DETAILED ACTION
Claims 10-21 are currently pending in the instant application.
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 .
Election/Restrictions
Applicant's election with traverse of Group I, drawn to claims 10 and 15-18 with election of species trimetazidine hemisuccinate in the reply filed on 06/09/2026 is acknowledged. The traversal is on the ground(s) that the cited reference of US Pub 2008/0004284 discloses commercially available trimetazidine as trimetazidine hydrochloride or trimetazidine dihydrochloride. This is not found persuasive because ‘284 discloses salts beyond trimetazidine hydrochloride or trimetazidine dihydrochloride as a salt does not have to be commercially available in order to be taught by a prior art reference. Additionally, the claimed trimetazidine salts do not define a contribution over the prior art as discussed in the below 103 rejection.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-14 and 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/09/2026.
In accordance with the MPEP, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species and the claims drawn to the elected species are allowable, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
Applicants' elected species of trimetazidine hemisuccinate does not appear allowable, therefore the search and examination of the claims has not been extended beyond the elected species (see the following 35 USC 103(a) rejection).
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Information Disclosure Statement
Applicant's Information Disclosure Statements filed on 04/18/2024 and 06/10/2026 have been considered. Please refer to Applicant's copies of the 1449 submitted herewith.
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.
Claim(s) 10 and 15-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rahman et al (see US PG Pub No. 2008/0004284, pub. 01/03/2008), and further in view of Korn (see European Journal of Pharmaceutical Science, 2014, Vol.57, p. 257-263), Bharate (see Drug Discovery Today, Vol 26, No. 2, Feb. 2021) and Francis (see US PG Pub. 2014/0350116, pub. 11/27/2014).
Rahman et al teaches trimetazidine compound and pharmaceutically acceptable salts, which can include salts prepared with inorganic acids, organic acids, etc which includes succinate, hydrochloride or dihydrochloride salt (see paragraph [0032], p. 3). Rahman teaches trimetazidine can encompass any derivatives which includes any pharmaceutically acceptable salt form that may be used in the method of invention (see paragraph [0071], p. 7). Trimetazidine is taught in a composition with an excipient (see paragraph [0078], p. 7) with a beta blocker (see paragraph [0075], p. 7) and as an oral tablet (see paragraph [0091], p. 8) with administration once daily (see paragraph [0110], p. 9).
Regarding pharmaceutically acceptable salts, Korn teaches a set of pharmaceutically acceptable acids and based frequently used in pharmaceutical industry proposed is
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(see p. 258). Korn teaches succinic acid as a first set of acid used in salt screen for pharmaceutically acceptable salts.
Bharate teaches salt formation is well-known technique for optimizing the properties of ionizable drugs and preclinical candidates. The chemical, biological and physical characteristics of drug candidates can be manipulated by converting them to a suitable salt form, and an optimal salt form must be selected on the basis of its physicochemical properties, solubility, dissolution rate and processability into the dosage form. Salts falling into Class I as preferred for drug development salts include succinate (see Fig. 1, p. 385) and include 6.5% of counterion falling within FDA-approved API salt forms (see Fig. 4, p. 388).
Francis et al teach that the term “pharmaceutically acceptable salt” is intended to include salts derived from inorganic or organic acids including, for example hydrochloric, hydrobromic, etc. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate (see paragraph [0065], p. 4).
Prior to the filing of the instant application, a PHOSITA following the teachings of Francis et al would have found it prima facie obvious to synthesize the hemisuccinate salt of trimetazidine as Rahman et al teaches trimetazidine can encompass any derivatives which includes any pharmaceutically acceptable salt form that may be used in the method of treating fibromyalgia syndrome (FMS). Rahman et al specifically name succinate as a pharmaceutically acceptable salt. Korn and Bharate further teach preferences for succinate as a well-known pharmaceutically acceptable salt of compounds. Francis et al teach that the hemi-salt, are derived from acids comprising two carboxylic acids, and include the hemisuccinate salt. As succinate has two carboxylic acids, it would be obvious to utilize one succinate acid equivalent to two equivalents of the claimed compound to minimize the amount of succinic acid needed, hence forming the hemisuccinate salt of the claimed compound, trimetazidine.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 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. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary 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.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
The motivation to synthesize a hemisuccinate salt form of trimetazidine would derive from (A) or (B) from KSR. Since Rahman et al teach trimetazidine for treating fibromyalgia syndrome (FMS), one of ordinary skill in the art would be motivated to synthesize other pharmaceutically acceptable salts of the compound, specifically the succinate salt, a popular salt form as taught by Korn and Bharate as the hemi-succinate salt form as taught by Francis et al, to find a pharmaceutically acceptable salt form having improved physicochemical characteristics, such as solubility, dissolution, bioavailability, stability and crystallinity of the compound for administration in methods of treating FMS.
Regarding claim 18, although Rahman et al do not name bisoprolol or metoprolol as a betablocker, according to Live Hospital, (see https://int.livhospital.com/common-beta-blockers-8-names-and-uses/ retrieved on 06/16/2026), the top beta blockers are metoprolol, carvedilol, atenolol, propranolol, bisoprolol, labetalol, timolol, and nadolol. Thus, metoprolol and bisoprolol are well known beta blockers. As Rahman teaches the trimetazidine in a composition with betablockers, it would be obvious to include bisoprolol or metoprolol, known beta blockers into said composition.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN CHENG whose telephone number is (703)756-4699. The examiner can normally be reached M-F, 9AM-6PM PST.
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/KAREN CHENG/Primary Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
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