DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1, 3, 12, 15-16, 19 and 21-23 are pending in the present application.
Withdrawn Rejections
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.
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.
Claims 1, 3, 12 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Bong et al. (WO 2012/011740 A2) in view of Gu (US 2016/0310411 A1) and Kim et al. (US 2014/0072531 A1).
Regarding instant claim 1, Bong et al. teach sustained release microspheres comprising a drug, such as rivastigmine, and a polymer, such as polylactide and poly(lactide-co-glycolide) (PLGA), preferably PLGA (Abstract; [0058], [0061], [0147]). Bong et al. further teach polymeric microspheres wherein the loading amount (loading amount (%) = (weight of detected drug/weight of microsphere) x 100) of drug is 24.68% to 32.97% (Table 23). Bong et al. teach that the polymer compound may be used in an amount of 1 to 500 parts by weight, preferably of 1 to 50 parts by weight, with respect to 1 part by weight of a drug (i.e., ~0.2 to 50 parts by weight of the drug) ([0063]). Bong et al. teach PLGA comprising a ratio of lactide to glycolide of 75:25 and 64:36, and a viscosity of 0.25 dL/g and 0.49 dL/g ([0176]; Tables 1 and 4).
Bong et al. also teach microspheres having an average particle size of 30-60 µm ([0102], 0137], [0702]-[0714]; Table 23). Bong et al. further teach that when the polymeric microsphere prepared by the inventive method was injected, a drug can be continuously released a maximum of 120 days ([0147]).
Bong et al. do not explicitly disclose an example of a microsphere comprising rivastigmine pamoate and one or more biodegradable polymers selected from the group consisting of poly(lactide-co-glycolide), polylactide, and mixtures thereof, as instantly claimed. However, Bong et al. teach that the drug includes rivastigmine ([0061]; Claim 11), and the polymer is preferably PLGA ([0058]; Claims 9-10).
Gu teaches formulations comprising pamoate salts of rivastigmine and at least one pharmaceutically acceptable carrier, wherein the carrier includes a biodegradable and bioerodable carrier, such as polylactide and poly(lactide-co-glycolide) ([0014], [0059], [0062]; and Claims 6 and 8-11). Gu teaches that the pamoate salts of rivastigmine are suitable for treating dementia associated with Alzheimer’s disease, wherein the composition can be administered by injection, and the pamoate salts result in a desired long acting and/or extended release profile and the active is released from the composition over a period of at least 7 days, preferably at least about 14 days, alternatively for at least 2, 3, 4, 6, or 8 weeks ([0014], [0051], [0061]-[0062]; Example 10; Claims 6, 8-11, 15-21).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to prepare microspheres according to Bong et al. comprising rivastigmine as the drug and PLGA as the polymer. Such would have been obvious because Bong et al. teach a finite number of drugs for use in preparing their microspheres, and teach that PLGA is the preferred polymer. A person of ordinary skill in the art would reasonably expect to be able to prepare microspheres comprising rivastigmine and PLGA, wherein the loading amount is greater than 7%. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Also, it would have been prima facie obvious to prepare microspheres comprising pamoate salts of rivastigmine in the biodegradable polymer carrier. Such would have been obvious because Bong et al. teach sustained release microspheres comprising a drug, such as rivastigmine, and a polymer, such as polylactide, poly(lactide-co-glycolide) (PLGA), and polycaprolactone, and Gu teaches that the pamoate salt of rivastigmine is suitable for preparing an extended release formulation that is minimally dependent on the pH of the environment ([0007], [0013]; Claims 8-11). A person of ordinary skill in the art would have been motivated to use rivastigmine pamoate in the formulations of Bong et al. in order to prepare a formulation that has extended release of the rivastigmine.
Regarding the sustained release and the initial burst, Bong et al. teach that the polymeric microspheres provide sustained release of the active for up to 120 days (Abstract; [0134], [0142], [0147], 0149], [0160]).
Bong et al. do not explicitly disclose that less than 15% of the active ingredient is released within one day of administration.
Kim et al. teach that in a microparticle system of prolonged release formulation, in many cases, a high initial drug release, that is, an initial burst, occurs. This is because a drug is quickly diffused through water-filled pores existing in surfaces and/or the insides of microparticles, and water channels connecting them. This initial burst may cause side effects such as a toxic response. Thus, in development of the microparticle system, an initial burst should be minimized or eliminated ([0006]). The polymer microparticles having a significantly reduced initial drug release can significantly reduce side effects caused by the initial drug release ([0059]).
Kim et al. teach methods for preparing sustained release microspheres comprising an active ingredient, such as rivastigmine, and polymers, such as polylactide and poly(lactide-co-glycolide), wherein the microspheres have a reduced initial burst ([0011], [0039]-[0040]; Claims 11-12). Kim et al. teach a solvent evaporation and solvent extraction method can be used to prepare the microspheres, wherein the polymer and active ingredient are dissolved in an organic solvent as a dispersed phase, followed by adding an aqueous phase to prepare an emulsion, and then the organic solvent is diffused in the dispersion medium and evaporated ([0031]-[0033]). Kim et al. further teach microspheres according to their invention having less than 15% of the active ingredient released within 24 hours (Tables 2, 4-9).
Therefore, it would have been prima facie obvious to prepare microspheres according to Bong et al., Gu and Kim et al. comprising rivastigmine pamoate in a PLA and/or PLGA polymer, wherein the microspheres have a reduced initial burst. Such would have been obvious because Kim et al. teach that initial burst may cause side effects such as a toxic response. Kim et al. further teach methods for preparing microspheres wherein the initial burst is minimized or eliminated. A person of ordinary skill in the art would have been motivated to prepare microspheres according to Kim et al. in order to significantly reduce side effects caused by the initial drug release.
Regarding instant claim 3, Gu teaches preparations of rivastigmine pamoate salt comprising a molar ratio of 1:1 (Example 10).
Regarding instant claim 12, Bong et al. teach that the resultant product is freeze-dried ([0255], [0512], [0689], [0692]). Gu teaches that the pamoate salts may be heated at an elevated temperature to obtain the anhydrous form ([0082]; Example 9).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to prepare the anhydrous form of rivastigmine pamoate by heating the salt at an elevated temperature or freeze-drying.
Regarding instant claim 23, Bong et al. teach that the microspheres are injectable ([0133], [0149]). Gu teaches that the pamoate salts of rivastigmine are suitable for treating dementia associated with Alzheimer’s disease, wherein the compositions are administered by injection ([0014]).
It is noted that the recitation of “for preventing or treating Alzheimer’s disease” is a recitation of intended use. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, the microspheres according to Bong et al. could be injected into an individual for the treatment of Alzheimer’s disease when the drug is rivastigmine.
Response to Arguments
Applicant's arguments filed 30 September 2025 have been fully considered but they are not persuasive. Applicant argues that Bong et al. do not disclose, exemplify or even suggest the use of rivastigmine pamoate or rivastigmine free base co-formulated with pamoic acid or the specific fatty acids now claimed, do not teach the required 2.0-50% by-weight content of pamoic acid/release-adjusting agent based on the microsphere.
The examiner respectfully argues that Bong et al. teach the that polymer compound may be used in an amount of 1 to 500 parts by weight, preferably of 1 to 50 parts by weight, with respect to 1 part by weight of a drug ([0063]). Gu teaches rivastigmine pamoate with a ratio of 1:1 of rivastigmine to pamoic acid (Example 10). A person of ordinary skill in the art would have been motivated to prepare compositions comprising 1 to 50 parts by weight polymer with respect to 1 part by weight rivastigmine, wherein the rivastigmine is a 1:1 ratio of rivastigmine pamoate.
The examiner respectfully points out the following from MPEP 2144.05: “[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); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Applicant further argues that Gu also does not supply what Bong et al. lacks. Gu analyzes the structure and forms of rivastigmine pamoate and include general statements that pamoate salts may be formulated with biodegradable carriers, and in a separate context they report a 1:1 molar ratio in a salt preparation. However, Gu does not teach injectable PLA/PLGA microspheres containing rivastigmine pamoate at the high active-load levels as now claimed.
The examiner respectfully argues that Bong et al. teach sustained release microspheres comprising a drug, such as rivastigmine, and a polymer, such as polylactide and poly(lactide-co-glycolide) (PLGA), preferably PLGA (Abstract; [0058], [0061], [0147]). Gu teaches the need for an injectable extended release formulation ([0002]-[0007]). Gu teaches pamoate salts of rivastigmine and at least one pharmaceutically acceptable carrier suitable for treating a subject having dementia associated with Alzheimer’s disease comprising administering a therapeutically effective amount of said compositions, wherein the composition is administered by injection ([0014], [0062]). Gu further teaches preparation of rivastigmine pamoate salt comprising a 1:1 ratio of rivastigmine to pamoic acid (Example 10). See also Claims 6, 8-11, and 15-20.
Therefore, a person of ordinary skill in the art would have been motivated to use the pamoate salt of rivastigmine (1:1 ratio) in the formulations according to Bong et al. in order to provide a sustained release microsphere for treating Alzheimer’s disease.
Applicant also argues that the paragraph [0059] of Gu the Office relies upon addresses surgically implanted systems and expressly provides ultra-low drug levels on the order of 1:1,000 to 1:20,000 relative to the carrier, which is antithetical to the present 9-35% rivastigmine content limitation for an injectable depot.
The examiner respectfully argues that Gu teaches injectable formulations as well as formulations that can be surgically implanted ([0059]). Gu further teaches that polylactides and PLGA are biodegradable and bioerodable carriers suitable for use with rivastigmine pamoate. Bong et al. teach microspheres for sustained release of a drug preferably comprising PLGA as the polymer compound and including rivastigmine as the drug. Bong et al. further teach that the polymer is included in an amount of 1 to 500 parts by weight, preferably of 1 to 50 parts by weight, with respect to 1 part by weight of drug. A person of ordinary skill in the art would have been motivated to prepare microspheres comprising PLGA and rivastigmine pamoate, wherein the PLGA is used in an amount of 1 to 50 parts by weight with respect to 1 part by weight of rivastigmine pamoate, as reasonably taught by Bong et al. and Gu.
Applicant further argues that Gu expressly points out that polymeric extended-release systems have high manufacturing costs and are difficult to produce, and proposes chemical modification of donepezil as an alternative (see paragraphs [0002], [0005]). Accordingly, Gu actually teaches away from the instantly claimed polymeric microparticles as an injectable formulation.
The examiner respectfully argues that Gu teaches that there still exists a need for improved methods of delivering extended release systems which maximize the medical benefits of the active agent, can be administered more conveniently at a dosing interval longer than 24 hours, and can be produced in a more cost effective manner ([0002], [0005]). It is desirable to find an injectable extended release formulation in which the release rate of the active ingredient is minimally dependent on pH ([0007]). Gu then teaches that the pamoate salts of donepezil, rivastigmine and memantine provide long acting and/or extended release profile ([0008]; Claims 6, 8-11, and 15-20). A person of ordinary skill in the art would reasonably expect the long-acting and/or extended release rivastigmine pamoate according to Gu to be suitable for use in the microspheres according to Bong et al. wherein the resulting microspheres will have sustained release of the rivastigmine pamoate for the treatment of Alzheimer’s disease.
Applicant further argues that Kim describes a post-formation alcohol treatment to reduce initial burst in generic PLA/PLGA microparticles and reports examples meeting a "<15% in 24 hours" criterion. However, Kim does not teach or suggest that the specific combination of rivastigmine pamoate or rivastigmine free base with pamoic acid/lauric acid/myristic acid, within the precise 2.0-50% mass fraction of organic acid, can deliver the claimed, simultaneous triad of features: (i) high rivastigmine loading at 9-35% w/w, (ii) <15% released in one day, and (iii) ≥1-month release, all within the specified polymer molecular characteristics and particle-size window. The mere availability of a general burst-reduction technique does not provide a reasonable expectation that the above constellation of outcomes would be achieved for the particular, poorly soluble tertiary amine drug at issue and the particular organic acid levels now required by the claims.
The examiner respectfully argues that Kim et al. teach in a microparticle system of prolonged release formulation, in many cases, a high initial drug release, that is, an initial burst, occurs. This is because a drug is quickly diffused through water-filled pores existing in surfaces and/or the insides of microparticles, and water channels connecting them. This initial burst may cause side effects such as a toxic response. Thus, in development of the microparticle system, an initial burst should be minimized or eliminated ([0006]). Kim et al. teach methods for preparing drug-loaded polymer microparticles with a reduced initial burst, wherein the drug includes rivastigmine and the polymers include polylactide and PLGA ([0039]-[0040]; Claims 11-12). Kim et al. teach a solvent evaporation and solvent extraction method can be used to prepare the microspheres, wherein the polymer and active ingredient are dissolved in an organic solvent as a dispersed phase, followed by adding an aqueous phase to prepare an emulsion, and then the organic solvent is diffused in the dispersion medium and evaporated ([0031]-[0033]).
A person of ordinary skill in the art would have been motivated to prepare microspheres that minimize or eliminate the initial burst in order to reduce toxicity, as suggested by Kim et al. It would have been obvious to prepare microspheres according to the method of Kim et al. comprising dissolving rivastigmine pamoate and polylactide or PLGA in a solvent, adding the dispersed phase to an aqueous phase containing a surfactant to form an emulsion, and extracting and evaporating the organic solvent to form microspheres. A person of ordinary skill in the art would have a reasonable expectation that following the method according to Kim et al. would reduce or eliminate the initial burst.
Applicant further argues that merely selecting an "insoluble salt" does not predict success. When the same microsphere process was run with rivastigmine decanoate (an insoluble fatty-acid salt), target loads of 20% produced only ~5% rivastigmine in the microspheres with ~25% encapsulation efficiency, whereas a 15% target load using rivastigmine pamoate (1:1) yielded 14.27% rivastigmine content at ~95% efficiency; free base at a 16% target load delivered ~9.25% rivastigmine at ~58% efficiency.
The examiner respectfully argues that Gu provides motivation for using rivastigmine pamoate for the preparation of microspheres. Bong et al. teach loading efficiencies for other active agents of greater than 70%, greater than 85% (Example 7-2, 8-2; Tables 16, 19, 23). A person of ordinary skill in the art would have been motivated to prepare microspheres comprising rivastigmine pamoate and polylactide or PLGA with the reasonable expectation of a high loading efficiency. Obviousness does not require absolute predictability of success, but at least some degree of predictability is required. See MPEP 2143. In the instant case, a person of ordinary skill in the art would have some degree of predictability that preparing microspheres comprising rivastigmine pamoate and polylactide or PLGA would result in a microsphere containing a therapeutically effective amount of rivastigmine.
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant further argues that whereas Bong et al. eschew solvent-evaporation/extraction in favor of a different manufacturing scheme, Kim et al. expressly assume that very scheme and add a subsequent processing step; the approaches are mutually exclusive. Accordingly, a skilled artisan would have lacked motivation to combine Bong et al. and Kim et al. and, even if attempted, because each teaching depends on a different process foundation, there would be no reasonable expectation that the distinct technical effects reported in each reference could be achieved simultaneously.
The examiner respectfully argues that Bong et al. teach mixing a water-insoluble organic solvent with a dispersion solvent; mixing a polymer compound, a drug and a water-insoluble organic solvent so as to prepare a dispersed phase; mixing the dispersed phase with the dispersion solvent mixed with the water-insoluble organic sol vent so as to prepare an 0/W (oi 1-inwater), 0/0 (oil-in-oil) or W/0/W (water-in oil-in-water) type emulsion; adding a base or an acid to the prepared emulsion so as to remove the water-insoluble organic solvent from the emulsion; and obtaining the prepared polymeric microsphere whose water-insoluble organic solvent is removed and re-dispersing the obtained polymeric microsphere in a warmed dispersion solvent.
Kim et al. teach that the preparation of the polymer microparticles may be carried out by a conventional method known in the art ([0026]). Kim et al. teach that preferably, a solvent evaporation/extraction method or a solvent ammonolysis (or hydrolysis) method through emulsion may be used ([0027]-[0033]).
Therefore, Kim et al. do not teach away from the method of Bong et al. Rather, Kim et al. teach that any conventional method known in the art is suitable for the preparation of microspheres.
Applicant also argues that numerous variables can influence drug release from microspheres, including the drug's size and physicochemical properties, the amount of drug incorporated (loading), drug-polymer interactions, polymer characteristics (e.g., molecular weight and monomer molar ratio), and microsphere attributes (e.g., particle size, span value, and surface porosity). In particular, the monomer molar ratio of the polymer that constitutes the microsphere determines the polymer's hydrophobicity and directly affects water uptake and erosion rate. Intrinsic viscosity-proportional to molecular weight-likewise modulates polymer degradation and drug diffusivity, and thus is a key lever for controlling both the duration and the profile of drug release (see Fredenberg et al, Table 2 and p. 38). Because drug loading and the release profile result from the complex interplay of these factors, knowledge of any single parameter does not allow one to predict how a given microsphere formulation will perform. By contrast, the instantly claimed invention demonstrably achieves high drug content and encapsulation efficiency (see Examples 2 and 5) together with a reduced initial burst and stable sustained release (Examples 4 and 7). These results arise from the particular combination of features recited in the claims and could not have been predicted from the art of record, which disclose only individual factors in isolation.
The examiner respectfully argues, as discussed above, that Bong et al., Gu, and Kim et al. provide motivation to prepare microspheres comprising rivastigmine pamoate and polylactide or PLGA. A person of ordinary skill in the art would have been motivated to prepare microspheres according to the teachings of Bong et al. and Kim et al., with the reasonable expectation that the microspheres will have a high loading efficiency and reduced or eliminated initial burst. Obviousness does not require absolute predictability of success, but at least some degree of predictability is required. See MPEP 2143.
Claims 15-16, 19 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2019/108030 A1) in view of Bong et al. (WO 2012/011740 A2), Gu (US 2016/0310411 A1) and Kim et al. (US 2014/0072531 A1).
Regarding instant claims 15-16, 19 and 21-22, Lee et al. teach a method for preparing rivastigmine microspheres comprising dissolving rivastigmine and the biocompatible polymer in an organic solvent, combining with an aqueous solution containing a surfactant to prepare an emulsion, extracting and evaporating the organic solvent and recovery of the microspheres (Example 7). Lee et al. teach that the biodegradable polymer preferably includes polylactide and poly(lactide-co-glycolide) (pg. 5, para. 3; Claim 2).
Lee et al. do not explicitly disclose rivastigmine pamoate or rivastigmine free base combined with pamoic acid or a fatty acid.
Gu teaches formulations comprising pamoate salts of rivastigmine and at least one pharmaceutically acceptable carrier, wherein the carrier includes a biodegradable and bioerodable carrier, such as polylactide and poly(lactide-co-glycolide) ([0014], [0059], [0062]; and Claims 6 and 8-11). Gu teaches that the pamoate salt of rivastigmine is suitable for preparing an extended release formulation that is minimally dependent on the pH of the environment ([0007], [0013]; Claims 8-11).
Lee et al. do not explicitly disclose the amount of rivastigmine present in the microspheres being 9% by weight or more, as instantly claimed.
Bong et al. teach sustained release microspheres comprising a drug, such as rivastigmine, and a polymer, such as polylactide, poly(lactide-co-glycolide) (PLGA), polycaprolactone (Abstract; [0058], [0061], [0147]). Bong et al. further teach polymeric microspheres wherein the loading amount (loading amount (%) = (weight of detected drug/weight of microsphere) x 100) of drug is 24.68% to 32.97% (Table 23).
It would have been prima facie obvious for a person of ordinary skill in the art to optimize the amount of rivastigmine in the microspheres according to Lee et al., such as up to 24.68% to 32.97% drug loading taught by Bong et al. A person of ordinary skill in the art would have been motivated to incorporate as much drug in the microspheres as possible while maintaining a sustained release formulation. Further, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to select rivastigmine pamoate as the active agent for use in the method according to Lee et al. in view of the teaching of Gu that the pamoate salt of rivastigmine is suitable for preparing an extended release formulation that is minimally dependent on the pH of the environment.
Regarding the release of less than 15% of the active ingredient within one day of administration, Kim et al. teach that in a microparticle system of prolonged release formulation, in many cases, a high initial drug release, that is, an initial burst, occurs. This is because a drug is quickly diffused through water-filled pores existing in surfaces and/or the insides of microparticles, and water channels connecting them. This initial burst may cause side effects such as a toxic response. Thus, in development of the microparticle system, an initial burst should be minimized or eliminated ([0006]). The polymer microparticles having a significantly reduced initial drug release can significantly reduce side effects caused by the initial drug release ([0059]).
Kim et al. teach methods for preparing sustained release microspheres comprising an active ingredient, such as rivastigmine, and polymers, such as polylactide and poly(lactide-co-glycolide), wherein the microspheres have a reduced initial burst ([0011], [0039]-[0040]; Claims 11-12). Kim et al. teach a solvent evaporation and solvent extraction method can be used to prepare the microspheres, wherein the polymer and active ingredient are dissolved in an organic solvent as a dispersed phase, followed by adding an aqueous phase to prepare an emulsion, and then the organic solvent is diffused in the dispersion medium and evaporated ([0031]-[0033]). Kim et al. further teach microspheres according to their invention having less than 15% of the active ingredient released within 24 hours (Tables 2, 4-9).
Therefore, the method according to Lee et al., which comprises the same steps as Kim et al. of dissolving the drug in an organic solvent, mixing the solution in an aqueous phase to form an emulsion, and extracting and evaporating the organic solvent from the dispersed phase, would necessarily result in microspheres that have a reduced or eliminated initial burst.
Regarding instant claim 16, Lee et al. teach mixing 4.0 g of a biocompatible polymer with 1.0 g rivastigmine (Example 7).
Regarding instant claim 19, Lee et al. teach the example of the solvent for dissolving the biodegradable polymer is not particularly limited, but is preferably one or more solvent selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol and a mixed solvent thereof, more preferably dichloromethane, ethyl acetate or a mixed solvent thereof (pg. 6, para. 1; Example 7).
Regarding instant claim 21, Lee et al. teach that the surfactant is preferably selected from the group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives and mixtures thereof, and most preferably polyvinyl alcohol can be used (pg. 6, para. 6; Example 7).
Regarding instant claim 22, Lee et al. teach that the continuous phase is water, or a mixed solvent of water with methyl alcohol, ethyl alcohol, propyl alcohol or ethyl acetate (pg. 7, para. 9).
Response to Arguments
Applicant relies on the same arguments as above. Therefore, the examiner’s response above is repeated here as well.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 15-16, 19 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,311,854 in view of Gu (US 2016/0310411 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because US ‘854 claims a method for preparing biodegradable microspheres comprising: (a) forming a biodegradable polymer solution by dissolving a biodegradable polymer and a drug in an organic solvent; (b) uniformly mixing the biodegradable polymer solution of step (a) with an aqueous solution containing a surfactant, to form an emulsion containing the biodegradable polymer solution as a dispersed phase and an aqueous solution containing the surfactant as a continuous phase; (c) extracting and evaporating the organic solvent from the dispersed phase in the emulsion of step (b) to the continuous phase to produce microspheres, and (d) recovering the microspheres from the continuous phase containing the produced microspheres of step (c).
US ‘854 further claims that the organic solvent is one or more selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and a mixture thereof; that the surfactant is one or more selected from the group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives and a mixture thereof; that the aqueous solution containing the surfactant of step (b) comprising (i) water, or a mixed solvent comprising water and one or more organic solvent selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol and ethyl acetate as a solvent; and (ii) a surfactant; and that the drug includes rivastigmine.
Gu teaches formulations comprising pamoate salts of rivastigmine and at least one pharmaceutically acceptable carrier, wherein the carrier includes a biodegradable and bioerodable carrier, such as polylactide and poly(lactide-co-glycolide) ([0014], [0059], [0062]; and Claims 6 and 8-11).
Therefore, it would have been prima facie obvious to prepare microspheres comprising pamoate salts of rivastigmine in the biodegradable polymer carrier. Such would have been obvious because US ‘854 claim preparation of biodegradable microspheres comprising a drug, such as rivastigmine, and a biodegradable polymer, such as polylactide, poly(lactide-co-glycolide) (PLGA), and polycaprolactone, and Gu teaches that the pamoate salt of rivastigmine is suitable for preparing an extended release formulation that is minimally dependent on the pH of the environment ([0007], [0013]; Claims 8-11). A person of ordinary skill in the art would have been motivated to use rivastigmine pamoate in the formulations of US ‘854 in order to prepare a formulation that has extended release of the rivastigmine.
Response to Arguments
Applicant relies on the same arguments as above. Therefore, the examiner’s response above is repeated here as well.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.W.S/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616