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 .
Claim Status
Claims 1-17 were filed on 06/23/2023. No preliminary amendment was submitted.
Claims 1-17 are currently pending and under examination.
Priority
The instant application does not claim domestic benefit or foreign priority to any earlier application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/26/2023 and 02/14/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 9-17 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation "the L-carnitine in an aqueous solution" in the first line in the body of the claim. Claim 2 depends on claim 1 which does not recite any aqueous solution. Therefore, there is insufficient antecedent basis for this limitation in the claim. In the interest of compact prosecution, the claim limitation for claim 2 reciting “the L-carnitine in an aqueous solution” will be interpreted by the examiner to mean the L-carnitine is in an aqueous solution.
Claims 9-17 also recite the limitation of “the L-carnitine”. Claims 9, 10, and 14-17 depend from claim 1 which recites both “L-carnitine in a mixed solvent” and “crystalline L-carnitine”. The claim limitation of “the L-carnitine” is therefore made unclear of whether it is “crystalline L-carnitine” or “L-carnitine in a mixed solvent”. Claim 11 depends on claim 3 which depends on claim 1 but does not overcome the described indefinite issue. Claim 12 depends on claim 4 which depends on claim 1 but does not overcome the described indefinite issue. Claim 13 depends on claim 5 which depends on claim 1 but does not overcome the described indefinite issue. In the interest of compact prosecution, the claim limitation of “the L-carnitine” in claims 9-13 will be interpreted by the examiner to mean the crystalline L-carnitine.
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.
Claims 1-5 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A, published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP 0001681A1, published on 02/05/1979, found in PTO-892).
Takigawa et al. teaches a method for the production of crystalline L-carnitine comprising the steps of preparing an aqueous solution of L-carnitine, a step of crystallizing L-carnitine from the adjusted solution obtained in the first step, and a step of recycling the mother liquid obtained in the second step or the L-carnitine contained in the mother liquid to the first step and/or second step (see paragraph 0007). The crystallizing step is a step of adding solvents other than water to an aqueous solution of L-carnitine, and then further performing operations such as a heat step, a concentration step, a solvent-replacement step, and a cool step to obtain crystals (see paragraph 0018). The solvent replacement refers to an operation of replacing the solvent of the carnitine solution with a solvent having a low boiling point from a mixed liquid of a plurality of solvents by concentration operation and allowing one of the solvents to remain, and an operation of adding a solvent having mutual solubility with the solvent to a solution sufficiently concentrated within a range not to be dried to obtain a solution of the solvent. In particular, it refers to an operation in which one or more solvents other than water are added to an aqueous solution of L-carnitine, and then water is finally removed and replaced with solvents used for crystallization (see paragraph 0019). The solvents to be used are preferably non-toxic or low-toxic solvents because L-carnitine is orally ingested in some cases, and examples thereof include alcohol-based solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, 1-pentanol, and hydrocarbon-based solvents such as pentanes, hexanes, and heptanes (see paragraph 0021). These solvents may be used in combination of two or more. Such a mixed solvent is selected from two or more of the above-mentioned solvents (see paragraph 0024). Based on the above teachings of Takigawa et al., it would have been obvious to select the recited alcohols or mixtures thereof for the crystallization of L-carnitine.
Takigawa et al. does not teach the mixed solvent used for crystallization comprising explicitly cyclohexane and Takigawa et al. does not explicitly teach wherein the crystalline L-carnitine produced by a mixed solvent crystallization is free of ethanol, acetone, and isopropanol.
Cane et al. teaches processes for the removal of water from aqueous alcohols, preferably from alcohols which form azeotropic mixtures with water using cyclohexane as entrainer. Various methods have been suggested for drying alcohols whether obtained from fermentation or synthetic processes. One such method is azeotropic distillation using an entrainer. Several entrainers have been used for this purpose including, glycols and hydrocarbon solvents. Of the hydrocarbon solvents, benzene has hitherto been the most widely used. Benzene, however, suffers from several disadvantages. Firstly, the toxicity of benzene has rendered it unacceptable especially if such alcohols are to be used as potable spirits. Secondly, the rate of phase separation of azeotropic distillates containing benzene is very slow (see lines 5-16 of page 1). It has now been found that by using cyclohexane as an entrainer under specific distillation-conditions, the toxicity problems may be minimized and substantially complete separation of aqueous phase may be achieved in a relatively short time (see lines 12-15 of page 2).
It would have been obvious to combine Takigawa et al. with Cane et al. before the effective filing date of the claimed invention to improve the production of crystalline L-carnitine from an aqueous solution of L-carnitine by performing a crystallization utilizing a solvent replacement step such as azeotropic distillation, and selecting an alcohol from the Markush group of Takigawa et al. as a first solvent and a hydrocarbon such as cyclohexane as the second solvent or entrainer as used by Cane et al. to arrive at the claimed invention of a crystallization of L-carnitine using an alcohol and cyclohexane to remove water through azeotropic distillation and crystallize L-carnitine. It would have been prima facie obvious for one of ordinary skill in the art to choose an alcohol such as isobutanol, n-propanol, n-butanol, and/or a mixture thereof based on the Markush group of Takigawa and use cyclohexane as an entrainer in the azeotropic distillation to use a mixed solvent system that has shown to decrease the amount of time of an azeotropic distillation for the removal of water as taught by Cane et al. One of ordinary skill in the art would have a reasonable expectation of success because both references aim to use low-toxic or non-toxic solvents in purification processes. Since the process as made obvious by the combined teachings of Takigawa et al. and Cane et al. does not include ethanol, acetone, and isopropanol, one would recognize that the product produced from this process would necessarily be free of ethanol, acetone, and isopropanol.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A , published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP0001681A1, published on 05/02/1979, found in PTO-892) as applied to claims 1-5 and 10 above, and further in view of EP 2,325,164 A1 ('164, published on 05/25/2011, found in IDS dated 07/26/2023).
The combined teachings of Takigawa et al. and Cane et al. were discussed above.
The combined teachings of Takigawa et al. and Cane et al. differ from that of the instantly claimed invention in that the combined teachings of Takigawa et al. and Cane does not teach the solution of L-carnitine in the mixed solvent contains less than 5% water by weight, less than 3% of water by weight, and less than 1% water by weight.
'164 teaches a method for the production of L-carnitine, comprising the steps of
(a) providing a solution comprising at least 5% (w/w)
carnitine in a first solvent, wherein the carnitine is a
mixture of D- and L-carnitine,
(b) optionally seeding the solution with L-carnitine
crystals,
(c) adding a second solvent, in which the L-carnitine
is not soluble or has a low solubility,
(d) isolating crystals comprising L-carnitine.
In a preferred embodiment, the solution in step (a) is essentially free of water. This means that the carnitine and the solvent should be essentially free of water or comprise as little water as possible. It was found that the method is more efficient when only a low amount of water is present. Preferably, the overall water content in the solution (a) is below 2%, below 1 % or below 0.5% (w/w). The second solvent is selected from acetone, isopropanol, isobutanol, 2-propanol, 1-pentanol, 2-butanone, methyl acetate, ethyl acetate, butyl acetate, tetrahydrofuran, toluene and mixtures thereof. Preferably, the second solvent is acetone. The second solvent is a solvent, in which L-carnitine is not soluble or only has a low solubility. In a preferred embodiment of the invention, the solubility of L-carnitine in the second solvent is below 3%, below 2% or below 1 % (w/w) at 25°C. When adding the second solvent, the overall solubility of carnitine in the solution is decreased, and carnitine is crystallized. Thus, upon addition of the second solvent, solid carnitine crystals are formed in the solution. (see paragraphs 21, 27, and 28).
It would have been obvious to modify the combined teachings of Takigawa et al. and Cane et al. with the teachings of '164 before the effective filing date of the claimed invention by using solvents having an overall water content below 2% to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to choose solvents with an overall water content below 2% because ‘164 teaches the crystallization of L-carnitine is more efficient when only a low amount of water is present. One of ordinary skill in the art would have a reasonable expectation of success because ‘164, Takigawa et al., and Cane et al. all aim to improve the purification of potentially ingestible or potable products.
Claims 9 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A , published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP0001681A1, published on 05/02/1979, found in PTO-892) as applied to claims 1-5 and 10 above, and further in view of "Impurities: Guideline for Residual Solvents" (ICH, published on 04/22/2021, found in PTO-892).
The combined teachings of Takigawa et al. and Cane et al. were discussed above.
The combined teachings of Takigawa et al. and Cane et al. differ from that of the instantly claimed invention in that Takigawa et al. and Cane et al. do not teach wherein the L-carnitine contains cyclohexane, n-propanol, isobutanol, and n-butanol as a residual solvent
ICH teaches residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility (see Introduction section).
It would have been obvious to combine the known elements of Takigawa et al. and Cane et al. with ICH before the effective filing date of the claimed invention to conclude and have a reasonable expectation of success that the solvents used in the crystallization of L-carnitine (cyclohexane, n-propanol, isobutanol, and n-butanol) would be residual solvents because the solvent would not be completely removed from the L-carnitine by practical manufacturing techniques.
Claim 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A , published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP0001681A1, published on 05/02/1979, found in PTO-892) as applied to claims 1-5 and 10 above, and further in view of U.S. Patent No. 5,073,376 ('376, published on 12/17/1991, not furnished with instant application).
The combined teachings of Takigawa et al. and Cane et al. were discussed above.
The combined teachings of Takigawa et al. and Cane et al. differ from that of the instantly claimed invention in that Takigawa et al. and Cane et al. do not teach a method for the production of crystalline L-carnitine further comprising the steps of reacting the crystalline L-carnitine with L-tartaric acid to produce L-carnitine-tartrate.
'376 teaches the production and handling of L-carnitine to suitable forms of administration have been made difficult because of the high hygroscopicity of L-carnitine. It has been found that L-carnitine-L-tartrate at normal air moisture is stable in storage and can be processed without special precautions. L-carnitine-L-tartrate forms a crystalline powder which can be easily processed and is particularly suitable for processing with rapidly running machines, since it does not tend to stick together or become lumpy. The production of L-carnitine-L-tartrate which includes dissolving L-tartaric acid in the required quantity of hot 90 percent aqueous ethanol and the calculated quantity of L-carnitine was added, the salt brought to crystallization by cooling, filtered, and dried (see paragraphs 3, 6, and 9).
It would have been obvious to combine the teachings of Takigawa et al. and Cane et al. with the teachings of '376 before the effective filing date of the claimed invention to produce L-carnitine-L-tartrate from crystalline L-carnitine. It would have been prima facie obvious for one of ordinary skill in the art to further convert crystalline L-carnitine to L-carnitine-L-tartrate by reacting crystalline L-carnitine with tartaric acid because ‘376 teaches L-carnitine-L-tartrate at normal air moisture is stable in storage and can be processed without special precautions unlike L-carnitine. One of ordinary skill in the art would have a reasonable expectation of success because ‘367 teaches that L-carnitine is used in the process of conversion to L-carnitine-L-tartrate.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A , published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP0001681A1, published on 05/02/1979, found in PTO-892) as applied to claims 1-5 and 10 above, and further in view of Park et al. (KR 20190017310 A, published on 02/20/2019, found in PTO-892).The combined teachings of Takigawa et al. and Cane et al. were discussed above.
The combined teachings of Takigawa et al. and Cane et al. differ from that of the instantly claimed invention in that Takigawa et al. and Cane et al. do not teach a method for the production of crystalline L-carnitine further comprising the steps of reacting the crystalline L-carnitine with fumaric acid to produce L-carnitine-fumarate as required by claim 15.
Park et al. teaches that it is widely known that when L-carnitine is present as an inner salt, the stability of the compound is poor. L-carnitine intramolecular salts have very high hygroscopicity which results in many difficulties in the process of storing or formulating compounds using them. The acid addition salts of L-carnitine aim to solve the problem of poor stability and high hygroscopicity of L-carnitine inner salts. The method for preparing an acid addition salt of an L-carnitine compound comprises a first step of reacting L-carnitine and a pharmaceutically acceptable addition salt in a mixed solvent containing an organic solvent and water, a second step of precipitating the acid addition salt of L-carnitine, and a third step of filtering and drying the precipitate of the second step. The pharmaceutically acceptable addition salts may include fumaric acid and the acid addition salt of the L-carnitine compound may include L-carnitine-fumarate. Park further discloses that L-carnitine-fumarate solves the problem of hygroscopicity when compared to L-carnitine (see paragraphs 0003, 0006, 0008, 0013, 0023, and 0027).
It would have been obvious to combine the teachings of Takigawa et al. and Cane et al. with the teachings of Park et al. before the effective filing date of the claimed invention to react L-carnitine with fumaric acid to produce L-carnitine-fumarate to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to further convert L-carnitine to L-carnitine-fumarate by reacting L-carnitine with fumaric acid because Park et al. teaches L-carnitine-fumarate has a lower hygroscopicity than L-carnitine and is more suitable for processing. One of ordinary skill in the art would have a reasonable expectation of success because Park et al. teaches that L-carnitine is used in the process of conversion to L-carnitine-fumarate.
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Takigawa et al. (JP 2009102263A , published on 05/14/2009, found in IDS dated 07/26/2023) in view of Cane et al. (EP0001681A1, published on 05/02/1979, found in PTO-892) as applied to claims 1-5 and 10 above, and further in view of Kramer et al. (US 2015/0166466 A1, published on 06/18/2015, not furnished with instant application).
The combined teachings of Takigawa et al. and Cane et al. were discussed above.
The combined teachings of Takigawa et al. and Cane et al. differ from that of the instantly claimed invention in that Takigawa et al. and Cane et al. do not teach reacting L-carnitine with acetyl chloride to produce acetyl-L-carnitine hydrochloride or reacting the crystalline L-carnitine with propionyl chloride to produce propionyl-L-carnitine hydrochloride.
Kramer et al. teaches the typical method of production for propionyl-L-carnitine and acetyl-L-carnitine involves the reaction of propionyl chloride and acetyl chloride respectively. During the reaction the end product would be propionyl-L-carnitine and acetyl-L-carnitine which would readily react with the hydrochloric acid formed by the reaction to wield the respective hydrochloric salts. Both acetyl-L-carnitine and propionyl-L-carnitine are believed to have many advantageous properties over L-carnitine, such as increased bioavailability (see paragraphs 005 and 006).
It would have been obvious to combine the teachings of Takigawa et al. and Cane et al. with the teachings of Kramer et al. before the effective filing date of the claimed invention to produce react L-carnitine with acetyl chloride and propionyl chloride to produce acetyl-L-carnitine hydrochloride and propionyl-L-carnitine hydrochloride respectively to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to react L-carnitine with propionyl chloride and acetyl chloride to produce propionyl-L-carnitine and acetyl-L-carnitine respectively because Kramer et al. teaches acetyl-L-carnitine and propionyl-L-carnitine are believed to have many advantageous properties over L-carnitine, such as increased bioavailability. One of ordinary skill in the art would have a reasonable expectation of success because Kramer et al. teaches that L-carnitine is used in the process of conversion to acetyl-L-carnitine and propionyl-L-carnitine.
Conclusion
No claim is found allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN WEEKS BRADY whose telephone number is (571)272-5906. The examiner can normally be reached 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at (571) 272-5960. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTEN W BRADY/ Examiner, Art Unit 1692
/SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693