a solution known in the art and taught by the references.
Conclusion
Claims 1-5 and 17-20 are rejected.
Claims 6-14 and 16 are withdrawn.
Note to Applicant
Not every piece of prior art 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