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
This application is a DIV of 16497269, filed 9/25/2019. 16497269 is national stage entry of PCT/IB2018/052699, filed 4/19/2018, and claims foreign priority to MX/A/2017/014725, filed 11/16/2017.
Claim Status
Receipt of Remarks/Amendments filed on 9/12/2025 is acknowledged. Claims 15 and 18-21 are currently pending and presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Withdrawn Rejections/Objections
The objection of claim 18 made in the previous office action has been withdrawn due to appropriate amendments to the claim.
The rejections of claims 20-23 under 112(b) and 112(d) have been withdrawn due to appropriate amendments to the claim.
New/Maintained Claim Rejections/Objections
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 15 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al. (WO 2013/154347 A1; Oct. 17, 2013) (cited in IDS) in view of Banderali et al. (Journal of International medical research, 1995, 23(3), 175-183) (cited in IDS).
Woo throughout the reference teaches liquid formulations for oral administration comprising ambroxol or a pharmaceutically acceptable salt thereof and levodropropizine or a pharmaceutically acceptable salt thereof for treatment of acute and chronic cough (Abstract; Claims). Woo teaches ambroxol is preferably ambroxol hydrochloride (Page 5, lines 17-20). The reference teaches the formulation comprises ambroxol in an amount of 100 mg to 1,000 mg per 100 mL of the liquid formulation and levodropropizine in an amount of 300 mg to 1,500 mg per 100 mL of the liquid formulation (Page 5, lines 21-25). These amounts taught by the reference overlap the amounts recited in the instant claims. Woo also teaches the formulation comprising pharmaceutically acceptable additives (Page 6). Woo discloses the formulation comprising citric acid, ethanol (ethyl alcohol), purified water, white sugar (sucrose), sodium pyrosulfite (sodium metabisulfite), sweetening agent (flavoring), glycerin (glycerol), preservatives and viscosity modifying agents (see: Page 6, lines 3-33). Further, Woo discloses that ambroxol is effective in the treatment of acute and chronic respiratory diseases associated with viscid or excessive mucus, e.g., acute and chronic bronchitis, asthmatic bronchitis, sinusitis, rhinitis sicca, and the like. Woo states ambroxol stimulates mucus secretion and promotes normalization of mucus viscosity and ambroxol has secretolytic activity. (Page 1, lines 15-27). Woo also discloses the formulation having antitussive effect and suppresses cough reflex and show expectorant activity. (Page 2, lines 4-23).
The teachings of Woo have been set forth above.
Woo teaches levodropropizine, which is the levo isomer of dropropizine, and has an antitussive effect (Page 2, lines 4-5). It does not expressly teach the formulation comprising particularly the racemic mixture of dropropizine (i.e. DL-dropropizine). However, this deficiency is cured by Banderali.
Banderali teaches antitussive efficacy and tolerability of dropropizine racemic mixture and of its enantiomer levodropropizine were evaluated in patients with cough. There were significant decreases in the frequency of cough and nocturnal awakening with both levodropropizine and dropropizine treatments. Banderali teaches levodropropizine and dropropizine racemic mixture are both effective antitussive agent. (see: Abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified Woo to incorporate the teachings of Banderali and use dropropizine racemic mixture as disclosed by Banderali instead of the levo isomer of dropropizine taught in Woo. One of ordinary skill in the art would have been motivated to replace levodropropizine with dropropizine racemic mixture because both are taught by Banderali as functional equivalents (i.e. both being equally effective antitussive agents and used in the treatment of cough). This is simply the substitution of one known element for another where each element and its function were already known in the art for treating cough. MPEP 2144.06. Additionally, since Woo teaches a composition comprising levodropropizine for use in the treatment of cough and levodropropizine having antitussive effect and Banderali also teaches dropropizine having antitussive effect in treating cough, the use of dropropizine racemic mixture instead of its levorotatory enantiomer in a composition for treating cough with antitussive would have been obvious to one of ordinary skill in the art. As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06.
With respect to the claimed limitation wherein the liquid oral administration form is a syrup, while Woo does not explicitly state the formulation is a syrup, Woo discloses that the ambroxol and levodropropizine formulations are generally prepared in the form of syrup (Page 1, line 25-29; Page 2, lines 14-26). Therefore, it would have been obvious to one skilled in the art to prepare the formulation of Woo in the form of syrup since Woo clearly suggests that syrup formulations containing ambroxol and levodropropizine are known in the art.
With respect to the instantly claimed concentration of ambroxol and DL-dropropizine in the composition, as discussed supra, the amounts taught by Woo et al. overlap the amounts recited in the instant claims and it would have been prima facie obvious to one skilled in the art to manipulate and optimize the amount of the ambroxol and DL-dropropizine depending on parameters such as severity of cough, disease, size of patient, etc. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With respect to the claimed limitation wherein the pharmaceutical composition does not present the adverse somnolence and/or headache effects of DL-dropropizine on the central nervous system, the combination of Woo et al. and Banderali teach structurally the same composition and method steps recited in the claims. Therefore, the composition and the method taught by the cited prior art would necessarily result in the composition not presenting the adverse somnolence and/or headache effects of DL-dropropizine.
Similarly, with respect to instant claim 18, the combination of Woo et al. and Banderali teach structurally the same composition and method steps recited in the claims. Therefore, the composition and the method taught by the cited prior art would necessarily have fewer adverse effects than its active ingredient separately.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al. (WO 2013/154347 A1; Oct. 17, 2013) (cited in IDS) in view of Banderali et al. (Journal of International medical research, 1995, 23(3), 175-183) (cited in IDS) as applied to claims 15 and 18-19 above and further in view of Zayed (Int. J. Electrochem. Sci., 10 (2015) 3250-3259).
The teachings of Woo and Banderali have been set forth above.
Woo and Banderali do not teach wherein the composition is in a solid form such as tablet, the concentration of ambroxol and DL-dropropizine in w/w in the solid form and the pharmaceutically acceptable additives in the solid form recited in claim 20. However, Zayed cured these deficiencies.
Zayed discloses dropropizine cough suppressant drugs in pharmaceutical formulation in the form of tablets wherein the formulation contains 20 mg dropropizine per tablet. Zayed also teaches the tablet formulation comprises excipients which include lactose or magnesium stearate. (see: abstract; introduction; experimental section; results and discussion section; entire document).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Woo, Banderali and Zayed and formulate the composition in the form of a tablet comprising excipients such as lactose and magnesium stearate. One would have been motivated to do so because Zayed teaches that pharmaceutical formulation comprising dropropizine cough suppressant drugs can be in the form of a tablet, wherein tablet formulation comprises excipients which include lactose and magnesium stearate. It would have been obvious to use dropropizine composition either in a syrup or tablet form depending on the preference of the patient because both of these formulation types were well known in the art as taught by Woo and Zayed.
With respect to the instantly claimed concentration of ambroxol and DL-dropropizine in the composition, as discussed supra, it would have been prima facie obvious to one skilled in the art to manipulate and optimize the amount of the ambroxol and DL-dropropizine depending on parameters such as severity of cough, disease, size of patient, etc. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With respect to the claimed limitation wherein the pharmaceutical composition does not present the adverse somnolence and/or headache effects of DL-dropropizine on the central nervous system, the combination of Woo et al., Banderali and Zayed teach structurally the same composition and method steps recited in the claims. Therefore, the composition and the method taught by the cited prior art would necessarily result in the composition not presenting the adverse somnolence and/or headache effects of DL-dropropizine.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant argued that the claimed composition not only treats cough but also significantly decreases central nervous system (CNS) effects previously reported for DL-dropropizine as shown in example 3 of specification. It was argued that Banderali states somnolence is one the inconveniences of antitussive centrally acting medications. Applicant also pointed to Borsa (US4699911) to argue that Borsa teaches levodropropizine has lower degree of CNS activity than DL-dropropizine. It was argued that one skilled in the art would have expected that a combination of ambroxol and dl-dropropizine would present the known adverse CNS effect of dropropizine.
In response, the comparative example (example 3) in the instant specification does not provide comparison to the closest prior art (Woo. et al.). As discussed above, Woo et al. teaches the combination of levodropropizine and ambroxol and the data in the specification does not provide a comparison which shows combination of DL-dropropizine and ambroxol having statistical and practical significance over the combination of levodropropizine and ambroxol, which is taught by Woo. The examples in the specification make comparison to either dropropizine alone or ambroxol alone and this is not a comparison to the closest prior art. Additionally, example 3 states two volunteers having headache and another having dermatitis with administration of individual dropropizine. However, none of the subject left the study due to these side effects and applicant’s data fails to show how these events in 3 volunteers out of 41 are of practical significant because it appears that none of the adverse events warranted the subjects stopping the therapy with dropropizine alone. The instant specification do not appear to show there being unexpected results with the combination of DL-dropropizine and ambroxol.
Further, Banderali teaches levodropropizine and dropropizine having equivalent efficacy in treating cough (Discussion; pg. 181; Tables 2-3 and Fig. 1). While Banderali teaches daytime somnolence being higher among patients treated with dropropizine, Banderali teaches the difference in frequency of somnolence between the two groups was not statistically significant because of the limited number of patients experiencing this. Banderali also states that no patient reported any serious adverse events during the study. (Discussion; pg. 181). Banderali also teaches somnolence was generally mild (Tolerability; pg. 179). Therefore, while Banderali teaches droproprizine racemic mixture having higher somnolence, the reference does not teach that levodroprozine is superior or teach against using dropropizine.
Regarding Borsa, the examiner again argues that the combination of the cited references suggest that levodropropizine and DL-dropropizine have equivalent efficacy in treating cough and that the difference in frequency of somnolence (CNS effect) between the two groups was not statistically significant because of the limited number of patients experiencing this. The instant specification also do not appear to show there being unexpected results with the combination of DL-dropropizine and ambroxol. Therefore, applicant’s arguments are not found persuasive at this time.
Conclusion
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.
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/A.S/Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616