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 .
Formal Matters
Applicant’s response in the reply filed on 21 November 2025 are acknowledged and have been fully considered. Claims 1-2, 4-6, 9-13, 16-17, and 19-23 are pending. Claims 1-2, 4-6, 9-13, and 23 are under consideration in the instant office action. Claims 16-17 and 19-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 3, 7-8,14-15, and 18 are canceled.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11 November 2022 is noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. A signed copy is attached herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-2, 4-13, and 23) in the reply filed on 21 November 2025 is acknowledged. Additionally, Applicant’s election of acetyl-L-carnitine as specific type of carnitine; vitamin B6 as the vitamin type; methyl folate calcium salt as the active ingredient; ascorbic acid as specific antioxidant/stabilizing agent; microcrystalline cellulose as diluent; polyvinylpyrrolidone as the binding agent; and magnesium stearate as lubricant; colloidal silica as glidant; and vitamin B6 as additional component for the tablets in the reply filed on 21 November 2025 is also acknowledged.
The traversal is on the ground(s) that Applicants would like to point out that the preparation method disclosed by the cited reference is completely different from that of the present invention, L-5-methyltetrahydrofolate is mixed with cyanocobalamin and calcium hydrogen phosphate and HPMC and then granulated, L-carnitine is mixed with liquid paraffin and granulated, and then a third granule comprising the herbal extract is added, and the 3 granules are tableted together. This is clearly a completely different process from that disclosed in the present invention. Applicants argue unexpected and surprising results are provided in the application as filed as shown in tables 16 and 17 at p. 33 and 34 as well as tables 25 and 26 at p. 41 and 42, that will be discussed in detail. Applicant then explained the results in the specification in detail.
The examiner appreciates Applicant’s efforts explaining the surprising or unexpected results provided in the specification at this stage of prosecution. The examiner does recognize that Applicant’s data do show some surprising results in comparison with the referenced examples. However, Applicant’s arguments are not found persuasive because Applicant ignores the fact that CN109498771 do teach granulation of L-5-methyl tetrahydrofolic acid (MTHF) and granulation of L-carnitine separately first and then the granules were mixed and tableted which is the process that Applicant alleges is the main reason why the formulation demonstrated unexpected stability properties. Applicant is reminded that the claimed invention should be compared with the closest prior art See: In re Holladay, 584 F.2d 384, 199 USPQ 516 (CCPA 1978). Applicant should compare their composition to the composition of CN109498771. Furthermore, Applicant’s examples used for the testing in particular those disclosed in Table 1, Table 2, Table 3, Tables 8-9 are drawn to single data points comprising different specific ingredients at specific amounts that are not commensurate in scope with claim 1. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Furthermore, the examiner reminds Applicant that claim 1 does not require the two granules to be granulated first separately as alleged. Additionally, claim 1 would have lacked inventive step as per the rejections set forth below under 35 USC 103 as well.
The requirement is still deemed proper and is therefore made FINAL.
Allowable Subject Matter
Claims 11-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The claims use the transitional phrase “consisting of” with specific ingredients with specific amounts.
Claim Objections
Claims 4-6, 11-13, and 23 are objected to because of the following informalities: claim 1 recites “crystalline calcium L-methylfolate (MTHF)” where claims 4-6, 11-13 and 23 directly or indirectly depend from. For consistency and clarity reasons Applicant should pick one name that would be applicable throughout the claim recitations referring the compound. Appropriate correction is required.
Claims 1 and 23 are objected to because of the following informalities: claim 1 recites “calcium L-methylfolate” while claim 23 recites “calcium-L-methylfolate”. For consistency and clarity reasons Applicant should pick one format. Appropriate correction is required.
Claims 1, 11-13, and 23 are objected to because of the following informalities: claims 1 and 23 recite “acetyl L-carnitine hydrochloride” while claims 11-13 recites “acetyl L-carnitine HCl”. For consistency and clarity reasons Applicant should pick one format for the hydrochloride recitation. Appropriate correction is required.
Claim 9 is objected to as being of improper dependent form because claim 9 depends from canceled claim 7 (See 37 CFR § 1.75(c) and MPEP § 608.01(n)). Appropriate correction is required.
Claims 2, 4-13, and 23 are objected to as being of improper dependent form because claim 9 depends from canceled claim 7 (See 37 CFR § 1.75(c) and MPEP § 608.01(n)). Appropriate correction is required.
Claims 2, 4-13, and 23 are objected to because of the following informalities: claim 1 recites “A tablet composition” in the preamble while dependent claims 2, 4-13, and 23 recite in the preamble “The composition”. For consistency and clarity reasons Applicant should start the recitations in claims 2, 4-13, and 23 with the phrase “The tablet composition”. Appropriate correction is required.
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 1-2, 4-6, 11-13, and 23 are 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 1 recites the limitation "the methylfolate" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 in line 2 recites “crystalline calcium L-methylfolate (MTHF)” Applicant should recite the active agent in consistent manner across all claims to provide a proper antecedent to the name. Similarly, claims 4-6 and 11-13 recite the limitation "calcium methylfolate", “methylfolate granules”, and “methylfolate calcium salt” directly or indirectly in claim 1. There is insufficient antecedent basis for these limitations in the claim. Claim 1 in line 2 recites “granules of crystalline calcium L-methylfolate (MTHF)” Applicant should recite the active agent in consistent manner across all claims to provide a proper antecedent to the name.
Claims 4-5 recite the limitation "antioxidant agent(s) or stabilizer(s)" directly or indirectly in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites "at least an antioxidant or a stabilizing agent".
Claim 23 recite the limitation "calcium -L-methylfolate granules" in claim 10 and directly or indirectly in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 10 recites “MTHF granules” and claim 1 which claim 10 depends on recites "crystalline calcium L-methylfolate (MTHF)".
Claim 6 recite the limitation "the granules" din claim 5. There is insufficient antecedent basis for this limitation in the claim. Claim 5 recites "MTHF granules".
Claim 1 recites the phrase “at least an antioxidant or a stabilizing agent”. The phrase does not clearly define the minimum requirement or the metes and bounds of the claim. It is unclear whether the phrase requires at least one antioxidant (which may or may not function as a stabilizer); at least one stabilizing agent (which may or may not function as an antioxidant); or at least one substance that satisfies either category. The use of the phrase “at least an” introduces ambiguity regarding quantity and whether zero or more than one is permitted in a manner that fails to inform a person of ordinary skill in the art with reasonable certainty of the claim scope (see MPEP 2173.05(a) and (b)).
The terms “antioxidant” and “stabilizing agent” are functional and overlapping recitations in claim 1. Many compounds as conventionally known the art (e.g., ascorbic acid, tocopherols, BHT) function as both antioxidants and stabilizers in pharmaceutical formulations rendering the “or” unclear as to whether overlapping compounds satisfy the limitation in one way, both, or neither in a specific context. No objective boundaries, structural requirements, or specific examples are provided in the claim to delineate what substances qualify.
Claim 2 read in relevant parts "the antioxidant or the stabilizing agent" (claim 1, lines 1-2). However, base claim 1 recites "at least an antioxidant or a stabilizing agent" (line 6), which with the broadest claim interpretation encompasses multiple antioxidants and stabilizing agents. Because of the multiplicity (i.e., at least an antioxidant or a stabilizing agent), it is unclear whether the singular reference, i.e., "the antioxidant or the stabilizing agent" are intended to refer to just one, more than one, or all of the antioxidant or stabilizing agent i.e., do the further limitations apply to just one, more than one or all of the antioxidant or stabilizing agent. Similarly, claims 4-5 read in relevant parts “antioxidant agent(s) or stabilizer(s). However, base claim 1 recites "at least an antioxidant or a stabilizing agent" (line 6), which with the broadest claim interpretation encompasses multiple antioxidants and stabilizing agents. Because of the multiplicity (i.e., at least an antioxidant or a stabilizing agent) entails. It is unclear whether the mixed reference, i.e., "antioxidant agent(s) or stabilizer(s)" are intended to refer to just one, more than one, or all of the antioxidant or stabilizing agent i.e., do the further limitations apply to just one, more than one or all of the antioxidant or stabilizing agent.
Claim 9 recites “The composition according to claim 7, wherein the acetyl L-carnitine granules comprise acetyl L-carnitine in an amount from 75% to 90% (w/w), polyvinylpyrrolidone in an amount from 3 to 10% (w/w) and microcrystalline cellulose in an amount from 3 to 10% (w/w), on the weight of the granules.” However, claim 7 has been canceled. Therefore, there is no proper antecedent basis for the phrase “The composition according to claim 7”. Because claim 7 no longer exists, the metes and bounds of claim 9 cannot be determined with reasonable certainty by one of ordinary skill in the art. See MPEP § 608.01(n) (If the base claim has been canceled, a claim which is directly or indirectly dependent thereon should be rejected as incomplete).
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.
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.
Note: The claims are examined with respect to the elected species wherein acetyl-L-carnitine as specific type of carnitine; vitamin B6 as the vitamin type; methyl folate calcium salt as the active ingredient; ascorbic acid as specific antioxidant/stabilizing agent; microcrystalline cellulose as diluent; polyvinylpyrrolidone as the binding agent; and magnesium stearate as lubricant; colloidal silica as glidant; and vitamin B6 as additional component for the tablets.
Claims 1-2 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over CN109498771 (previously provided) in view of Gennari (US Patent No. 5,223,500), Venkatesh et al. (US2015/0030676), and Du et al. (EP2147671).
Applicants’ claims
Applicants claim a tablet composition comprising the ingredients as recited. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
CN 109498771 in Example 1 teach preparation of a tablet comprising granulation a-c, wherein granules formed by step a comprise L-5-methyl -tetrahydrofolic acid (MTHF) granulated with HPMC and granules c comprise L-carnitine granulated with liquid paraffin. The granules were mixed and tabletted, followed by application of a film coat. Example 2 discloses mixing the granules in a capsule. The composition for treating cognitive dysfunction. The final composition comprising 20-30% carnitine and 0.01-0.038% MTHF. The final amount of MTHF in the final composition (5% granules with 2% MTHF (see claim 4)). The final amount of the carnitine granules (50% of 80% active granules (of claim 9)) also close enough to render the recited amount obvious.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
CN 109498771 do not specifically teach the crystalline form of calcium L-methylfolate (MTHF) and the amount as recited and also the inclusion of ascorbic acid as an antioxidant and its amounts. These deficiencies are cured by the teachings of Gennari and Venkatesh et al.
Gennari teaches a stable therapeutic composition consisting essentially of an alkali or calcium or magnesium salt of 5-methyl tetrahydrofolic acid and 5-50% of an organic compound of biological origin containing at least one --SH group and selected from the group consisting of cysteine, cysteamine, pantetheine and reduced glutathione (see claim 1). Gennari teaches tablet composition in Example 8 as follows:
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One of ordinary skill in the art can calculate 25/150 x 100=16.7% of active agent.
Venkatesh et al. teach a stabilized, modified-release pharmaceutical composition comprising a folic acid derivative, and optionally at least one pharmaceutically acceptable excipient (see claim 1). The pharmaceutical composition of claim 1, wherein the folic acid derivative is L-methylfolate calcium salt (see claim 6). In most embodiments, “salts” refers to salts that are pharmaceutically (biologically compatible) acceptable, i.e., non-toxic, particularly for mammalian cells. The salts of drugs useful in the invention may be crystalline or amorphous, or mixtures of different crystalline forms and/or mixtures of crystalline and amorphous forms (paragraph 0032). Venkatesh et al. teach all folate compounds are sensitive and easily degraded under high temperatures, air or oxygen, light, low pH, and reducing agents. Antioxidants such as ascorbates have shown to minimize such degradations during processing and storage. It is reported that L-5-MTHF-Ca in microencapsulated form, preferably with an ascorbate as an antioxidant, protects the methylfolate from degradation during processing, thereby resulting in a long term stability in a variety of foodstuffs (see paragraph 004). The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipient is an antioxidant selected from the group consisting of anhydrous citric acid, sodium ascorbate, ascorbic acid, and a mixture thereof, and said pharmaceutical composition is in the form of a modified release tablet (see claim 15).
CN 109498771, Gennari, and Venkatesh et al. do not specifically teach acetyl L-carnitine hydrochloride and its amounts. These deficiencies are cured by the teachings of Du et al.
Du et al. teach use of a composition comprising an active ingredient selected from L-carnitine, derivatives of L-carnitine, pharmaceutically acceptable salts of L-carnitine, or combinations thereof for treating hyperuricemia disease or a related disorder (claim 1). Use of a composition comprising an active ingredient selected from L-carnitine, derivatives of L-carnitine, pharmaceutically acceptable salts of L-carnitine, or combinations thereof for treating hyperuricemia disease or a related disorder (claim 2). The use of claim 2, wherein the pharmaceutically acceptable salt is selected from hydrochloride salt, hydrobromide, iodate, sulfate, nitrate, phosphate, acetate, maleate, fumarate salt, citrate, oxalate, succinate, tartrate, malate, mandelate , trifluoromethyl acetate, pantothenate, methanesulfonate, or toluenesulfanate (claim 3). The L-carnitine derivatives of this invention can be selected from acetyl L-carnitine, propionyl L-carnitine and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of L-carnitine. An example of the active ingredient is L-carnitine, acetyl L-carnitine and their pharmaceutically acceptable salts, especially L-carnitine and its pharmaceutically acceptable salts (paragraph 0012). The pharmaceutical preparations of the invention can be the forms of appropriate oral administration, such as tablets, sustained-release tablets, capsules, solutions, suspension or syrup; Optimum choices are solution, suspension, syrup, tablets and capsules (paragraph 0026). Du et al. teach for example
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The examiner calculates for instance 500/830x100=60.24% carnitine which is applicable to acetyl L-carnitine which overlaps with the claimed range.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of CN 109498771 by utilizing the crystalline form of calcium L-methylfolate (MTHF) and the amount as recited because Gennari teaches a stable therapeutic composition consisting essentially of an alkali or calcium or magnesium salt of 5-methyl tetrahydrofolic acid and 5-50% of an organic compound of biological origin containing at least one --SH group and selected from the group consisting of cysteine, cysteamine, pantetheine and reduced glutathione (see claim 1). Gennari teaches tablet composition in Example 8 as follows:
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One of ordinary skill in the art can calculate 25/150 x 100=16.7% of active agent. With regard to the use of the crystalline form of MTHF, Venkatesh et al. teach a stabilized, modified-release pharmaceutical composition comprising a folic acid derivative, and optionally at least one pharmaceutically acceptable excipient (see claim 1). The pharmaceutical composition of claim 1, wherein the folic acid derivative is L-methylfolate calcium salt (see claim 6). In most embodiments, “salts” refers to salts that are pharmaceutically (biologically compatible) acceptable, i.e., non-toxic, particularly for mammalian cells. One of ordinary skill in the art would have been motivated to do so because Venkatesh et al. teach that in preparing a stable composition comprising L-methylfolate calcium salt and at least one pharmaceutically acceptable excipient the salts of drugs useful in the invention may be crystalline or amorphous, or mixtures of different crystalline forms and/or mixtures of crystalline and amorphous forms (paragraph 0032). One of ordinary skill in the art would have been motivated to include ascorbic acid in the composition because Venkatesh et al. teach all folate compounds are sensitive and easily degraded under high temperatures, air or oxygen, light, low pH, and reducing agents. Antioxidants such as ascorbates have shown to minimize such degradations during processing and storage. It is reported that L-5-MTHF-Ca in microencapsulated form, preferably with an ascorbate as an antioxidant, protects the methylfolate from degradation during processing, thereby resulting in a long term stability in a variety of foodstuffs (see paragraph 004). The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipient is an antioxidant selected from the group consisting of anhydrous citric acid, sodium ascorbate, ascorbic acid, and a mixture thereof, and said pharmaceutical composition is in the form of a modified release tablet (see claim 15). The amount of antioxidant or stabilizing agent is clearly covered by Genarri as described above in overlapping manner. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). Furthermore, in the case where the claimed amounts of active agents and other ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) Furthermore, differences in concentration or any measurable parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of CN 109498771, Gennari, and Venkatesh et al. because all of the references teach compositions containing L-methyl folate.
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of CN 109498771, Gennari, and Venkatesh et al. by incorporating or utilizing acetyl L-carnitine hydrochloride and its amounts because Du et al. teach use of a composition comprising an active ingredient selected from L-carnitine, derivatives of L-carnitine, pharmaceutically acceptable salts of L-carnitine, or combinations thereof for treating hyperuricemia disease or a related disorder (claim 1). One of ordinary skill in the art would have been motivated to do so because Du et al. teach use of a composition comprising an active ingredient selected from L-carnitine, derivatives of L-carnitine, pharmaceutically acceptable salts of L-carnitine, or combinations thereof for treating hyperuricemia disease or a related disorder (claim 2). The use of claim 2, wherein the pharmaceutically acceptable salt is selected from hydrochloride salt, hydrobromide, iodate, sulfate, nitrate, phosphate, acetate, maleate, fumarate salt, citrate, oxalate, succinate, tartrate, malate, mandelate , trifluoromethyl acetate, pantothenate, methanesulfonate, or toluenesulfanate (claim 3). The L-carnitine derivatives of this invention can be selected from acetyl L-carnitine, propionyl L-carnitine and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of L-carnitine. An example of the active ingredient is L-carnitine, acetyl L-carnitine and their pharmaceutically acceptable salts, especially L-carnitine and its pharmaceutically acceptable salts (paragraph 0012). The pharmaceutical preparations of the invention can be the forms of appropriate oral administration, such as tablets, sustained-release tablets, capsules, solutions, suspension or syrup; Optimum choices are solution, suspension, syrup, tablets and capsules (paragraph 0026). Du et al. teach for example
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The examiner calculates for instance 500/830x100=60.24% carnitine which is applicable to acetyl L-carnitine which overlaps with the claimed range.
The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). Furthermore, in the case where the claimed amounts of active agents and other ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) Furthermore, differences in concentration or any measurable parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of CN 109498771, Gennari, Venkatesh et al., Du et al. because CN 109498771 teach the inclusion of MTHF and carnitine, Gennari and Venkatesh et al. MTHF teach L-methyfolate, while Du et al. teach the use of acetyl L-carnitine hydrochloride.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 4-6 and 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over CN109498771 (previously provided) in view of Gennari (US Patent No. 5,223,500), Venkatesh et al. (US2015/0030676), and Du et al. (EP2147671) as applied to claims 1-2 and 23 above, and further in view of Swinney et al. (US 2016/0354316).
Applicants’ claims
Applicants claim a tablet composition comprising the ingredients as recited. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of CN 109498771, Gennari, Venkatesh et al., and Du et al. is described in detail above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
CN 109498771, Gennari, Venkatesh et al., and Du et al. do not specifically teach the incorporation of diluting agents, binding agents, lubricants, glidants and their respective amounts as recited in claims 4-6 and 9-10. These deficiencies are cured by the teachings of Swinney et al.
Swinney et al. teach in one embodiment, the process of preparing pharmaceutical compositions of the present invention comprise 30 to 55 percent by weight Compound 1 Form I, and 10 to 45 percent by weight solid dispersion comprising substantially amorphous Compound 2. (paragraph 0021). As indicated, in addition to Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2, in some embodiments of the invention, the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof (paragraph 0159). Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof (paragraph 0160). Thus, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt % (e.g., at least about 20 wt %, at least about 30 wt %, or at least about 40 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt %, from about 25 wt % to about 50 wt %, or from about 27 wt % to about 45 wt %) of filler, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 20 wt % (e.g., at least 30 wt % or at least 40 wt %) of microcrystalline cellulose, for example MCC Avicel PH102, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt % or from about 25 wt % to about 45 wt %) of microcellulose, by weight of the composition (see paragraph 0161). Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof (paragraph 0162). Thus, in one embodiment, the pharmaceutical composition comprises disintegrant in an amount of about 10 wt % or less (e.g., about 7 wt % or less, about 6 wt % or less, or about 5 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition (paragraph 0163). Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof (paragraph 0166). Thus, in one embodiment, the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 3 wt %, at least about 4 wt %, or at least about 5 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 10 wt % or from about 2 wt % to about 7 wt %) of binder, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 2 wt %, at least about 3 wt %, or at least about 4 wt %) of polyvinylpyrrolidone, by weight of the composition. In yet another example, the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 8 wt % or from about 2 wt % to about 5 wt %) of polyvinylpyrrolidone, by weight of the composition (paragraph 0167). Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof (paragraph 0168). Thus, in one embodiment, the pharmaceutical composition comprises a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 40 wt % to about 1 wt % (e.g., from about 35 wt % to about 5 wt % or from about 30 wt % to about 7 wt %, from about 25 wt % to about 10 wt %, from about 20 wt % to about 15 wt %) of diluent, by weight of the composition. Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof (paragraph 0170). Thus, in one embodiment, the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of glidant, by weight of the composition. In another example, the pharmaceutical composition comprises 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) of colloidal silicon dioxide, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of colloidal silicon dioxide, by weight of the composition (paragraph 0171). In some embodiments, the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.5 wt % or from about 3 wt % to about 1 wt %) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.15 wt % or from about 3.0 wt % to about 0.50 wt %) of magnesium stearate, by weight of the composition (paragraph 0172). In another example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of a film coating comprising a colorant (paragraph 0174).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of CN 109498771, Gennari, Venkatesh et al., and Du et al. by including diluents (fillers), binders, glidants, lubricants, and film coatings because these are conventionally know ingredients utilized in formulating tablets during granulation process as demonstrated by Swinney et al. in overlapping amounts for each of the ingredients. Swinney et al. teach in one embodiment, the process of preparing pharmaceutical compositions of the present invention comprise 30 to 55 percent by weight Compound 1 Form I, and 10 to 45 percent by weight solid dispersion comprising substantially amorphous Compound 2. (paragraph 0021). As indicated, in addition to Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2, in some embodiments of the invention, the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof (paragraph 0159). Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof (paragraph 0160). Thus, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt % (e.g., at least about 20 wt %, at least about 30 wt %, or at least about 40 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt %, from about 25 wt % to about 50 wt %, or from about 27 wt % to about 45 wt %) of filler, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 20 wt % (e.g., at least 30 wt % or at least 40 wt %) of microcrystalline cellulose, for example MCC Avicel PH102, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt % or from about 25 wt % to about 45 wt %) of microcellulose, by weight of the composition (see paragraph 0161). Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof (paragraph 0162). Thus, in one embodiment, the pharmaceutical composition comprises disintegrant in an amount of about 10 wt % or less (e.g., about 7 wt % or less, about 6 wt % or less, or about 5 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition (paragraph 0163). Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof (paragraph 0166). Thus, in one embodiment, the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 3 wt %, at least about 4 wt %, or at least about 5 wt %) by weight of the composition. For example, the pharmaceutical composition comprises from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 10 wt % or from about 2 wt % to about 7 wt %) of binder, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 2 wt %, at least about 3 wt %, or at least about 4 wt %) of polyvinylpyrrolidone, by weight of the composition. In yet another example, the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 8 wt % or from about 2 wt % to about 5 wt %) of polyvinylpyrrolidone, by weight of the composition (paragraph 0167). Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof (paragraph 0168). Thus, in one embodiment, the pharmaceutical composition comprises a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 40 wt % to about 1 wt % (e.g., from about 35 wt % to about 5 wt % or from about 30 wt % to about 7 wt %, from about 25 wt % to about 10 wt %, from about 20 wt % to about 15 wt %) of diluent, by weight of the composition. Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof (paragraph 0170). Thus, in one embodiment, the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of glidant, by weight of the composition. In another example, the pharmaceutical composition comprises 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) of colloidal silicon dioxide, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of colloidal silicon dioxide, by weight of the composition (paragraph 0171). In some embodiments, the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.5 wt % or from about 3 wt % to about 1 wt %) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.15 wt % or from about 3.0 wt % to about 0.50 wt %) of magnesium stearate, by weight of the composition (paragraph 0172). In another example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of a film coating comprising a colorant (paragraph 0174). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). The examiner reminds Applicant that all of the ingredients and their amounts are known in the art as clearly shown by Swinney et al. Furthermore, in the case where the claimed amounts of active and other ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or any measurable parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of CN 109498771, Gennari, Venkatesh et al., Du et al., and Swinney et al. because all of the references teach granules based tablet compositions.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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