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 .
Applicant’s amendments filed 11/20/2025 have been entered.
Claims 1-3, 6-9, 11-13, 15, 16, 18-22 are pending.
Claims 11-13, 15, 16, 18-20 and 22 are withdrawn from consideration as they are directed to non-elected invention.
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.
Claim(s) 1-3, 6-9, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over RU2377989 (‘989), English translation is also provided in view of Gustafsson et al., European Journal of Pharmaceutical Sciences, 9 (1999) 171-184, Handbook of Pharmaceutical Excipients, 6th Ed, 2009, pages 326-329, WO2018/236745 (‘745), and Lin et al., AAPS PharmSciTech 5, 54 (2004).
‘989 teaches a composition comprising trimetazidine (wt percent 23.33%) and Hydroxypropyl methylcellulose (Methicel K4M) or (combination of methocel K4M and K100 LV CR Premium) (weight percent of 10% or 9%) (see page 7, Table 1). ‘989 teaches the total weight of the tablet is 150mg (see Table 1). The ratio between the active and the hydroxypropyl methylcellulose is about 2.5:1.
‘989 does not expressly teach the viscosity nor the percentage of substitution. ‘989 does not expressly teach the herein claimed trimetazidine derivative compound (X). ‘989 does not expressly teach the composition would release the herein claimed trimetazidine derivative compound (X) over an 8-hour duration nor the total weight of the composition as 550mg.
‘745 teaches the compound of formula (X) as a trimetazidine prodrug, as it would turn into active trimetazidine once entering the body and could have a better side effect profile as it is not easy to get across to the CNS (see page 25, central paragraph). ‘745 teaches one of the suitable excipients as Hydroxypropyl methylcellulose (see page 28, last line for example).
Gustafsson et al. teaches the Methocel K4M having percent of methoxy substitution as 22-23% and hydroxypropyl 8.3-5% (see page 172, Table 1).
Handbook of Pharmaceutical Excipients teaches Methocel K4M and K100M as type 2208 of Hypromellose (see page 328, Table II). Handbook of Pharmaceutical Excipients teaches the percentage of methoxy substitution for type 2208 as 19-24% and hydroxypropoxy content as 4-12% (see page 327, Table 1). Handbook of Pharmaceutical Excipients teaches the nominal viscosity for K4M and K100M Premium as 4000 and 100,000 mPa s (cP) (see page 328, Table II).
Lin et al. teaches the various release rate of tablets coated with HPMC. The release rate ranges from less than 3 hours to 16 hours and beyond depending on the ratio of HPMC ratio (see Fig. 1).
It would have been obvious to one of ordinary skill in the art as the time of filing to incorporating the herein claimed trimetazidine derivative (compound (X)), in the herein claimed amount, into the 8-hour controlled release composition of ‘989.
One of ordinary skill in the art would have been motivated to incorporating the herein claimed trimetazidine derivative (compound (X)), in the herein claimed amount, into the 8-hour controlled release composition of ‘989. By substituting the trimetazidine with the herein claimed compound (X) into the formulation of ‘989, it would be reasonably expected to impart beneficial CNS side effect to the composition; while retaining the therapeutic effect of trimetazidine.
The examiner notes that the characteristic of the polymer (methoxy substitution and hydroxypropoxy substitution) is the same as that of the polymer used in the cited prior art. The viscosity of the composition depends on the concentration and which hydroxypropyl methylcellulose combinations being used. Adjusting viscosity to the desired one would be considered obvious as being within the purview of skilled artisan. Furthermore, adjust the ratio of the HPMC used can alter the release rate as it is well-known in the art as taught in Lin et al. The optimization of result effect parameters (i.e., concentration of the excipients – viscosity and weight ratio affecting the release rate) is obvious as being within the skill of the artisan. The optimization of known effective amounts of known active agents to be administered, is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that “[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). Since the herein claimed viscosity is within the range taught in the prior art, prima facie case of obviousness exists. Adjusting the weight ratio and the viscosity of the HPMC in order to the 8-hour release would be considered as obvious as it is well-known in the art to control the release over from 3-16 hours of duration.
The examiner further notes that the weight ratio between HPMC and trimetazidine derivative stays the same although the total weight of the composition increase to 550mg from 200 mg. Since the release profile depends on the amount of the HPMC, the amount of the active agent to be released, as well as the molecular weight of the HPMC, as the amount of the active increases, the amount of HPMC also increases (because the ratio between the HPMC and the active agent stays the same) and therefore, the release profile would still be adjusted by one of skilled artisan.
Response to Arguments
Applicant's arguments filed 11/20/2025 averring the change of the total amount of the composition would render the instant composition unobvious over the cited prior art, have been fully considered but they are not persuasive. It is not clear why the increase of the amount would render the composition unobvious over the cited prior art. As discussed above, the examiner notes that absent evidence with regard to the change of release profile for large amount of actives present in a composition, the controlled release profile still depends on the amount of HPMC relative to that of the actives. Since the weight ratio between the two stays the same, it would be obvious to one of ordinary skill in the art to adjust the release profile.
No claims are allowed.
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 SAN MING R HUI whose telephone number is (571)272-0626. The examiner can normally be reached Mon - Fri 9:30-5:30.
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/SAN MING R HUI/Primary Examiner, Art Unit 1627