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 1-10 are pending.
Information Disclosure Statement
The information disclosure statements submitted on 7 January 2025, 18 February 2026 and 1 July 2026 were filed before the mailing of an Office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 7 is objected to because of the following informalities: the term “[Test Conditions]” should be deleted and “Water” should not be capitalized. Appropriate correction is required.
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 1-4 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Kim ‘924 (WO 2019/225924 A1; English-language equivalent US 2021/0205221 A1 referred to herein) in view of Han et al. (CN 102 631 326 A).
Kim ‘924 teaches throughout dutasteride-containing microparticles comprising dutasteride and a biodegradable polymer, wherein the microparticles have a dutasteride drug evenly distributed in a spherical biodegradable polymer and have an average particle diameter of 20 to 70 µm (Claim 1).
Regarding claims 1 and 6, Kim ‘924 teaches microparticles comprising dutasteride evenly distributed in PLGA, wherein the weight ratio of PLGA and dutasteride is 4:1, 9:1, 2:1, or 12:1 (Examples 1-9). Kim ‘924 teaches that the microparticles have an average particle diameter of 20 to 70 µm ([0069]; Claim 1); and that the microparticles continuously release dutasteride for 1 month to 3 months (Claim 3).
Regarding the amount of dutasteride in the sustained-release injectable composition being 8 mg to 100 mg, Kim ‘924 does not explicitly disclose the total concentration of dutasteride in the injectable composition. However, Kim ‘924 teaches a composition for treating and preventing hair loss and promoting hair growth, and a composition for preventing, treating or alleviating prostatic hyperplasia and prostate cancer, said composition comprising the microparticles comprising dutasteride evenly distributed in a biodegradable polymer ([0002], [0011], [0020]-[0021]; Claims 8-9). Kim ‘924 further teaches maintaining an effective concentration of dutasteride for 1 to 3 months ([0013]). Kim ‘924 also teaches preparation of compositions for injection comprising the microparticles added to a suspension solvent based on one-month aliquot corresponding to API 26 µg/day, and then uniformly suspended to prepare the injectable composition ([0093]).
Han et al. teach an injectable composition comprising microspheres containing dutasteride and a biodegradable polymer, wherein the dutasteride is present in a single dose in an amount of 5-100 mg, and the biodegradable polymers are selected from the group consisting of polylactide-co-glycolide, polylactide, polylactic-co-glycolic acid, polyglycolic acid, β-carboxybutyrate, polyorthoester, polycaprolactone, polyanhydride, polyphosphate, polyphosphazene, polybutylcyanoacrylate, and polyamide, preferably PLGA ([0017]).
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 a sustained-release injectable composition according to Kim ‘924 wherein the concentration of dutasteride in the composition is such that an effective concentration is continuously released for 3 months, such as 5-100 mg as reasonably taught by Han et al. A person of ordinary skill in the art would have been motivated to determine through routine experimentation the necessary concentration of dutasteride for the sustained-release injectable composition to maintain effective concentrations for 3 months.
Regarding claims 2-3, Kim ‘924 teaches microparticles comprising dutasteride and PLGA in a weight ratio of 1:2 to 1:12, and further teaches preparation of compositions for subcutaneous injection comprising the microparticles added to a suspension solvent based on one-month aliquot corresponding to API 26 µg/day ([0093]). Kim ‘924 does not explicitly disclose the composition exhibiting a plasma Cmax of dutasteride after 1 week, nor the plasma Cmax concentration of dutasteride being 200-2,500 ng/ml, as instantly claimed.
The instant specification teaches microparticles comprising dutasteride and PLGA in a weight ratio of 1:3 (Production Examples 3-4). The instant specification further teaches that the injectable compositions comprising microparticles in a suspension solvent, which is the same as Kim ‘924, were administered to a beagle dog and resulted in a plasma Cmax of dutasteride after 1 week, with the Cmax being about 213-1050 ng/ml (Experimental Example 2, Table 2).
Therefore, in the absence of evidence to the contrary, the injectable compositions according to Kim ‘924 which comprise the same components as the instant specification compositions would also result in a plasma Cmax of dutasteride within the range of 200-2,500 ng/ml after 1 week, similar to the injectable compositions according to the instant specification.
Regarding claim 4, Kim ‘924 teaches that the biodegradable polymer may be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and a combination thereof, preferably polylactide-co-glycolide (PLGA) ([0017], [0025], [0048]; Examples 1-9; Claims 4-5 and 13).
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 select a combination of biodegradable polymers for the preparation of microparticles according to Kim ‘924. Such would have been obvious because Kim ‘924 teaches that the biodegradable polymer includes the recited polymers and a combination thereof.
Regarding claim 7, Kim ‘924 teaches a drug release test comprising combining the microparticles with a 2% aqueous sodium lauryl sulfate solution in a 120 ml glass vial closed with a rubber stopper and sealed with an aluminum lid, placing the glass vial in a constant temperature stirring water bath and performing an elution test for 35 days under conditions of 37 °C and 120 RPM ([0085]-[0092]). According to the experimental results, the microparticles in Example 1 (4:1) were continuously eluted, 90% or more of which were eluted on day 28. The microparticles in Example 2 (9:1) were eluted less than 70% even on day 28 and day 35. The microparticles in Example 3 (2:1) were eluted 90% or more on day 14, and the elution rate did not increase after day 21. The microparticles in Example 4 (12:1) were eluted at less than 50% even on day 28 and day 35 ([0091]). All of the microparticles tested release less than 50 wt% of the dutasteride for 24 hours (Figure 7).
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Kim ‘783 (WO 2022/050783 A1; English-language equivalent US 2022/0249452 A1 referred to herein) in view of Kim ‘924 (WO 2019/225924 A1; English-language equivalent US 2021/0205221 A1 referred to herein) and Han et al. (CN 102 631 326 A).
Kim ‘783 teaches throughout sustained-release microparticles comprising a drug and a biodegradable polymer, wherein the microparticles have an average diameter between 20 µm and 100 µm (Abstract; [0002], [0014]; Claims 1-7).
Regarding claim 1, Kim ‘783 teaches that the drug contained in the microparticles is selected from the group consisting of Donepezil, Aripiprazole, Olanzapine, Palonosetron, Minocycline, Memantine, Naltrexone, Alendronate, Deoxycholate, Risedronate, Ibandronate, Zoledronate, Liraglutide, Exenatide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, and Finasteride ([0018], [0065]-[0066]; Examples). Kim ‘783 teaches that at the time of injection using the composition for injection of the present disclosure, the drug is continuously released from the body for a desired release period selected for 1 week to 12 months so that it may improve the convenience of users by solving the problem of having to take the drug every day ([0106]).
Kim ‘783 does not explicitly disclose microparticles comprising dutasteride as the drug, as instantly claimed. However, Kim ‘783 teaches finasteride for the treatment of benign prostatic hyperplasia or hair loss ([0066]). Kim ‘924 teaches sustained-release injectable compositions comprising microparticles with dutasteride uniformly distributed in biodegradable polymers, wherein dutasteride is suitable for treatment of benign prostatic hyperplasia, prostate cancer and male pattern alopecia ([0002]). It is noted that dutasteride and finasteride are structurally similar compounds, depicted below, and are used to treat the same conditions.
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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 the microparticles according to Kim ‘783 comprising a drug and biodegradable polymer, wherein the drug finasteride is substituted with dutasteride, and the microparticles have an average diameter of between 20 µm and 100 µm and the drug is released in a continuous manner for up to 12 months. Such would have been obvious because dutasteride and finasteride are structurally similar compounds used for the same purposes, and Kim ‘783 and Kim ‘924 both teach microparticles for use in sustained-release injectable compositions.
Regarding the sustained-release injectable composition containing 8-100 mg dutasteride, Kim ‘783 teaches a microparticle comprising a one-month dose of finasteride and a microparticle comprising a three-month dose of finasteride, wherein the microparticles comprising a one-month dose comprise 28.0 mg finasteride and the microparticles comprising a three-month dose comprise 84 mg of finasteride ([0111]-[0112], [0120]-[0121]).
Han et al. teach an injectable composition comprising microspheres containing dutasteride and a biodegradable polymer, wherein the dutasteride is present in a single dose in an amount of 5-100 mg, and the biodegradable polymers are selected from the group consisting of polylactide-co-glycolide, polylactide, polylactic-co-glycolic acid, polyglycolic acid, β-carboxybutyrate, polyorthoester, polycaprolactone, polyanhydride, polyphosphate, polyphosphazene, polybutylcyanoacrylate, and polyamide, preferably PLGA ([0017]).
A person of ordinary skill in the art would have been motivated to determine the effective three-month dose of dutasteride for incorporation into the microparticles of Kim ‘783, such as 5-100 mg dutasteride as reasonably taught by Han et al.
Regarding claim 2, Kim ‘783 teaches microparticles comprising 84 mg finasteride and a 1:1 mixture of biodegradable polymers polylactide and polylactide-co-glycolide (PLGA), wherein the weight ratio of the polymer mixture and finasteride is 2:1 ([0120]-[0121]). Kim ‘783 teaches that the sustained-release microparticles are characterized in that the ratio of the maximum blood concentration (Cmax) to the initial blood concentration (Cint) of the drug released from the microparticles is 2 to 30 ([0021], [0055]; Claim 6). The Cint is the maximum blood concentration value measured within 24 hours ([0056]). Kim ‘783 further teaches that the peak concentration of finasteride in the plasma occurs at approximately 240 hours (Fig. 18).
Regarding claim 3, Kim ‘783 does not explicitly disclose the Cmax of the drug is 200 ng/ml to 2,500 ng/ml, as instantly claimed.
Kim ‘924 teaches microparticles comprising dutasteride and PLGA in a weight ratio of 1:2 to 1:12, and further teaches preparation of compositions for subcutaneous injection comprising the microparticles added to a suspension solvent based on one-month aliquot corresponding to API 26 µg/day ([0093]). The instant specification teaches microparticles comprising dutasteride and PLGA in a weight ratio of 1:3 (Production Examples 3-4). The instant specification further teaches that the injectable compositions comprising microparticles in a suspension solvent, which is the same as Kim ‘783 and Kim ‘924, were administered to a beagle dog and resulted in a plasma Cmax of dutasteride after 1 week, with the Cmax being about 213-1050 ng/ml (Experimental Example 2, Table 2).
Therefore, in the absence of evidence to the contrary, the injectable compositions according to Kim ‘924 which comprise the same components as the instant specification compositions would also result in a plasma Cmax of dutasteride within the range of 200-2,500 ng/ml after 1 week, similar to the injectable compositions according to the instant specification. Thus, it would have been prima facie obvious for a person of ordinary skill in the art to prepare sustained-release injectable compositions according to Kim ‘783 wherein the drug is dutasteride, the biodegradable polymer is polylactide, PLGA, or a combination thereof, and the Cmax of the dutasteride is within the range of 200 ng/ml to 2,500 ng/ml, as reasonably suggested by Kim ‘783 and Kim ‘924.
Regarding claims 4-5, Kim ‘783 teaches that the biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazenes, polyiminocarbonates, polyphosphoesters, polyanhydrides, polyorthoesters, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acids, and combinations thereof, and is particularly preferably selected from polylactide, polylactide-co-glycolide (PLGA), and a combination thereof ([0060], [0064]). Kim ‘783 teaches microparticles comprising a 1:1 mixture of polylactide and PLGA ([0121]).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to select a 1:1 mixture of polylactide and PLGA as the biodegradable polymers of Kim ‘783.
Regarding claim 6, Kim ‘783 teaches microparticles comprising a 2:1 weight ratio of polymer mixture to finasteride ([0121]).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to prepare microparticles comprising a 2:1 weight ratio of polymer mixture to dutasteride.
Regarding claim 7, Kim ‘783 teaches sustained-release compositions wherein the compositions release the drug for up to 12 months, but does not explicitly disclose the accelerated release test instantly claimed.
Kim ‘924 teaches a drug release test comprising combining the microparticles with a 2% aqueous sodium lauryl sulfate solution in a 120 ml glass vial closed with a rubber stopper and sealed with an aluminum lid, placing the glass vial in a constant temperature stirring water bath and performing an elution test for 35 days under conditions of 37 °C and 120 RPM ([0085]-[0092]). According to the experimental results, the microparticles in Example 1 (4:1) were continuously eluted, 90% or more of which were eluted on day 28. The microparticles in Example 2 (9:1) were eluted less than 70% even on day 28 and day 35. The microparticles in Example 3 (2:1) were eluted 90% or more on day 14, and the elution rate did not increase after day 21. The microparticles in Example 4 (12:1) were eluted at less than 50% even on day 28 and day 35 ([0091]). All of the microparticles tested release less than 50 wt% of the dutasteride for 24 hours (Figure 7).
Regarding claim 8, Kim ‘783 teaches that the stirring-completed microparticles were washed several times with sterilized filtered purified water, treated with a 4% mannitol solution as a cryoprotectant, and dried after freezing to obtain microparticles ([0135]). The instant specification states that a mannitol aqueous solution may be added to the microparticles from which the surfactant has been removed, thereby forming a mannitol coating layer on the outer surface of the microparticles, followed by freeze-drying (pg. 20, ln. 19-22; Experimental Example 3). When the microparticles having the coating layer formed using mannitol as described above do not aggregate together when freeze-dried (pg. 12, ln. 8-14).
Therefore, the aqueous mannitol solution according to Kim ‘783 will form a coating layer on the outer surfaces of the microparticles and act as a cryoprotectant.
Regarding claim 9, Kim ‘783 does not explicitly disclose the standard deviation for diameters of the microparticles is 2 to 7, as instantly claimed.
However, Kim ‘783 teaches that the microparticles are composed of particles having a uniform particle size-showing narrow particle size distribution width and a specific surface area range ([0023]). The sustained-release microparticles of the present disclosure have a particle size distribution width of 35 microns or less, and are composed of particles having a very narrow particle size distribution width, that is, monodisperse particles having a very uniform particle size. Therefore, even though the average particle diameter (D50) is the same, since the microparticles of the present disclosure have a narrow particle size distribution width compared to particles having a particle size distribution width exceeding 35 microns, thereby having a large specific surface area and increasing the density of the particles per unit volume, they can also play a role in lowering the dosage of the drug as well as the uniform drug release ([0101]). The small average particle diameter and narrow particle size distribution width of the microparticles of the present disclosure play a decisive role in eliminating the initial excessive release problem ([0235]). The microparticles prepared according to the present disclosure may provide injection formulations consisting only of uniform particles that are much smaller in size and have a narrow particle size distribution width compared to the particles prepared by the conventional solvent evaporation method ([0238]).
Regarding claim 10, Kim ‘783 teaches that the microparticles have a particle size distribution width of 7.24 µm, 7.60 µm, 8.69 µm, 10.38 µm, 10.23 µm, 15.33 µm, and 15.27 µm ([0118], [0127], [0136], [0145], [0154], [0163], [0172]).
Therefore, in the absence of evidence to the contrary, a person of ordinary skill in the art would have been able to prepare microparticles according to the method of Kim ‘783 wherein the microparticles are uniform and have a narrow particle size distribution. A person of ordinary skill in the art would have been able to optimize the standard deviation for diameter of the microparticles and the width of a peak of the microparticles by following the process steps according to Kim ‘783 to prepare the microparticles.
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 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,911,508 in view of Han et al. (CN 102 631 326 A). Although the claims at issue are not identical, they are not patentably distinct from each other because US ‘508 claims microparticles comprising dutasteride and a biodegradable polymer, wherein the microparticles have dutasteride evenly distributed in a spherical biodegradable polymer, the microparticles have an average particle diameter of 20 µm to 70 µm, and the weight ratio of biodegradable polymer to dutasteride is 3:1 to 9:1. US ‘508 further claim that the microparticles continuously release dutasteride for 1 to 3 months. Also, the biodegradable polymers claimed in US ‘508 are the same as instantly claimed. Regarding the amount of dutasteride, US ‘508 does not explicitly claim the amount of dutasteride in the composition for preventing, treating or alleviating prostate hyperplasia and prostate cancer.
Han et al. teach an injectable composition comprising microspheres containing dutasteride and a biodegradable polymer, wherein the dutasteride is present in a single dose in an amount of 5-100 mg, and the biodegradable polymers are selected from the group consisting of polylactide-co-glycolide, polylactide, polylactic-co-glycolic acid, polyglycolic acid, β-carboxybutyrate, polyorthoester, polycaprolactone, polyanhydride, polyphosphate, polyphosphazene, polybutylcyanoacrylate, and polyamide, preferably PLGA ([0017]).
Therefore, a person of ordinary skill in the art would have been motivated to determine through routine experimentation the necessary amount of dutasteride to include in an injectable formulation for the effective prevention, treatment or alleviation of prostatic hyperplasia and prostate cancer, such as 5-100 mg as taught by Han et al.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nathan W Schlientz whose telephone number is (571)272-9924. The examiner can normally be reached 10:00 AM to 6:00 PM, Monday through Friday.
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/N.W.S/Examiner, Art Unit 1616
/MONICA A SHIN/Primary Examiner, Art Unit 1616
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