DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/29/2026 has been entered.
Response to Amendment
Applicant’s response of 01/29/2026 has been received and entered into the application file. Claims 1, 4, and 7-15 are pending in this application.
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.
Claims 1, 4, and 7-15 are rejected under 35 U.S.C. 103 as being unpatentable over Na et al (WO 2018/218208 A1), Bitar et al. (US 2022/0249374 A1, Priority: 05/23/2019), Porcu et al. (Engineered polymeric microspheres obtained by multi-step method as potential systems for transarterial embolization and intraoperative imaging of HCC: Preliminary evaluation, European Journal of Pharmaceutics and Biopharmaceutics, 2017), Song et al. (Preparation and Evaluation of Liposomes Co-Loaded with Doxorubicin Phospholipase D Inhibitor 5-fluoro-2-Indolyl Deschlorohalopemide (FIPI) and D-Alpha Tocopheryl Acid Succinate (α-TOS) for Anti-Metastasis, Nanoscale Research Letters, April 2019), and Drobnik et al. (US 2021/0177997 A1, Filed 05/17/2019, Provisional priority May 2018), further evidenced by Pilch et al. (Liposomes with an Ethanol Fraction as an Application for Drug Delivery, Molecular Sciences, 2018).
Na discloses a chemoembolization therapy, which combines therapeutic effects of peripheral arterial occlusion with the local administration of an anti-cancer agent. The anti-angiogenic agent is an anti-cancer drug (Abstract). Na discloses the microbead can be made from biodegradable polymer such as polyvinyl alcohol ([0041]). A drug-loaded microsphere (or microbead) comprises vesicular agents, the vesicular agent affixed to or attached to the microsphere through ionic or other non-covalent interactions, and the vesicular agent being a liposome, a therapeutic agent contained within the vesicular agent; anti-cancer agent being sorafenib ([0006]). In some embodiments, the microsphere further includes a non-encapsulated therapeutic agent affixed to or attached to the microsphere ([0009]). Na discloses a microbead comprising two therapeutic agents within a liposome (See Figure 2). Na discloses a second therapeutic agent not contained within the individual vesicular agent (See figure 7). Na teaches anti-cancer agents to be doxorubicin, paclitaxel, cisplatin, bevacizumab, idarubicin and others ([0054]). Na discloses liposomes comprising DOPS, DOPE ([0060]).
Na does not explicitly mention a second therapeutic agent contained within the lipid bilayer of the individual vesicular agents.
Bitar teaches methods of producing alginate microspheres that contain liposomes encapsulating chemotherapeutics such as doxorubicin (Abstract). Liposomes comprising phospholipids and/or sphingolipids may be used to deliver hydrophilic therapeutic compounds encapsulated within the inner liposomal volume and/or to deliver hydrophobic therapeutic agents dispersed within the hydrophobic bilayer membrane ([0013]).
Above references do not explicitly teach biodegradable material to be a modified cellulose such as cellulose acetate butyrate (CAB).
Porcu teaches a novel microspheres as embolic agent for transarterial embolization. Biocompatible indocyanine green (ICG)-loaded microspheres (CAB-CS-ICG) were prepared using a multi-step method. Chitosan-ICG particles were prepared via spray-dryer and then loaded into CAB microspheres (Abstract). CAB was chosen to form microsphere matrix due to its biocompatibility (pg 161, left col, last paragraph).
Above references do not explicitly mention three therapeutic agents within liposomes.
Song discloses a novel liposome delivery system co-loading a specific PLD inhibitor 5-fluoro-2-indolyldes-chlorohalopemide (FIPI) in combination with antitumor drug doxorubicin (DOX) and functional excipient D-alpha tocopheryl acid succinate (α-TOS) for anti-metastasis. The liposomes containing three components with different physicochemical properties were successfully prepared. The liposomes showed uniform particle size, high drug encapsulation efficiency, slow-release characteristics and stability (Abstract). At first, based on different physicochemical properties of DOX, FIPI, and α-TOS, liposomes were prepared using film dispersion method, which encapsulated drug via pH-gradient method; α-TOS, a lipophilic, and amphiphilic ingredient was incorporated into the lipid bilayer when the lipid membrane was hydrated, while DOX and FIPI as weakly basic drugs penetrated the inner aqueous phase of liposomes through active pH-gradient encapsulation to achieve high drug loading (pg 7, Discussion section). One of ordinary skill in the art would immediately envisage that lipophilic drugs can be incorporated into the lipid bilayer while hydrophilic drugs can be incorporated into the core.
Above references do not explicitly mention the limitation of “wherein the drug-loaded microbead composition comprises a water content of less than 1%”. However, the above references also do not explicitly mention the compositions comprising a water content of more than 1%.
Drobnik discloses that the microspheres can include water. In example embodiments, the microspheres may have a low water content such as less than 1% by weight, or less than 0.5% by weight, or less than 0.1% by weight, or less than 0.05% by weight, or even less than 0.001% by weight. It is believed that a low water content of the microbead increases the shelf-life and long-term stability of the microbead. A water content greater than 1% by weight based on the total weight of the microbead, may lead to decomposition or hydrolysis of the therapeutic agent ([0039]).
Na teaches drug-loaded microbead comprising biodegradable polymer, vesicular agents contained within microbeads, a first/second therapeutic agent. Bitar teaches that a hydrophilic and hydrophobic agents can be contained within a liposome. Porcu teaches that the microspheres can be constructed from cellulose acetate butyrate given its favorable biocompatibility. Song discloses that 3 drugs can be contained within liposomes. Drobnik teaches that lower water content of microbead is important for long-term stability. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at the present invention. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 4, hydrophilic and hydrophobic is discussed above.
Regarding claim 7, Na discloses a second therapeutic agent not contained within the individual vesicular agent (See figure 7).
Regarding claims 8-10, Porcu discloses the polymeric microparticles, as well as other embolic agents, can generate a permanent or temporary occlusion, depending on their biocompatible composition. For their fabrication, natural polymers, such as gelatin, starch and chitosan and synthetic polymers such as polylactic-co-glycolic acid have been used (pg 161, left col, 1st paragraph). Porcu teaching cellulose as the material is discussed above.
Regarding claim 11, Bitar teaches that other suitable lipids include glycolipids, sphingolipids, ether lipids, glycolipids. Additional lipids suitable for use in liposomes are known to persons of skill in the art ([0062]).
Regarding claim 12, The drug-loaded microbead comprising liposomes, first and second therapeutic agents either contained or not contained within the individual vesicular agent and associated by ionic or non-covalent interaction and the biodegradable material being cellulose is discussed and taught in combination of teachings above.
Regarding claim 13, therapeutic agents sorafenib and doxorubicin are discussed above.
Regarding claim 14, one of ordinary skill in the art would be motivated to experiment with either liposomes or ethosomes. As evidenced by Pilch, Pilch discloses that liposomes containing a certain amount of ethanol are often referred to as ethosomes. Ethosomes are defined as lipid drug carriers composed of phospholipids, ethanol, and water (Introduction).
Regarding claim 15, DOPS and DOPE are discussed above. Bitar discloses phospholipids such as phosphatidylcholine ([0054]).
Response to Arguments
Applicant’s arguments filed 01/29/2026 have been fully considered and a new reference is added to maintain the rejection.
The examiner thanks the applicants for continuing to amend the claims. In particular, the examiner cannot determine if a water content of less than 1% in a drug-loaded microbead is unexpectedly significant compared to what is practiced within the art.
Therefore, claims remain rejected.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615