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 .
Priority
This application is a Continuation of 17488826, filed 09/29/2021, 17488826 is a Continuation of 16163695, filed 10/18/2018, 16163695 is a Continuation of 15017817, filed 02/08/2016, 15017817 Claims Priority from Provisional Application 62113496, filed 02/08/2015.
Status of Action/Claims
Receipt of Remarks/Amendments filed on 6/23/2026 is acknowledged. Claims 1-9, 11-13, 15-18, 20, 22, 39-42 are currently pending and presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Note: This is a second non-final office action that is prompted by further consideration of the instant claims and the prior art.
Claim Interpretation
Claim 20 recites "consisting essentially of". The "consisting essentially of" language recited in the claims still allows for inclusion of other components not recited in the instant claims. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355. If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of "consisting essentially of," applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of applicant’s invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd. Pat. App. & Inter. 1989). See MPEP 2111. Thus, in the instant case, "consisting essentially of" is interpreted as "comprising of" which does not exclude ingredients not positively recited in the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-9, 11, 16-17, 20, 22, 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Goldman (US Patent Application Publication 2013/0216615 A1, Published 08/22/2013) in view of Zeidan et al. (US Patent 8669281 B1, Published 03/11/2014).
The claims are directed to a capsule composition comprising a plurality of tablet cores containing 70-80% 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate comprising having an enteric coating on the cores. The core further comprises microcrystalline cellulose and crosslinked polyvinylpyrrolidone (crospovidone). The coating further comprises controlled release polymer, plasticizer and talc.
Goldman teaches formations of capsules containing microtablets (e.g. paragraph 0232) comprising a core comprising 83.60% dimethyl fumurate, 0.46% croscarmellose sodium, 7.00% microcrystalline cellulose, 0.26% magnesium stearate, 0.43% silica colloidal anhydrous and coating comprising 0.11% methacrylic acid methyl acrylate, 4.34% methacrylic acid ethyl acrylate (controlled release polymer), 0.97% triethyl citrate, 2.65% talc, 0.02% simethicone, 0.11 polysorbate 80, and 0.05% sodium lauryl sulfate (paragraphs 0232-0235, example 5). Goldman also teaches the total amount of dimethyl fumarate in the composition ranges from about 43% w/w to about 95% w/w (see e.g. claim 1).
Disintegrants can be selected from croscarmellose sodium and crospovidone (e.g. paragraph 0163). Silica colloidal anhydrous can be substituted with colloidal silica (colloidal silicon dioxide) (e.g. para 0163-0164).
The microtablets can be coated with one or more of methacrylic acid-methyl acrylate copolymer or methacrylic acid-ethyl acrylate copolymer (e.g. claim 13). Fillers can be selected from polysorbate 80, simethicone and talc (e.g. paragraph 0162). Lubricants can be selected from magnesium stearate, talc, and sodium lauryl sulfate (e.g. paragraph 0165).
The microtablets can be coated by one or more coatings (e.g. paragraph 0122). The coatings can be an enteric coating (e.g. paragraph 0194). The enteric coating can comprise one or more of plasticizes, fillers, lubricants, polymers, copolymers, or combinations thereof (e.g. paragraphs 0202-0210).
Goldman lacks a teaching wherein the core comprises 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate.
Zeidan et al. teach a pharmaceutical composition comprising 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate (see prior art claims 1 and 2). 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate is derivative of monomethyl fumurate which offer improved properties relative to dimethyl fumurate (column 1, lines 13-17). Dimethyl fumurate is known to cause side effects (column 2, lines 62-67). The compound 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate results in decreased side effects upon administration (column 5, lines 39-42).
It would have been prima facie obvious to one of ordinary skill in the art to substitute diemthyl fumurate with 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate in the composition of Goldman and have a reasonable expectation of success. One would have been motivated to do so since Zeidan et al. teach that 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate has reduced side effects relative to dimethyl fumurate.
With regards to the amount of coating to applied to the core, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed amounts (e.g. claims 6-8), through routine optimization of the composition. One would have been motivated to do so in order to arrive at a preferred release profile, which would depend on the amount of coating applied to the core. For example, higher amount/thicker coating will delay the release of the drug whereas a lesser amount or thinner coating would release the drug quicker as the coating will dissolve faster.
With regard to the instant release profile instantly claimed (e.g. claims 9-11), it would have been obvious to one of ordinary skill in the art to achieve the release profile through routine optimization of the composition. One would have been motivated to do so in order to arrive at a preferred release profile, which would depend on the amount of coating applied to the core. For example, higher amount/thicker coating will delay the release of the drug whereas a lesser amount or thinner coating would release the drug quicker as the coating will dissolve faster. Further, the combination of the cited prior art teaches the composition which is the same as the instantly claimed composition and thus it would necessarily have the release profile recited in the instant claims.
Regarding the claimed amount of monomethyl fumarate, as discussed supra, Goldman teaches the total amount of dimethyl fumarate in the composition ranges from about 43% w/w to about 95% w/w. It would have been obvious to one skilled in the art to manipulate and determine an optimal amount of monomethyl fumarate during routine optimization which would depend on parameters such as severity of disease or size, gender, age, etc. of the subject being treated. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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).
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claims 12-13, 15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Goldman (US Patent Application Publication 2013/0216615 A1, Published 08/22/2013) in view of Zeidan et al. (US Patent 8669281 B1, Published 03/11/2014) as applied to claims 1-9, 11, 16-17, 20, 22, 39-41 above and further in view of Naringrekar et al. (US2009/0317473A1; Dec. 24, 2009).
The teachings of Goldman and Zeidan have been set forth above.
As discussed supra, Goldman teaches formations of capsules containing microtablets having a core and coating which comprises a controlled release polymer. Goldman also teaches the active (dimethyl fumarate), croscarmellose sodium, talcum, colloidal silicon and magnesium stearate are mixed to formed a blend (see e.g. example 2). As such, the active would be dispersed throughout the carrier matrix. Goldman does not expressly teache wherein the capsule contains pellets instead of microtablets. However, Naringrekar cures this deficiency.
Naringrekar also teaches controlled release pharmaceutical formulations wherein the active agent is blended with other material to form a matrix mixture, which is then compressed to form mini-tablets or pelletized to form pellets. Minitablets and pellets can be filled into capsules. Pellets can be produced through extrusion method. (see e.g. para 0004; 0075; 0079).
It would have been prima facie obvious to one of ordinary skill in the art to have combined the teachings of Goldman and Naringrekar and fill the capsule of Goldman with either minitablets or pellets because Naringrekar teaches both minitablet form and pellet form as being suitable for filling capsules in a controlled release formulation. Moreover, Naringrekar teaches extrusion method can be used to produce pellets and thus, one skilled in the art would have found it obvious to use the known method to produce pellets. Further, claim 13 recites a method of producing the pellets and the instant claims are directed to a product. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113 (I).
With regard to the instant release profile instantly claimed (e.g. claims 14-15), as discussed supra, it would have been obvious to one of ordinary skill in the art to achieve the release profile through routine optimization of the composition. One would have been motivated to do so in order to arrive at a preferred release profile. Further, the combination of the cited prior art teaches the composition which is the same as the instantly claimed composition and thus it would necessarily have the release profile recited in the instant claims.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Goldman (US Patent Application Publication 2013/0216615 A1, Published 08/22/2013) in view of Zeidan et al. (US Patent 8669281 B1, Published 03/11/2014) as applied to claims 1-9, 11, 16-17, 20, 22, 39-41 above and further in view of and Mulye (US6475493B1; Nov. 5, 2002).
The teachings of Goldman and Zeidan discussed supra are incorporated herein.
As discussed supra, Goldman teaches formations of capsules containing microtablets (e.g. paragraph 0232) comprising a core comprising 83.60% dimethyl fumurate, 0.46% croscarmellose sodium, 7.00% microcrystalline cellulose, 0.26% magnesium stearate, 0.43% silica colloidal anhydrous and coating comprising 0.11% methacrylic acid methyl acrylate, 4.34% methacrylic acid ethyl acrylate (controlled release polymer), 0.97% triethyl citrate, 2.65% talc, 0.02% simethicone, 0.11 polysorbate 80, and 0.05% sodium lauryl sulfate (paragraphs 0232-0235, example 5). Goldman also teaches the total amount of dimethyl fumarate in the composition ranges from about 43% w/w to about 95% w/w (see e.g. claim 1).
Disintegrants can be selected from croscarmellose sodium and crospovidone (e.g. paragraph 0163). Silica colloidal anhydrous can be substituted with colloidal silica (colloidal silicon dioxide) (e.g. para 0163-0164). The microtablets can be coated with one or more of methacrylic acid-methyl acrylate copolymer or methacrylic acid-ethyl acrylate copolymer (e.g. claim 13). Fillers can be selected from polysorbate 80, simethicone and talc (e.g. paragraph 0162). Lubricants can be selected from magnesium stearate, talc, and sodium lauryl sulfate (e.g. paragraph 0165). Thus, one skilled in the art would have readily envisioned using crospovidone instead of croscarmellose in the core, and only methacrylic acid ethyl acrylate as the copolymer, and talc as the filler/lubricant. Thus, Goldman does not require materials which are excluded from the claims with the use of consisting of language.
Goldman further teaches the microtablets can be coated by one or more coatings (e.g. paragraph 0122). The coatings can be an enteric coating (e.g. paragraph 0194). The enteric coating can comprise one or more of plasticizes, fillers, lubricants, polymers, copolymers, or combinations thereof (e.g. paragraphs 0202-0210).
Goldman lacks a teaching wherein the core comprises 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate.
Zeidan et al. teach a pharmaceutical composition comprising 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate (see prior art claims 1 and 2). 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate is derivative of monomethyl fumurate which offer improved properties relative to dimethyl fumurate (column 1, lines 13-17). Dimethyl fumurate is known to cause side effects (column 2, lines 62-67). The compound 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate results in decreased side effects upon administration (column 5, lines 39-42).
Goldman also does not expressly teach the coating also includes colloidal silicon dioxide. However, Mulye cures this deficiency.
Mulye teaches controlled release formulations having a core containing medicament and a coating which controls the release of drug. The coating may contain lubricants such as colloidal silicon dioxide. (see e.g. Background of Invention; Col. 8, line 5-25).
It would have been prima facie obvious to one of ordinary skill in the art to substitute diemthyl fumurate with 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate in the composition of Goldman and have a reasonable expectation of success. One would have been motivated to do so since Zeidan et al. teach that 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumurate has reduced side effects relative to dimethyl fumurate.
It would have been prima facie obvious to one of ordinary skill in the art to have further included colloidal silicon dioxide in the coating of Goldman’s composition because Goldman teaches the coating can include lubricant and Mulye teaches controlled release formulations having a core containing medicament and a coating which controls the release of drug wherein the coating may contain lubricants such as colloidal silicon dioxide. Thus, one skilled in the art would have found it obvious to include colloidal silicon dioxide in the coating of Goldmans composition with a reasonable expectation of success.
With regard to the amount of the materials in the core and the coating, while Goldman does not expressly disclose the exact which are recited in the claim, Goldman in its disclosure teaches general amounts which can be used (see e.g. para 0155-0178) and which overlap the claimed amounts. It would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed amounts through routine optimization of the composition. For example, Goldman teaches the lubricant (e.g. magnesium stearate) can be contained in the composition, for example, in a total amount ranging from about 0.1% w/w to about 3.0% w/w, which overlaps the claimed amount of magnesium stearate. Further, it would have been obvious to manipulate and determine an optimal amount based on the amount of lubrication desired. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). Thus, absence any evidence of unexpected effect, the amounts of the ingredients in the core and coating would have been obvious because all of the ingredients in the core and coating have result effective parameters.
From the combined teaching of the cited reference, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art.
Response to Arguments
Applicant argued that Goldman found it surprising that a high concentration of dimethyl fumarate (DMF), which is a small, symmetrical compound, could be compacted into a suitable dosage form. One skilled in the art would not have found it predictable that replacing DMF with a high dose of the claimed monomethyl fumarate prodrug (DRF), an asymmetrical compound having a larger ethyl-linked succinimide at one end of the fumarate, could be compacted into a suitable dosage form with a reasonable expectation of success.
In response, firstly the examiner argues that the only difference between the DRF prodrug and DMF prodrug is that DRF has a succinimide attached to the ethyl of DMF prodrug. There is no teaching in Goldman that the DMF prodrug being a small, symmetrical compound is what provides a high drug loading and neither have the applicants provided any evidence that a larger, asymmetrical compound would not provide a high drug loading similar to DMF. As discussed supra, Goldman teaches the amount of DMF in the composition can be up to 95% by weight. The instant claims recite 70-80% of the DRF prodrug. One skilled in the art would have expected to slightly lower the amount of the DRF prodrug (e.g. from 95% to 70%) due to there being addition of succinimide (i.e. DRF being slightly larger compound than DMF), and slightly lower the amounts of excipients (e.g. coating thickness) to allow for higher amount of DRF prodrug. Applicant have not provided any evidence that DRF prodrug because of addition of a succinimide group would have a much lower drug loading contend (e.g. less than 70%) compared to DMF prodrug. Further, applicant have not provided any evidence that DRF product was known to have a drug loading content of less that what is claimed (e.g. 70-80%) and that the claimed drug loading content is an unexpected effect.
Applicant argued that Goldman teaches uncoated compacts or microtablets "coated with a solution of methacrylic acid-methyl methacrylate copolymer and triethyl citrate in isopropanol (see amounts in Table 2 below). The coated microtablets are then coated with a second laver of coating consisting of methacrylic acid-ethylacrylate copolymer, polysorbate 80, sodium lauryl sulfate, triethyl citrate, simethicone, and talcum micronized suspended in water" (see Examples and paragraph [0235]; emphasis added). As such, Goldman fails to teach or suggest a composition providing this controlled release profile through the application of a single coating to the core.
In response, Goldman teaches the composition can be optionally coated or partially coated by one or more coatings. The term “coated microtablet” means a microtablet that is fully or partially coated by one or more coatings. (para 0022, 0194). “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. Thus, while Goldman in the examples of Table 2 may disclose more than one coating applied on the core, Goldman teaches that the microtablet can be coated with one coating. All of the claimed elements (e.g. single coating) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Applicant argued that the Examiner's assertion that it would have been obvious through routine optimization to have arrived at the release profile and at the amount of coating applied to the core that are specified in the claims, maintaining control over the release rate of such high drug load compositions is also understood in the art as often difficult. One skilled in the art must be motivated to do more than merely to vary all parameters or try each of numerous possible choices until one possibly arrives at a successful result.
In response, the examiner argues that the excipients recited in the instant claims are well known in the art and Goldman teaches the claimed excipients in the core and coating and teaches amounts which overlap the claimed amounts. Applicant have not provided any evidence of the criticality of the claimed amounts of the excipients. The amount of an excipient (e.g. control release polymer) or thickness of the coating affects the release profile (e.g. a thicker coating would take longer to dissolve and thus provide a delayed release verses a less thick coating). Applicant need to bring forth evidence that the claimed combination of excipient, amount of the claimed excipient have criticality/unexpected effect over the amounts of the excipient taught in the prior art. Absence any evidence, a prima facie case of obviousness exists because all the excipients claimed have a result effective parameter. For example, Goldman teaches the lubricant (e.g. magnesium stearate) can be contained in the composition, for example, in a total amount ranging from about 0.1% w/w to about 3.0% w/w, which overlaps the claimed amount of magnesium stearate. It would have been obvious to manipulate and determine an optimal amount based on the amount of lubrication desired. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). Thus, absence any evidence of unexpected effect, the amounts of the ingredients in the core and coating would have been obvious because all of the ingredients in the core and coating have result effective parameters.
Conclusion
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/ALI S SAEED/Examiner, Art Unit 1616
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