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 .
DETAILED ACTION
Election/Restriction
Applicant elected with traverse Group I (claims 9-10, 13-17, 24, and 26- 27) and species : A. caffeine as the nootropic agent; B. Methyl acrylate, methyl methacrylate and methacrylic acid (7:3:1) (Eudraguard® Biotic) as the release-controlling polymeric system; and C. Melatonin as the sedative substance, on 12/23/2025.
The traversal is on the ground that “Jaenicke does not teach or suggest "pulsatile formulations." Moreover, the claims recite specific ratios of polymers that cannot be taught be a reference that allegedly discloses "variety of coating material...For example, when the recited ratios are present in a formulation, the "inventors have shown that the formulation... leads to a pulsatile burst release of nootropic agent... after 5 hours" differs from anything disclosed in Jaenicke”.
Applicant’s argument is fully considered, but NOT persuasive. Please note Restriction Requirement is not full examination. Although instant claim 9 recites ratio of polymers, the ratios are the property of Eudraguard® Biotic and/or Eudragit ® FS 30D as disclosed by instant specification( See page 46, Table 2): Eudraguard® Biotic is an anionic copolymer composed of methyl acrylate, methyl methacrylate, and methacrylic acid in a monomer ratio of 7:3:1. Eudragit ® FS30 D is Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 by Evonik). Jaenicke (US20010038863A1) teaches controlled-release composition comprising an active stimulating agent (e.g. caffeine) and a sedative ( valerian or melatonin), wherein the caffeine granules are coated with variety of coating material, e.g. ammonia methacrylate copolymer, metharylic acid copolymer ( e.g. Eudragit RS 30D) which read on instant active ingredients and inactive coating polymers. Exploration/selection of different commercial polymer coating system ( Eudragit RS 30D vs Eudragit ® FS 30 D) for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. As such, the requirement is still deemed proper and is therefore made FINAL.
Claims 41-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.
It’s noted the elected caffeine is nonselective adenosine receptor antagonist as taught by Lazarus (2011), NOT an adenosine receptor agonist. Instant specification ( See page 25) also disclosed caffeine as adenosine receptor antagonist. As such, claim 14 directing to formulation comprising an adenosine receptor agonist do not read on the elected species and withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected specie, there being no allowable generic or linking claim.
Claims 9-10, 13, 15-16, 17, 24, and 26- 27 read on the elected invention and species.
Status of Claims
Claims 9-10, 13-17, 24, 26-27, and 41-50 are pending in the instant application.
Claims 14, and 41-50 are withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species.
Claims 9-10, 13, 15-17, 24, and 26- 27 are currently under examination in this office action.
Priority
This application 18/249,229 filed on 07/06/2023 is a 371 of PCT/EP2022/050768 01/14/2022,which claims benefit to EP 21151905.3 filed on 01/15/2021.
The certified copy of EP 21151905.3 is submitted on 07/26/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/06/2023, 08/14/2024 and 12/04/2025 are in compliance with the provisions of 37 CFR 1.97.
Accordingly, the information disclosure statements are being considered by the Examiner. The reference written in foreign language is considered to the degree of English abstract or patent family of foreign patent if present.
Claim Interpretation
Independent claim 9 recites a pulsatile-release formulation comprising a nootropic agent and a release-controlling polymeric system, wherein the release-controlling polymeric system comprises a copolymer of methacrylic acid, methyl methacrylate and methyl acrylate with different ratios. Claim 10 further recite the molecular weight of the copolymer. Claim 13 recites specific copolymer Eudraguard® Biotic. It’s noted the molecular weight and ratios between components are the property of commercial copolymer, e.g. Eudraguard® Biotic and/or Eudragit ® FS 30D as disclosed by instant specification( See page 46, Table 2): Eudraguard® Biotic is an anionic copolymer composed of methyl acrylate, methyl methacrylate, and methacrylic acid in a monomer ratio of 7:3:1. Eudragit ® FS30 D is Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 by Evonik). For Eudragit ® FS30 D, the molar ratio of methacrylic acid to the sum of methyl methacrylate and methyl acrylate is calculated to be about 0.10 (=1/11) , and the molar ratio of methyl acrylate and methyl methacrylate is calculated to be about 2.3 =7:3), which reads on instant claim 9. Exploration/selection of different commercial polymer coating system ( Eudragit RS 30D vs Eudragit ® FS 30 D, or Eudraguard® Biotic) for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. If prior art use Eudraguard® biotic, Eudragit ® FS30D, or other similar copolymer as the coating material, it’s construed as read on instant claimed release-controlling polymeric system, even though the prior art is silent about the ratios and/or the molecular weight of the copolymer.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9-10, 13, 15, 17, 24, and 26- 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of pulsatile-release composition genus comprising nootropic agent genus and release-controlling polymeric system comprising specific ratio of methacrylic acid/methyl methacrylate and methyl acrylate. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the MPEP 2163 and Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
MPEP 2163.02 states “ Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, the inventor was in possession of the invention, and that the invention, in that context, is whatever is now claimed.”
Instant claims are drawn to composition comprising pulsatile-release composition genus comprising vast variety of nootropic agent that have different structure, different chemical/physical properties, different biological activity, etc. Claims 26 and 27 recite pulsatile-release composition further comprising variety of sedative substance that have different structure, different chemical/physical properties, different biological activity, etc. The Applicant is required to provide adequate written description and evidence of possession of the claimed pulsatile-release composition genus comprising the vast variety of nootropic agent and release-controlling polymeric system comprising specific ratio of methacrylic acid/methyl methacrylate and methyl acrylate, which further comprising the sedative substance genus.
MPEP 2163 II states; “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above)”. While applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. “A representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus” MPEP 2163 II.
Instant specification only disclose working example comprising caffeine and certain commercial polymeric system, e.g. Eudragit® S, Eudragit® L, Eudragit® RS, etc.(See Example 2-7 and 12) and list of methacrylic acid/methyl methacrylate and methyl acrylate component in the commercial polymeric system (See Table 2). Instant specification does not disclose working example of any other nootropic agent with specific amount methacrylic acid/methyl methacrylate and methyl acrylate at the specific ratio. Instant specification does not disclose working example comprising caffein in combination with any instantly claimed sedative substance as recited in claim 27.
In the absence of sufficient recitation/working sample of composition comprising other nootropic agents, one of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed pulsatile-release composition genus. The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed. Applicant is reminded that MPEP 2161 II makes clear that “ The written description requirement is separate and distinct from the enablement requirement”.
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.
Claims 13, 15, 17, 24, and 27 are rejected under 35 U.S.C. 112(b), 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 13 recites trademark/trade name Eudraguard® biotic . Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe copolymer comprising methacrylic acid, methyl methacrylate and methyl acrylate, Accordingly, the identification/description is indefinite.
Claim 15 recites limitation “ wherein the adenosine receptor agonist is xanthin derivative in particular theophylline or a pharmaceutically acceptable salt thereof ...caffeine...”. First, caffeine and theophylline are adenosine receptor antagonists, not agonists, Second, the term “derivatives” renders the claim indefinite, since the derivatives might include any modified compound related to xanthin having different chemical structure and pharmaceutical activities. Instant specification only disclose exemplary xanthin derivative(See page 10), but does not define the scope of xanthin derivatives that could be included in instant claimed “derivatives”. The phrase “in particular” is indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. It is not clear whether the claimed narrower range is a limitation. The lack of clarity do not clearly set forth the metes and bounds of the patent protection desired.
Claim 17 recites variety of nootropic agent “wherein the nootropic agent is a sympathomimetic, in particular ephedrine or a pharmaceutically acceptable salt thereof...”, “wherein the nootropic agent is a serotonin and noradrenalin reuptake inhibitor, in particular venlafaxine...”, “wherein the nootropic agent is a selective serotonin reuptake inhibitor, in particular fluoxetine...”. The phrase “in particular” is indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. It is not clear whether the claimed narrower range is a limitation. The lack of clarity do not clearly set forth the metes and bounds of the patent protection desired.
Claim 24 recites “wherein the ratio of the nootropic agent's weight to the total solid content's weight of the pulsatile-release formulation is between 10:1 to 1:100, optionally wherein the ratio of the weight of the release- controlling polymeric system to the weight of the rest of the pulsatile-release formulation is between 1:20 to 5:1”. It’s not clear if the polymeric system is considered as the “solid content” the pulsatile-release formulation and if it is an additional limitation to the weight limitation of nootropic agent.
Claim 27 recites vast variety of sedative substance, “wherein the sedative substance is an antihistaminic, in particular diphenhydramine...”, “wherein the sedative substance is an antipsychotic, in particular quetiapine...”, “wherein the sedative substance is a benzodiazepine, in particular alprazolam...” The phrase “in particular” is indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. It is not clear whether the claimed narrower range is a limitation. The lack of clarity do not clearly set forth the metes and bounds of the patent protection desired.
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 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 non-obviousness.
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 for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9-10, 13, 17 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Midha et al. (US 6340476 B1) in view of Chang et al. ("Polymethacrylates, Handbook of Pharmaceutical Excipients", 2009, page 525-533, Applicant’s IDS dated 07/06/2023 ) and EUDRAGIT® FS 30 D (technical information by Evonik, July 2015, Applicant’s IDS dated 12/04/2025 ).
Midha teaches a pulsatile release dosage form for oral administration of a nootropic agent/ stimulant (e.g. methylphenidate), and a delayed release copolymer system comprising methacrylic acid, methyl acrylate, methyl methacrylate, ethyl methacrylate, and/or derivatives thereof. (See abstract , Col. 4, lines 42-67; Col. 5 line. 1-16; Example 1 and 2; claims 1-47). Please note methylphenidate is nootropic agent disclosed by instant specification (See PGPub US20240316057A1 [0008], [0054], [0142]) and instant claim 17. Midha also teaches embodiments comprising other active agents, e.g. CNS stimulants, selective serotonin reuptake inhibitor SSRI , etc. (See Col. 8, lines 42-67, Col. 9, lines 1-26; claims 13,15).
Midha teaches pulsatile delivery of methylphenidate, wherein “plurality of drug doses are released at spaced apart time intervals. Generally, upon ingestion of the dosage form, release of the initial dose is substantially immediate, i.e., the first drug release “pulse” occurs within 1–2 hours of ingestion. This initial pulse is followed by a first time interval during which substantially no drug is released from the dosage form, after which a Second dose is then released. Typically, the second dose is released on the order of 3–5 hours following ingestion of the dosage form. Preferably, release of the second dose is followed by a Second non-release interval, which is again followed by a “pulse' of drug release. Ideally, release of a third dose occurs on the order of 7-9 hours following ingestion. In a preferred embodiment herein, either two or three release pulses are provided” (See Col.4, lines 44-61; claim 1).
Regarding claim 24, Midha teaches various amount of the active ingredient (e.g. 2.5mg, 5 mg, ) and Eudragit RS30D polymer (e.g. 6.34mg) ( See Example 1 ). The ratio of active ingredient to the total weight is calculated to be about 3.6 % (2.5mg/ (57.5mg+6.34mg+4.4mg+1.27mg).
Midha teaches the delayed release dosage comprise coating material, e.g. a polymeric material wherein the coating is used to provide delayed release of dosage units, and particularly preferred coating materials is a copolymer of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (sold under the tradename Eudragit® RS) (See Col. 5, lines 31-61; claim 20). Midha explicitly teaches embodiments comprising Eudragit® RS30D as the delayed release coating material (See Example 1, Tablet 2 and 3).
Midha is silent about the ratio of polymers as recited in claim 9 and molecular weight of copolymer recited in claim 10. As explained in preceding Claim Interpretation section, the ratios and molecular weight are the property of commercial copolymer. Exploration/optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. Chang teaches variety of polymethacrylates comprising methacrylic acid and methacrylic acid ester in different ratios, properties thereof(e.g. molecular weight, etc.), and their use in pharmaceutical formulation, e.g. polymeric system under the tradename of Eudragit ® (See Table I-III). For example, EUDRAGIT® FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 with average molar mass at 280,000 g/mol.
It would have been prima facie obvious for an ordinary skilled in the art to explore pulsatile release dosage form comprising nootropic agent and release-controlling polymeric system based on the collective teachings of Midha, Chang and further optimization based on general knowledge of drug delivery (e.g. controlled-release polymeric coating material ) for nootropic agent, and arrive at instant invention with reasonable expectation of success. Midha and Chang teach variety of commercial polymer coating system comprising methacrylic acid, methyl acrylate, e.g. Eudragit ®. A skilled artisan would be motivated to further explore different commercial polymer coating system for achieving the desired release profile of the active ingredient ( nootropic agent) because Midha explicitly teaches the benefit of pulsatile drug release, e.g. maximizing efficacy, reducing the potential for abuse or noncompliance (See Col 2. lines 47-52). Exploration/selection of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on collective teachings of Midha, Chang and general knowledge of drug delivery (e.g. coating polymeric materials) for CNS drug and nootropic agent. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 9-10, 13, 15-17 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Acharya et al. (WO2020194282A1), in view of Chang et al. ("Polymethacrylates", "Handbook of Pharmaceutical Excipients", 2009, page 525-533, Applicant’s IDS dated 07/06/2023 ) and EUDRAGIT® FS 30 D (technical information by Evonik, Applicant’s IDS dated 12/04/2025).
Acharya teaches a pulsed release formulation of caffeine, comprising plurality of particulate systems comprising caffeine and release retarding agents (See abstract, page 4, Summary; page 6, last para; Example 1; claims 1-13). Acharya teaches variety of controlled-release dosage form of caffein and benefit of pulsed release formulation that can release effective amount of caffeine in gradual way over entire gastrointestinal tract (GIT), making caffeine available in the body in the form of pulses for certain time duration over desired time interval, without any peaks or drops in caffeine levels, while avoiding the retention of caffeine in the individual’s system which hamper normal rest time at night (See page 4, para 2 and 3).
Regarding the release-controlling copolymer, Acharya teaches release retarding agents selected from variety of acrylate polymers, e.g. poly(methacrylic PMA), pH-sensitive polymers methacrylic acid and methyl methacrylate copolymers (See page 11, para 1 and 2; claim 2). Acharya explicitly teaches embodiments wherein the caffeine granules coated with methacrylic acid-ethyl acrylate copolymer (1:1) (See Example 1, Table No. 01, page 14 and 15; claim 2).
Regarding claim 24, Acharya teaches various amount of caffeine in each particulate system, e.g. 63 to 68 % w/w of the composition (See abstract, page 9, para 2-4; claim 1). Acharya teaches embodiments wherein the release retarding agent is present in the range of 1-50%, 1-30% w/w of composition (See page 11, last para; claim 1).
Acharya is silent about ratio of methacrylic acid, methyl acrylate as recited in claim 9, molecular weight recited in claim 10 and specific copolymer of claim 13. As explained in preceding Claim Interpretation section, the ratios and molecular weight are the property of commercial copolymer. Exploration/optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. Chang teaches variety of polymethacrylates comprising methacrylic acid and methacrylic acid ester in different ratios , properties thereof(e.g. molecular weight, etc.), and their use in pharmaceutical formulation, e.g. variety of polymeric system under the tradename of Eudragit ® (See Table 1). For example, EUDRAGIT® FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 with average molar mass at 280,000 g/mol.
It would have been prima facie obvious for an ordinary skilled in the art to explore pulsatile release dosage form comprising nootropic agent (e.g. caffeine) and release-controlling polymeric system based on the collective teachings of Acharya, Chang and general knowledge of drug delivery for CNS drug and nootropic agent. Acharya teaches a pulsed release formulation of caffeine, comprising plurality of particulate systems comprising caffeine and release retarding agents (e.g. pH-sensitive polymers methacrylic acid and methyl methacrylate copolymers). Chang teach variety of commercial polymer coating system comprising methacrylic acid, methyl acrylate, e.g. Eudragit ®. A skilled artisan would be motivated to further explore different commercial polymer coating system based on combined teaching of Acharya and Chang for achieving the desired pulse release profile of caffeine. Exploration/ optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on collective teachings of Acharya, Chang and general knowledge of drug delivery (e.g. coating polymeric materials) for CNS drug and nootropic agent. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 9-10, 13, 15-17, 24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Hirsh et al. (US20040121010A1), in view of Chang et al. ("Polymethacrylates", "Handbook of Pharmaceutical Excipients", 2009, page 525-533, Applicant’s IDS dated 07/06/2023 ) and EUDRAGIT® FS 30 D (technical information by Evonik, July 2015, Applicant’s IDS dated 12/04/2025).
Hirsh teaches a pulsatile release dosage form for oral administration of active CNS drug (e.g. milnacipran) which releases the drug in spaced apart “pulses”, wherein dosage forms are comprised of first, second and optional third dosage units, with each dosage unit having a different drug release profile (See abstract, [0053], [0017]-[0020], claims 1-24). Hirsh teaches pulsatile release dosage form further comprise one or more compounds, e.g. caffeine, melatonin, etc. (See [0053], claim 10) (which read on instant elected drug species).
Hirsh teaches embodiments of pulsatile release dosage form, wherein the dosage form comprises an immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. The immediate release dosage unit comprises a first dose of an active agent that is released substantially immediately following oral administration of the dosage form to a patient. The delayed release dosage unit comprises a second dose of the active agent and a means for delaying release of the second dose until approximately 3 hours to less than 14 hours following oral administration of the dosage form. The second delayed release dosage unit, when present, comprises a third dose of the active agent and a means for delaying release of the third dose until at least 5 hours to approximately 18 hours following oral administration of the dosage form (See [0020]).
Regarding claim 24, Hirsh teaches various dose amount of the active agent, e.g. 30 wt. % to 70 wt. % (See [0021]-[0022], [0086], Example 3-6).
Hirsh teaches suitable binders, e.g. methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers (See [0062]). Hirsh teaches the delayed release dosage units are prepared, by coating a drug or a drug-containing composition with a selected coating material wherein the drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule (See [0078]). Hirsh teaches suitable delayed release polymer coating materials for the pulsatile release, e.g. copolymers, preferably formed from methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit RTM (Rohm Pharma; Westerstadt, Germany), including Eudragit.RTM. L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit.RTM. L-100 (soluble at pH 6.0 and above), Eudragit.RTM. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits.RTM. NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability) (See [0058], [0078], [0081]).
Hirsh collectively teaches pulsatile release dosage form comprising caffeine, melatonin and release controlling polymer system comprising methacrylic acid, methyl acrylate, methyl methacrylate, e.g. commercial copolymer Eudragit®. Hirsh explicitly teaches Eudragit S 100 as the copolymer coating material (See [0118], Example 4).
Hirsh is silent about the ratio of methacrylic acid, methyl acrylate as recited in claim 9. As explained in preceding Claim Interpretation section, the ratios and molecular weight are the property of commercial copolymer. Exploration/optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. Chang teaches variety of polymethacrylates comprising methacrylic acid and methacrylic acid ester in different ratios , properties thereof(e.g. molecular weight, etc.), and their use in pharmaceutical formulation, e.g. variety of polymeric system under the tradename of Eudragit ® (See Table 1). For example, EUDRAGIT® FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 with average molar mass at 280,000 g/mol.
It would have been prima facie obvious for an ordinary skilled in the art to explore pulsatile release dosage form comprising nootropic agent (e.g. caffeine) and release-controlling polymeric system based on the collective teachings of Hirsh, Chang and general knowledge of drug delivery for CNS drug and nootropic agent. Hirsh and Chang teach variety of commercial polymer coating system comprising methacrylic acid, methyl acrylate, e.g. Eudragit ®. A skilled artisan would be motivated to further explore different commercial polymer coating system for achieving the desired release profile of the active ingredient because Hirsh teaches the benefit of pulsatile release dosage delivering active ingredient over approximately 24 hours with diminished incidence and decreased intensity of side effects (See [0102]-[0103]). Exploration/ optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on collective teachings of Hirsh and general knowledge of drug delivery (e.g. coating polymeric materials) for CNS drug and nootropic agent. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 9-10, 13, 15-17, 24, and 26- 27 are rejected under 35 U.S.C. 103 as being unpatentable over Jaenicke et al. (US20010038863A1, Applicant’s IDS dated 07/06/2023), in view of Chang et al. ("Polymethacrylates", "Handbook of Pharmaceutical Excipients", 2009, page 525-533, Applicant’s IDS dated 07/06/2023 ).
Jaenicke teaches pulsatile/controlled-release composition comprising an active stimulating agent (e.g. caffeine) and a sedative ( valerian or melatonin) with predetermined release profile, wherein the sedative is released immediately and the stimulant (caffeine) is released with a delay of an order of magnitude of five hours. Such a pharmaceutical provides for deep sleep and a refreshed awakening shortly after the release of the stimulant without the aftereffects of the sedative (See abstract, [0026], [0068], [0069], Examples 1-5; claims 1-26). The predetermined release profile of active stimulating agent/ nootropic agent (caffeine) is considered as pulsatile release of caffeine.
Regarding the nootropic agent/ stimulating agent , Jaenicke teaches stimulating agent is methylxanthines (for example, caffeine, theophylline, theobromine), amphetamines (such as dextroamphetamine or methamphetamine), pemolines, methylphenidates (for example, methyl phenidate hydrochloride) or modafinil; or antidepressants, especially selected from the group consist ing of imipramine, desipramine, clomipramine, protriptyline, fluoxetine, paroxetine, sertraline, citalopram, fluvox
amine, paroxetine, fluoxetine, sertraline, amitriptyline, desipramine, nortriptyline, mirtazepine, Venlafaxine, phenelzine, tranylcypromine, nefazodone, trazodone and buprion; or dextroamphetamine. Especially preferred are caffeine (most preferred), theophylline or theobromine, or a pharmaceutically acceptable Salt thereof. an active ingredient of an extract of caffeine-containing, theophylline-containing, theobromine containing plants, etc. ( See [0057]-[0058], Examples 1-6; claims 11, 14-16).
Regarding the coating polymer, Jaenicke teaches the caffein granules are coated with variety of coating material, e.g. metharylic acid copolymer, Eudragit RL30D, Eudragit RS 30 D, etc.(See [0047], [0049]).
Regarding claim 24, Jaenicke teaches various amount of caffein, e.g. 2% to 60% (See [0051], Examples 1-6).
Regarding the sedative substance in claim 27, Jaenicke teaches embodiments comprising additional active substance, e.g. tranquilizing/sleeping agent/sedative agent (e.g. melatonin) (See [0054]-[0055], Example 4-6; claim 7).
Jaenicke explicitly teaches embodiments comprising caffeine and melatonin (See Example 4-6, [0098]): Caffeine tablets, are filled into gelatine capsules of 1 to 1.5 cm size (6 caffeine tablets per capsule). 0.5 mg of melatonin is added and the capsules (preferably Snap-caps) are closed. The capsules are then coated with Eudragit RL30D (or Eudragit RL 30 S) to be resistant to gastric juice. Due to these properties, the capsules disintegrate fast in the small intestine after passing the stomach, and the melatonin is thus released immediately in the small intestine. The caffeine release, due to the properties of the tablets, starts approximately 420 min later.
Jaenicke is silent about the specific ratio of methyl acrylic acid and methylacrylate within the copolymer coating material and molecular weight thereof. As explained in preceding Claim Interpretation section, the ratios and molecular weight are the property of commercial copolymer. Exploration/optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art. Chang teaches variety of polymethacrylates comprising methacrylic acid and methacrylic acid ester in different ratios , properties thereof(e.g. molecular weight, etc.), and their use in pharmaceutical formulation, e.g. variety of polymeric system under the tradename of Eudragit ® (See Table 1). For example, EUDRAGIT® FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1 with average molar mass at 280,000 g/mol.
It would have been prima facie obvious for an ordinary skilled in the art to explore pulsatile release dosage form comprising nootropic agent (e.g. caffeine) and release-controlling polymeric system based on the combined teachings of Jaenicke, Chang and general knowledge of drug delivery for CNS drug and nootropic agent. Jaenicke teaches controlled/pulsative release formulation comprising caffeine and melatonin with controlled-releasing polymeric system of metharylic acid copolymer (e.g. Eudragit RL30D, Eudragit RS 30 D). Chang teach variety of commercial polymer coating system comprising methacrylic acid, methyl acrylate, e.g. Eudragit ®. A skilled artisan would be motivated to further explore different commercial polymer coating system for achieving the desired release profile of the active ingredient (e.g. caffeine ) based on combined teachings of Jaenicke and Chang. Exploration/ optimization of different commercial polymer coating system for active ingredient in pharmaceutical industry is considered as routine experimentation and optimization that’s within the knowledge of ordinary skilled in the art.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on collective teachings of Jaenicke, Chang and general knowledge of drug delivery (e.g. coating polymeric materials) for CNS drug and nootropic agent. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628