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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/1/2025 has been entered.
103 Rejections Withdrawn
The rejection of claims 1-5, 7, 9-12, 14 and 15 under 35 USC 103, outlined in the previous Office Action, is withdrawn. Inventor’s amendment and arguments have been carefully considered and are persuasive. (The amendment cancels claim 3.) A newly formulated rejection follows.
Claim Objections Withdrawn
The objection to claim 8, outlined in the previous Office Action, is withdrawn. A rejection follows.
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 1, 2, 4, 5, 7-11 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over International Journal of Current Research (2016), 8(11), pp. 41500-41503, a newly cited reference, and further in view of Indian Journal of Gastroenterology (2105), 34(2), pp. 152-157, prior art of record.
Inventor teaches a method of preventing or treating chronic anal fissure comprising topically applying a composition which is an ointment, cream, suspension, emulsion, lotion, solution, paste, gel, spray, foam, oil or aerosol, in and around the anal region, where the composition comprises diltiazem, or its pharmaceutically acceptable salt, metronidazole, and a pharmaceutically acceptable carrier (independent claim 1).
Dependent claim 2 (from claim 1) teaches that the composition is applied at least once a day.
Dependent claim 4 (from claim 1) teaches that the composition further comprises at least one of emulsifiers, preservatives, buffering agents, surfactant, gelling agents, paraffin and solvents.
Dependent claim 5 (from claim 1) teaches that the dosage of diltiazem is from about 2 mg/kg to about 25 mg/kg.
Dependent claim 7 (from claim 1) teaches that the composition is delivered in about a 1 inch dosage of cream.
Dependent claim 8 (from claim 7) teaches that the unit dosage is about 3 mg of diltiazem.
Dependent claim 9 (from claim 1) teaches that the composition is applied 3 times daily.
Dependent claim 10 (from claim 9) teaches that the composition is applied 3 times daily for 8 weeks.
Dependent claim 11 (from claim 1) teaches that the composition further comprises at least one anesthetic agent, a vasoconstrictor, an antipruritic agent, an anti-inflammatory agent, a muscle relaxant, an astringent, a keratolytic agent, an antibiotic agent, an antiseptic agent, or a combination thereof.
Dependent claim 14 (from claim 1) teaches that the composition comprises from about 10-40% w/w of metronidazole and 1-10% w/w of diltiazem, or their pharmaceutically acceptable salts.
Inventor further teaches a method of treating pain comprising topically applying a composition which is an ointment, cream, suspension, emulsion, lotion, solution, paste, gel, spray, foam, oil or aerosol, in and around the region of pain, where the composition comprises diltiazem, or its pharmaceutically acceptable salt, metronidazole, and a pharmaceutically acceptable carrier (independent claim 15).
Dependent claim 16 (from claim 1) teaches that the topical composition is applied to the mucosal surface of the anorectal region.
International Journal of Current Research (2016), 8(11), pp. 41500-41503, a comparison study, teaches inter alia a method of treating chronic anal fissure comprising applying to the anal region a topical cream mixture which includes bacitracin, neomycin sulfate, neomycin, diltiazem and dexapanthenol (abstract). That is, the reference teaches a method of treating chronic anal fissure comprising applying to the anal region a topical cream mixture which includes a bacitracin-neomycin antibacterial, diltiazem (a calcium channel blocker) and dexapanthenol for epithelialzation (and which is known in the art as an anti-inflammatory, anti-itch, moisturizing, wound-healing promoter) (page 41500, column 2, text line 6; page 41502, column 1, DISCUSSION, text line 10).
The topical mixture was prepared by adding crushed diltiazem tablets (30mg ea. X 48 tablets = 1400 mg diltiazem) to 15000 IU of bacitracin, 150 mg of neomycin sulfate containing 105 mg of neomycin base, and 1500 mg of dexapanthenol (page 41501, column 1, text line 23ff). (The bacitracin-neomycin and dexapanthenol are sourced from commercial formulations in 30 g tubes – which commercial formulations will intrinsically comprise appropriate excipients - such as, for instance, solvents - in order to accommodate dispensation from the tube-style commercial packaging.) The cream was applied in 1 cm3 amounts 3 times a day for 6 weeks (page 41501, column 1, text line 35).
The reference explicitly states that perhaps in future other antibacterial agents will be of use in the treatment of anal fissure (page 41502, column 1, DISCUSSION, text line 15). That is, the reference explicitly teaches that it is contemplated that other antibacterials - besides the exemplified bacitracin-neomycin antibacterial - may prove useful as antibacterials in the method of treating chronic anal fissures utilizing topical cream antibacterial/diltiazem/dexapanthenol mixtures.
Indian Journal of Gastroenterology (2015), 34(2), pp. 152-157 teaches the topical application of metronidazole for the treatment of chronic anal fissure and which results in a more rapid resolution of pain and healing of the fissure (abstract; page 156 Discussion).
Inventor principally distinguishes over International Journal of Current Research (2016), 8(11), pp. 41500-41503 in that the antimicrobial/antibacterial metronidazole is substituted for the bacitracin-neomycin antibacterial/antimicrobial of the cited art. However, as the reference itself make explicitly clear, it is expected that other antibacterials, besides the exemplified bacitracin-neomycin antibacterial, may be utilized. That is, the reference has demonstrated a successful proof-of-concept topical treatment for chronic anal fissures utilizing a particular antibacterial/diltiazem/dexapanthenol topical cream mixture and then suggested that the antibacterial component of this efficacious mixture may be extrapolated to encompass other antibacterials. Given this suggestion, and the fact that the choice of antibacterial/antimicrobial would be expected to be a results-effective variable, one of ordinary skill in the art, before the effective filing date of the instant invention, would have found it obvious, and with a reasonable expectation of success, to optimize the choice of antibacterial/antimicrobial. One of ordinary skill would have been motivated to choose metronidazole as the antibacterial/antimicrobial since it already has a demonstrated efficacy, in particular with respect to pain, in the treatment of chronic anal fissure - as evidenced by Indian Journal of Gastroenterology (2015), 34(2), pp. 152-157.
Claims 5, 7, 8 and 10 are included in this rejection because the limitations -diltiazem dosage based upon patient body mass (claim 5), dosage of 1 (linear) inch of cream (claim 7), dosage of about 3 mg of diltiazem (claim 8), and application 3 times daily for 8 weeks (claim 10) - are all drawn to the results-effective variable of dosage, and one of ordinary skill in the art, i.e. highly skilled individual such as clinical physician, would have found it obvious - absent unexpected results - to optimize the topical formulation dosage based upon ordinary clinical considerations (e.g. efficacy).
Claim 14 is included in this rejection because its limitation, with respect to the proportion of diltiazem and metronidazole in the topical composition, represents a results-effective variable and one of ordinary skill in the art, i.e. highly skilled individual such as clinical physician, would have found it obvious - absent unexpected results - to optimize the topical formulation proportions based upon ordinary clinical considerations (e.g. efficacy).
Claim 16 is included in this rejection because its limitation, that the topical composition is applied to the mucosal surface of the anorectal region, is intrinsic to the prior art method. This so because the topical formation must be physically applied to the anorectal region, which is transitional region of the body where a mucosal surface transitions to a non-mucosal surface. It would appear intrinsically impossible, given the anatomy, not to apply at least a portion of the cream, even if inadvertently, to the mucosal surface.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over International Journal of Current Research (2016), 8(11), pp. 41500-41503, a newly cited reference, and further in view of Indian Journal of Gastroenterology (2105), 34(2), pp. 152-157, prior art of record, and Drug Development and Industrial Pharmacy (2010), 36(10), pp. 1195-1206, a newly cited reference.
Inventor teaches a method of preventing or treating chronic anal fissure comprising topically applying a composition which is an ointment, cream, suspension, emulsion, lotion, solution, paste, gel, spray, foam, oil or aerosol, in and around the anal region, where the composition comprises diltiazem, or its pharmaceutically acceptable salt, metronidazole, and a pharmaceutically acceptable carrier (independent claim 1).
Dependent claim 12 (from claim 1), teaches that the composition further comprises propylene glycol and or glycerol monostearate in an amount so as to increase permeability of diltiazem.
International Journal of Current Research (2016), 8(11), pp. 41500-41503 has been outlined above.
Indian Journal of Gastroenterology (2105), 34(2), pp. 152-157 has been outlined above.
Drug Development and Industrial Pharmacy (2010), 36(10), pp. 1195-1206 teaches the effect of permeation enhancers, such as propylene glycol, on the viscosity and release profile of transdermal gel formulations containing diltiazem HCl (abstract).
As above, inventor principally distinguishes over International Journal of Current Research (2016), 8(11), pp. 41500-41503 in that the antimicrobial/antibacterial metronidazole is substituted for the bacitracin-neomycin antibacterial/antimicrobial of the cited art. However, as the reference itself make explicitly clear, it is expected that other antibacterials, besides the exemplified bacitracin-neomycin antibacterial, may be utilized. That is, the reference has demonstrated a successful proof-of-concept topical treatment for chronic anal fissures utilizing a particular antibacterial/diltiazem/dexapanthenol topical cream mixture and then suggested that the antibacterial component of this efficacious mixture may be extrapolated to encompass other antibacterials. Given this suggestion, and the fact that the choice of antibacterial/antimicrobial would be expected to be a results-effective variable, one of ordinary skill in the art, before the effective filing date of the instant invention, would have found it obvious, and with a reasonable expectation of success, to optimize the choice of antibacterial/antimicrobial. One of ordinary skill would have been motivated to choose metronidazole as the antibacterial/antimicrobial since it already has a demonstrated efficacy, in particular with respect to pain, in the treatment of chronic anal fissure - as evidenced by Indian Journal of Gastroenterology (2015), 34(2), pp. 152-157.
Furthermore, one of ordinary skill, before the effective filing date of the instant invention, would have found it obvious to include a permeation enhancer, such as propylene glycol, for diltiazem in the instant formation. One of ordinary skill would have done so, and with a reasonable expectation of success, given the teachings of Drug Development and Industrial Pharmacy (2010), 36(10), pp. 1195-1206 that the stratum corneum layer, the outer layer of the skin, is the most formidable barrier to permeability and the rate controlling barrier to transdermal diltiazem administration (page 1198, line 1ff). One of ordinary skill would recognize the advantage of overcoming this most formidable barrier by means of a permeation enhancer.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN J DAVIS whose telephone number is (571)272-0638. The examiner can normally be reached M-F 8:30-5:00 PM EST.
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/BRIAN J DAVIS/Primary Examiner, Art Unit 1614 1/7/2026