Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed April 27, 2026. The amendment, filed April 27, 2026, has been entered, wherein claims 14 – 15 are amended and claims 1 – 13 are withdrawn.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.
The following are the maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed April 27, 2026, wherein claims 14 – 15 are amended and claims 1 – 13 are withdrawn. Previously cited references have been used to establish the maintained / modified grounds of rejection
Maintained / Modified 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 mailed June 9, 2025) in view of Illum et al. (WO99/12549A2, cited in the previous Office Action mailed January 26, 2026).
a. 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). Nause also recognizes a continuing need to find safe and effective methods of delivering Factor Xa inhibitors including apixaban (page 2, lines 11 – 12). Nause further teaches that controlled-release of apixaban is desirable because it may lower the maximum apixaban concentration in plasma while still providing good bioavailability, thereby decreasing undesirable side effects relative to an immediate-release dosage form containing an equivalent amount of apixaban (page 12, lines 25 – 29). The solubility-improved form taught by Nause may be selected from various formulation types, including nanoparticles (page 2, line 31) and the lipid vehicle formulations, wherein the lipid vehicle formulation comprises 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). Thus, Nause teaches apixaban formulations directed to controlled release, improved solubility, improved bioavailability, and alternative particulate or polymer-containing delivery forms.
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. Such a burst effect may result in unacceptable side effects, including problems associated with toxicity of the drug (page 3, lines 22 – 23). 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). Illum et al. teach that fatty acids suitable for use in the compositions include lauric acid and stearic acid (page 13, line 3). Suitable concentrations of fatty acids in the compositions are in the range of 1 to 50% w/w and suitable concentration of polymer materials in the compositions are in the range 5 to 98% w/w (page 7, lines 6 – 10). Illum et al. further teach that the composition may contain from 1 to 50 wt% of active ingredient (page 13, line 20).
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 Nause teaches that controlled-release apixaban formulations are desirable for lowering maximum plasma concentration while maintaining bioavailability and reducing undesirable side effects relative to immediate-release formulations and Illum et al. teaches that incorporation of drugs into polymeric microparticles containing fatty acid minimizes burst release and provides sustained and approximately linear drug release profiles, wherein burst release may otherwise result in unacceptable side effects and toxicity-related problems. Accordingly, one of ordinary skill in the art seeking the controlled-release apixaban formulation of Nause with reduced peak plasma concentration and reduced undesirable side effects would have been motivated to employ the polymeric microparticle comprising fatty acid of Illum et al. in order to provide a more controlled plasma exposure profile. One 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 fatty acid dispersed in the polymer in view of Illum et al. because Nause already teaches controlled-release apixaban formulations comprising particulate and polymer-containing delivery system, including nanoparticles and lipid vehicle formulations and Illum et al. teach biodegradable polymeric microparticle systems suitable for controlled-release administration with minimized burst release and sustain drug delivery. 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.
Regarding claim 14, Illum et al. teach that the suitable concentrations of fatty acids in the compositions are in the range of 1 to 50% w/w and the amount of active ingredient is 1 to 50 wt%. Nause teaches that the apixaban is in an amount of 1 – 50% by weight. Given the molecular weights of Apixaban is about 459.5 g/mol and stearic acid is about 284.5 g/mol, a composition containing 10 g stearic acid and 10 g Apixaban has a fatty acid:apixaban molar ratio of 1.6:1 ratio, which falls within the claimed range of more than 1 to less than 5. Therefore, the claimed molar ratio overlaps with the ranges taught by Nause and Illum et al. Furthermore, Illum et al. teach polymer concentrations of 5 – 98 % w/w. These disclosed ranges encompass embodiments wherein the weight of fatty acid is 50% or less relative to the weight of the polymer, as required by the claims. For example, a composition containing 10% w/w fatty acid and 20% w/w polymer results in the fatty acid being present at 50% by weight relative to the polymer. Accordingly, Illum et al. teach the claimed fatty acid-to-polymer weight relationship.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Nause (WO2010/147978A1, cited in the previous Office Action mailed June 9, 2025) in view of Illum et al. (WO99/12549A2, cited in the previous Office Action mailed January 26, 2026) as applied to claims 14 and 16 – 20 above, and further in view of Sah et al. (US20130224257A1, cited in the previous Office Action mailed January 26, 2026).
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 April 27, 2026, have been fully considered and are found to be not persuasive.
Regarding Illum et al., Applicant argues that Illum et al. disclose oleic acid as a more preferred fatty acid and Illum et al. do not confirm the effect of stearic acid and lauric acid used in the present invention. There is no suggestion of motivation in Illum et al. to select stearic or lauric acid as the fatty acid of the present invention and the drug release characteristics resulting from the selection of the fatty acid of the present invention are also considered difficult to predict from Illum et al. However, these arguments are not persuasive. Illum et al. explicitly disclose stearic acid and lauric acid as suitable fatty acids for use in the disclosed microsphere compositions. The fact that Illum et al. may identify oleic acid as a more preferred fatty acid, or provide working examples using other fatty acids does not negate from the teachings that stearic acid and lauric acid are suitable alternatives. A prior art reference is not limited to its preferred embodiments or working examples. Thus, one of ordinary skill in the art would have had reason to select stearic acid or lauric acid from the list of suitable fatty acids disclosed by Illum et al. for use in the claimed composition. Applicant’s assertion that drug release characteristics are difficult to predict is not sufficient to overcome the rejection. Illum et al. already teach the use of fatty acids in microsphere drug delivery systems to modify drug release and specifically identifies stearic acid and lauric acid as suitable fatty acids. Absent persuasive comparative evidence showing that the claimed selection produces unexpected results relative to the fatty acids taught by Illum et al., the selection of stearic acid or lauric acid from the disclosed list of Illum et al. would have been obvious.
Applicant argues that Illum et al. do not recognize Apixaban aggregation or this specific hydrogen bonding mechanism. However, the argument is not persuasive because the prior art need not to recognize the same problem solved by Applicant, so long as the claimed composition would have been obvious based on the teachings of the references. Illum et al. teach microsphere compositions comprising a drug, a biocompatible polymer, and fatty acid, including stearic acid and lauric acid. Nause teaches Apixaban-containing polymer-based sustained-release formulations. Thus, one of ordinary skill in the art would have had reason to apply the fatty acid-containing microsphere of Illum et al. to the Apixaban formulation of Nause to modify drug release and formulation properties. Moreover, the combination of Nause and Illum et al. suggests the same components, including apixaban, fatty acid, and polymer, inhibition of crystallization of apixaban by hydrogen bonding interactions formed between apixaban and the polymer would necessarily result.
Applicant argues that the molar ratio of the fatty acid to the drug (olanzapine) in Illum et al. is about 0.48 to 0.56, which is outside of the claimed range. Applicant’s argument is not persuasive because the claims are directed to Apixaban, and the relative calculation is the fatty acid to Apixaban molar ratio. Based on the molecular weights of Apixaban and the disclosed fatty acids, the composition ranges disclosed by Illum et al. encompass the fatty acid amounts that provide the claimed molar ratio relative to Apixaban.
Applicant further argues that it would not be easy for those skilled in the art to recognize the technical feature of the present invention even with reference to Nause because Nause does not teach direct contacting fatty acid with Apixaban. However, the argument is not persuasive. Nause is relied upon for teaching the controlled or sustained release formulations of Apixaban, for recognizing the poor aqueous solubility of Apixaban, and for teaching that controlled-release apixaban formulations are desirable for lowering maximum plasma concentration while maintaining bioavailability and reducing undesirable side effects. Illum et al. is relied upon for teaching polymeric microsphere drug delivery systems comprising a drug, a biocompatible polymer, and fatty acids, including stearic acid and lauric acid, wherein the fatty acid is incorporated into the microsphere formulation to improve drug loading, minimize burst release, and provide sustained and approximately linear release characteristics. Illum et al. further teach that incorporation of fatty acid into the polymeric microsphere system minimizes burst release and associated toxicity-related side effects. Thus, one of ordinary skill in the art would have had reasonable expectation to apply the fatty acid-containing polymeric microparticle system of Illum et al. to the controlled-release apixaban formulation of Nause in order to obtain a more controlled plasma exposure profile with reduced burst release and reduced undesirable side effects. Applicant’s assertion that Nause does not disclose direct contact between Apixaban and fatty acid does not overcome the rejection because the claimed arrangement results from the proposed modification using Illum et al. Once Apixaban and stearic acid or lauric acid are incorporated together in the dispersed polymer phase of a microsphere, interaction between the fatty acid and Apixaban would have been reasonably expected due to the formation of hydrogen bonding.
Regarding Nause and Illum et al., Applicant argues that Nause and Illum et al. have different release objectives because Nause aim for rapid release of Apixaban because Nause teaches releasing about 70% of Apixaban within 18 to 24 hours with the average rate of release of 2.9 to 35 wt% per hour and Illum et al. teach a linear release of a drug of less than 30 wt% within 24 hours. However, the argument is not persuasive. Nause is directed to controlled release Apixaban dosage forms and explicitly states that controlled release includes sustained release dosage forms. Nause further explains that Apixaban may be released slowly over time and that the time to release 70 wt% of Apixaban may be up to about 24 hours. Thus, Nause is not limited to rapid release formulations. Rather, Nause and Illum et al. are both concerned with controlled or sustained drug release. Accordingly, one of ordinary skill in the art would have recognized the polymeric microsphere and fatty acids teachings of Illum et al. as reasonably applicable to the Apixaban controlled release formulation of Nause.
Applicant further argues that it would not be easy for those skilled in the art to apply Illum et al. to Nause because Illum et al. do not disclose Apixaban and drug release behavior varies depending on the physical and chemical properties of the drug. However, the argument is not persuasive because the rejection relies on Nause for Apixaban and Illum et al. for the microsphere formulation features. A reference need not disclose every claim limitation when used in a combination rejection. Illum et al. teach fatty acid-containing polymeric microsphere drug delivery systems and Nause teaches Apixaban controlled/sustained release formulations. The combination is proper because both references address controlled drug delivery systems and one of ordinary skill would have had reason to apply the known microsphere excipient system of Illum et al. to the Apixaban formulation of Nause.
Regarding claim 15, Applicant argues that claim 15 is novel over the cited prior art because of the above arguments and Sah et al. do not remedy the deficiencies of Nause and Illum et al. The argument is not persuasive. The arguments over Nause and Illum et al. have been address above.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified 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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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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