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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 24, 2025 has been entered.
DETAILED ACTION
3. Claims 1 – 20 are pending in this application. Applicant’s Amendment and Remarks, filed October 24, 2025, is entered, wherein claim 14 is amended and claims 1 – 13 are withdrawn.
Claims 14 – 20 are examined on the merits herein.
Priority
This application is a national stage application of PCT/KR2020/003876, filed March 20, 2020, which claims benefit of foreign priority document KR10-2019-0035354, filed March 27, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Receipt is acknowledged of a certified English translation of the foreign application.
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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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 14 and 16 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Nause (WO2010/147978A1, cited in the previous Office Action) in view of Illum et al. (WO99/12549A2).
a. Regarding claims 14 and 16 – 20, , Nause teaches an invention that is related to a Factor Xa inhibitor dosage form comprising apixaban in a solubility-improved form, wherein the dosage form provides controlled release of apixaban (Abstract). Controlled release is intended to embrace sustained release, delayed release and immediate release followed by sustained release (page 4, lines 18 – 19). Nause discloses that apixaban has been formulated as an injection (page 2, lines 6 – 7). The invention may be used in the “use environment”, such as intrathecal, subcutaneous spaces, and intramuscular tissue (page 5, lines 26 – 28). Nause confirms that apixaban has a low solubility in aqueous environment (page 31, line 1). One of the solubility-improved form taught by Nause is the lipid vehicle formulations that combines apixaban, digestible oils, and a surfactant. The surfactant may be a hydrophilic surfactant, such as polyethylene (40 or 60) hydrogenated castor oil. The digestible oil acts as a solvent for apixaban and which disperses to form the oil droplet phase (page 55, lines 30 – 31; page 56, lines 1 – 33; page 59, lines 5 – 6). In one embodiment, apixaban is in an amount of 1 – 50% by weight (page 60, line 18).
However, Nause does not teach that the formulation is in the form of microsphere and apixaban and fatty acid are dispersed in the biocompatible polymer of the microsphere. Nause also does not teach that the release of apixaban is 5% or less in the initial 30 minutes.
Illum et al. teach a pharmaceutical composition comprising polymeric microparticles including a drug and a fatty acid (Abstract). Illum et al. disclose that a simple technique to incorporate drugs into polymeric microparticles without the presence of a fatty acid will cause an unacceptable burst effect. The combination of fatty acid, drugs in biodegradable polymeric microparticles not only improve the loading of drug into the microparticles, but may also provide a minimal initial burst of drug and an approximate linear release of drug (page 4, lines 5 – 14). The approximate linear release of drug may be over 30 days or more (Abstract; page 7, lines 16 – 17):
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The term “no significant burst effect” includes that no more than 20% of the loaded drug is release in one day (page 8, lines 9 – 11). The compositions may be prepared by dispersing drug and fatty acid in a polymer solution (page 5, lines 1 – 2). The compositions may be administered to a mammal in suitable dosage forms, wherein the invention are administered parenterally with a more preferred routes of intramuscular administration (page 9, lines 25 – 28; page 10, lines 1 – 4).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the lipid vehicle formulation of apixaban as taught by Nause with the polymeric microparticle formulation for a pharmaceutical composition comprising a drug and a fatty acid dispersed in the polymer in view of Illum et al. because Illum et al. teaches that the disclosed formulation improves the loading of drug and provides a minimal initial burst of drug. One would have been motivated to modify the lipid vehicle formulation of apixaban as taught by Nause with the polymeric microparticle formulation for a pharmaceutical composition comprising a drug and a fatty acid dispersed in the polymer in view of Illum et al. because Illum et al. teach that such formulation will provide an approximate linear release. As the combination of Nause and Illum et al. meet all structural limitations of claim 14, the same intended results will be achieved, including “fatty acid or triglyceride inhibits crystallization of the Apixaban and formation of biocompatible polymer-Apixaban precipitates by forming hydrogen bonds with the Apixaban”. For the release of apixaban in the initial 30 minutes, Illum et al. disclose that no more than 20% of drug is released in one day and the graph shows an approximate linear release. It is expected that no more than 0.5% of the drug will be released in the initial 30 minutes. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to modify the lipid vehicle formulation of apixaban as taught by Nause with the polymeric microparticle formulation for a pharmaceutical composition comprising a drug and a fatty acid dispersed in the polymer in view of Illum et al. because Nause teaches the lipid vehicle formulation of apixaban comprising a polymer, fatty acid, and apixaban and Illum et al. teach the controlled release microsphere delivery system that improves the loading of drug and minimizes the initial burst of drug, thereby, the modification will provide an improved microsphere formulation of apixaban.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Nause (WO2010/147978A1, cited in the previous Office Action) in view of Illum et al. (WO99/12549A2) as applied to claims 14 and 16 – 20 above, and further in view of Sah et al. (US20130224257A1).
b. Regarding claim 15, Nause and Illum et al. teach the limitations discussed above.
However, these references do not teach the composition comprising a halogen organic solvent.
Sah et al. teach a method for preparing microsphere and microspheres produced thereby. The method comprises mixing a water-insoluble organic solvent with a dispersion solvent; mixing a polymer compound, a drug and a water-insoluble organic solvent to prepare a dispersed phase; mixing the dispersed phase with the dispersion solvent mixed with the water-insoluble organic solvent to prepare an emulsion; and adding a base or an acid to the prepared emulation. With this method, it is possible to prepare a drug-containing polymeric microsphere cost-effectively and conveniently (Abstract). The water-insoluble organic solvent may be compounds having backbone of acid halogen (para. [0037]). In example 1, some amount of water-insoluble organic solvent is left after the addition of a base or an acid (para. [0106], Table 2).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the microsphere formulation of apixaban as taught by Nause and Illum et al. further with water-insoluble organic solvent, such as compounds having backbone of acid halogen, in view of Sah et al. because Sah et al. teach that a polymer compound, a drug, and a water-insoluble organic solvent may be mixed to formulate the dispersed phase. One would have been motivated to combine the microsphere formulation of apixaban as taught by Nause and Illum et al. further with water-insoluble organic solvent, such as compounds having backbone of acid halogen, in view of Sah et al. because Sah et al. teach that the mixture of the components will form a dispersed phrase for the microsphere formulation. Such combination will yield predictable results. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the microsphere formulation of apixaban as taught by Nause and Illum et al. further with water-insoluble organic solvent, such as compounds having backbone of acid halogen, in view of Sah et al. because it is known in the art to use water-insoluble organic solvent, such as compounds having backbone of acid halogen, when preparing dispersion phase for microsphere formulation.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed October 24, 2025, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that claim 14 has been amended to clarify that the fatty acid are dispersed in the biocompatible polymer of the microsphere and the fatty acid enables “inhibition of drug crystallization and formation of polymer-apixaban precipitates and stable encapsulation of drug into the microsphere”. Applicant argues that examples 1-4 and 3-2 demonstrate no precipitates when a fatty acid is included.
Regarding Lim et al., Applicant argues that Lim et al. disclose structure of microsphere that involves first encapsulating the bioactive material in a biocompatible polymer to form a polymer-drug complex, followed by additional encapsulation of the complex with a release inhibitor (fatty acid). Applicant further explains that Lim et al. disclose the structure of microsphere, which has the fatty acid distributed inside and outside the microsphere. The differences between the present application and Lim et al. are represented below:
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Applicant argues that the purpose and functions of the fatty acid in the present application and Lim et al. are different as Lim et al. teach that fatty acid is a release inhibitor.
Regarding Nause, Applicant argues that the structure of the apixaban microspheres as taught by Nause are different and the differences are represented below:
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Applicant argues that Nause is targeting an oral formulation instead of an injection. Applicant further argues that the purpose and functions of the fatty acid in the present application and Nause are different as the digestible oil is used for the purpose of increasing the concentration of a drug.
The examiner acknowledges Applicant’s arguments. However, the new 103 rejections are based on Nause and Illum et al. for achieving the claimed biocompatible polymer-based apixaban-loaded microsphere in the form of an injection for sustained release comprising apixaban, biocompatible polymer, and fatty acid, wherein apixaban and fatty acid are dispersed in the biocompatible polymer of the microsphere. Nause teach the lipid vehicle formulation of apixaban comprising apixaban, biocompatible polymer and fatty acid. Illum et al. teach the structure of a microsphere of drug with the drug and fatty acid dispersed in the polymer. It would be obvious to modify the lipid vehicle formulation of apixaban to a microsphere disclosed by Illum et al. because Illum et al. teach that such microsphere formulation has an improved drug load and minimum initial burst. The benefits disclosed by Illum et al. provide the motivation for a skilled artisan to modify the lipid vehicle formulation of apixaban. Such modification will also achieve the intended results of crystallization inhibition of apixaban. Moreover, the results shown are not commensurate with the broad scope of the claims, which encompass a wide range of fatty acid and triglyceride, not limited to those specifically tested.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693