DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 07 October 2025, in response to the Office Correspondence dated 07 April 2025, are acknowledged.
The listing of Claims filed 07 October 2025, have been examined. Claims 1, and 3-32 are pending. Claims 1, 3-6, 12-15, and 17-20 are amended and are supported by the originally-filed disclosure. Claim 2 is canceled and new claim 32 has been added.
Response to Amendment
The Applicant has amended claim 6 to remove “ovalbumin, collagen, gelatin, and protamine” from the serum albumin list. The amendment resolves the ambiguity regarding whether the recited species are “serum albumins.” Accordingly, the §112(b) rejection for claim 6 is withdrawn. The Applicant has corrected “a nanoparticle” to “the nanoparticle.” This corrects antecedent basis and as such the §112(b) rejection for claim 13 is withdrawn. The inclusion of the rejection of claim 15 in the §112(b) rejection was a typographical editing error and the §112(b) rejection for claim 15 is withdrawn.
The Applicant's amendments have cured the indefiniteness rejections. However, the claimed subject matter, as a whole, would have been obvious to a person of ordinary skill in the art at the time of the invention in view of the combined teachings of the cited prior art. The Applicant's arguments have been fully considered but they are not persuasive.
Claim 2 has been canceled, therefore the rejection of the claim is moot. The rejection of claims 1, 3-11 and 13 under 35 U.S.C. § 103 as being unpatentable over Cheng in view of Hanes is maintained. The rejection of claims 17-20 under 35 U.S.C. § 103 as being unpatentable over Cheng in view of Hanes and Han is maintained. The rejection of claims 26-31 under 35 U.S.C. § 103 as being unpatentable over Cheng in view of Hanes and Barnett is maintained.
Given the amendment of the dependency of claim 12 and the amendment to claim 14 to included newly cited limitations, from which claims 12, and 15-25 ultimately depend, the rejection of claims 12, 14-16, and 21-25 has been updated. The rejection of claims 12, 14-16, and 21-25 under 35 U.S.C. § 103 as being unpatentable over Cheng in view of Hanes is withdrawn and a new 35 U.S.C. § 103 rejection, necessitated by the amendment, has been made addressing the newly cited limitations as outlined below. A new rejection under 35 U.S.C. §103 has also been made for the newly added claim 32.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 07 April 2025, since the art which was previously cited continues to read on the amended/newly cited limitations.
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-AlA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AlA) 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:
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, 3-11 and 13 are rejected under 35 U.S.C. § 103 as being unpatentable over Cheng (CN108721250A; publication date: 02 November 2018) in view of Hanes (US20140329913A1; publication date: 06 November 2014).
Regarding instant claims 1, and 3-11, Cheng discloses a nanoparticle comprising bortezomib in the form of a bortezomib-tannic acid complex (claims 1, 4 and 5) in polyvinylpyrrolidone (PVP) polymer matrix. Cheng does not disclose encapsulation in a non-water-soluble polymer matrix.
Hanes teaches a therapeutic active agent encapsulation within a nanoparticle (paragraph [0132]) in a non-water-soluble polymer matrix as PLGA-PEG MPP (poly(lactic-co-glycolic acid)-polyethylene glycol-maleimide polypropylene glycol mucus-penetrating nanoparticles); paragraph [0147]) capable of encapsulating hydrophobic or hydrophilic drugs efficiently. Where PLGA is a biodegradable polyester, PEG is a block copolymer, and PLGA-PEG refers to the same di-block copolymer as PEG-b-PLGA.
Other biocompatible polymers used to prepare the nanoparticles (paragraph [0042]) include biodegradable polyesters poly(caprolactone) (PCL; paragraph [0044]), poly(D,L-lactide) (PDLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), and blends thereof (paragraph [0045]), and the polyether poly(ethylene glycol) (PEG; paragraph [0057]), and copolymers of the above, such as random, block, or graft copolymers, or blends of the polymers listed above can also be used (paragraph [0072]). Hanes further recites, “Copolymers of PEG or derivatives thereof with any of the polymers described above may be used to make the polymeric particles. In certain embodiments, the PEG or derivatives may be located in the interior positions of the copolymer. Alternatively, the PEG or derivatives may locate near or at the terminal positions of the copolymer. For example, one or more of the polymers above can be terminated with a block of polyethylene glycol. In some embodiments, the core polymer is a blend of pegylated polymer and non-pegylated polymer, wherein the base polymer is the same (e.g., PLGA and PLGA-PEG) or different (e.g., PLGA-PEG and PLA). In certain embodiments, the microparticles or nanoparticles are formed under conditions that allow regions of PEG to phase separate or otherwise locate to the surface of the particles. The surface-localized PEG regions alone may perform the function of, or include, the surface-altering agent. In particular embodiments, the particles are prepared from one or more polymers terminated with blocks of polyethylene glycol as the surface-altering material.” (paragraph [0074]). Moreover, “In one embodiment, the particles are coated with or contain polyethylene glycol (PEG). PEG can be applied as coating onto the surface of the particles. Alternatively, the PEG can be in the form of blocks covalently bound (e.g., in the interior or at one or both terminals) to the core polymer used to form the particles. In particular embodiments, the particles are formed from block copolymers containing PEG. In more particular embodiments, the particles are prepared from block copolymers containing PEG, wherein PEG is covalently bound to the terminal of the base polymer.” (paragraph [0086]).
Hanes also teaches nanoparticles containing therapeutic agent proteins or peptides (paragraph [0036]), targeting moiety proteins to aid in localization (paragraph [0038]), bovine serum albumin (BSA; paragraph [0147]), biocompatible polymers “used to prepare the nanoparticles” (paragraph [0042]) as a core polymer including proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate (paragraph [0076]). In addition, one or more surface-altering agents or materials including, but are not limited to, proteins, including anionic proteins (e.g., albumin) (paragraph [0084]). Serum albumin is the most known and widely used albumin species and would be a predictable selection from a very limited number of species options. Therefore, instant claims 5-6 are encompassed within the disclosure by Hanes. Of these proteins disclosed by Hanes, the molecular weight ranges for typical monomeric albumin is 66-69 kDa and more specifically BSA is 66.5 kDa, encompassing the instant claim 4 range. Further, while not explicitly stated, complexation via hydrogen bonding between polar groups (e.g., -OH, -NH2, COOH) of proteins such as albumin with boronic acid and tannic acid hydroxyl groups is expected to be the dominant interaction.
Hanes teaches that particles may be encapsulated therein, dispersed therein, and/or covalently or non-covalently associate with the surface one or more therapeutic agents including small molecule, protein, polysaccharide or saccharide, nucleic acid molecule and/or lipid (paragraph [0108]) and the agent to be delivered may be encapsulated within a nanoparticle and associated with the surface of the particle. Nutraceuticals can also be incorporated. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones (paragraph [0132]).
Encapsulation into a PLGA-PEG particle of the hydrophobic drug curcumin and hydrophilic protein BSA is taught (paragraph [0147]). Hanes discloses a nanoparticle composition containing PLGA-PEG and BSA in Example 3 of Specification (paragraph [0314]-[0318]), where the weight percent of the incorporated BSA in the nanoparticle was 16.7% (paragraph [0318]), and further in Table 7 with embodiments containing BSA with weight content in the nanoparticles (DL%) as 11.4 and 11.5% (paragraph [0318]), which are encompassed by the 5-20 w/w % range of instant claim 3. In addition, this example provides direct evidence that natural ingredients and proteins can be incorporated in the core of a nanoparticle coated with a polymer matrix (see also paragraph [0279]). The invention of Hanes explicitly particles may encapsulate one or more small molecule, protein, polysaccharide or saccharide, nucleic acid molecule and/or lipid (paragraph [0108]) and one or more core polymers and surface altering materials may be used (Abstract).
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teaching of the bortezomib-tannic acid complex nanoparticle by Cheng, replacing the PVP with the use of non-water-soluble polymer matrix encapsulation taught by Hanes to achieve a biodegradable nanoparticle, to improve biocompatibility and reduce potential long-term risks associated with polymer bio-persistence and accumulation in the body and add a serum albumin protein to the core complex as taught to be encapsulated by Hanes and used as a surface modification stabilizing protein within the concentration range taught by Hanes to achieve a more stable nanoparticle core, increase hydrophilicity and dispersion/enhance cellular uptake of the core, and optimize the nanoparticle to achieve a desirable bortezomib-tannic acid sustained release profile, with a reasonable expectation of success.
Regarding claim 13, Hanes discloses incorporation of one or more therapeutic agents in the nanoparticles (paragraph [0040], claim 17), wherein “The term “therapeutic agent” refers to an agent that can be administered to prevent or treat a disease or disorder.” (paragraph [0036]; see also paragraph [0037]) and as such would encompass the use of chemotherapeutic agents, used to treat cancer by targeting and kill cancer cells or inhibit their growth. Hanes specifically discloses therapeutic agents in more detail as, “Exemplary classes of small molecule therapeutic agents include, but are not limited to...anti-proliferatives, such as anti-cancer agent…” (paragraph [0110]), which can include chemotherapy agents.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teaching of the bortezomib-tannic acid complex nanoparticle by Cheng with the use of the PLGA-PEG polymer matrix nanoparticle comprising one or more anti-cancer therapeutic agents as taught by Hanes, such as chemotherapy agents, to enhance therapeutic efficacy with a reasonable expectation of success.
Claims 17-20 are rejected under 35 U.S.C. § 103 as being unpatentable over Cheng (CN108721250A; publication date: 02 November 2018) as applied to claim 14 above, and in view of Hanes (US20140329913A1; publication date: 06 November 2014) and Han (Han J, Zhu Z, Qian H, Wohl AR, Beaman CJ, Hoye TR, Macosko CW. A simple confined impingement jets mixer for flash nanoprecipitation. J Pharm Sci. 2012 Oct;101(10):4018-23; publication date 06 July 2012).
Regarding instant claims 17-20, Cheng disclose wherein the tannic acid and the bortezomib are mixed simultaneously as, “In another specific embodiment, in the dimethyl sulfoxide solution, bortezomib and tannic acid are mixed according to (1:1.443), and then respectively mixed with polyvinyl alcohol and polyoxyethylene polyoxypropylene ether block copolymer mixed aqueous solution to prepare the biocompatible boric acid nano drug complex of the present invention.” (page 3, paragraph 10), and where the complex and polymer are mixed in a solution comprising DMSO and 0% acetonitrile at a volume ratio of about 0 to about 1 as, “In a specific embodiment, in the organic solution dimethyl sulfoxide, bortezomib, tannic acid and polyvinylpyrrolidone are mixed according to a mass ratio of 1:1.476:1.754 to obtain a compound, and then the compound is added dropwise Add it into an aqueous solution, and drop it into a total volume of 168 microliters to obtain the biocompatible boric acid nano drug complex of the present invention.” (page 3, paragraph 9).
Cheng does not disclose wherein tannic acid and bortezomib are injected into a 2-inlet confined impinging jet (CIJ) mixer at a flow rate in the range of about 0.2-25 mL/min for mixing, explicitly specify the addition of protein, or mixing the protein complex and the non-water-soluble polymer by simultaneously injecting the BTZ/TA/protein complex and the non-water-soluble polymer into a 3-inlet CIJ mixer at a flow rate of about 0.1 to about 25 mL/min to form nanoparticles.
Hanes discloses adding a protein to the complex where “Examples of the surface-altering agents include, but are not limited to, proteins, including anionic proteins (e.g., albumin)…” (paragraph [0084]) and further as, “Examples of preferred natural polymers include proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate.” (paragraph [0076]).
Hanes describes the use of acetonitrile for nanoprecipitation of nanoparticles as, “PLGA45k-PEG5k solution in acetonitrile at concentration of 25 mg/ml was slowly injected into DI water under magnetic stirring (700 rpm).” (paragraph [0274]). Hanes teaches the use of DMSO as, “Suitable classes of penetration enhancers are known in the art and include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-methyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols).” (paragraph [0229]), where DMSO was also used in experimental procedure to dissolve nanoparticles as, “The encapsulation efficiency of curcumin in nanoparticles was measured by dissolving the freeze-dried nanoparticles in DMSO…” (paragraph [0324]).
Hanes does not disclose mixing the tannic acid and the bortezomib by simultaneously injecting into a 2-inlet confined impinging jet (CIJ) mixer at a flow rate in the range of about 0.2 to about 25 mL/min to form the BTZ/TA complex or wherein the BTZ/TA complex and the protein are mixed in an aqueous suspension by simultaneously injecting the BTZ/TA complex and the protein into a second 2-inlet CIJ mixer at a flow rate of about 0.2 to about 25 mL/min to form the protein complex or simultaneously injecting the BTZ/TA/protein complex and the non-water-soluble polymer into a 3-inlet CIJ mixer at a flow rate of about 0.1 to about 25 mL/min to form nanoparticles.
Han teaches the preparation of nanoparticles using a closed impinging jet (CIJ) mixer with 2-4 inlet jet streams, where flow rate of inlet streams is an experimental factor modified to vary nanoparticle size by varying the flow rate as, “Particle size was varied by varying the flow rate, Q.” (page 4, paragraph 3). Using the CIJ mixer with a 1 mm diameter tubing dimension where Reynolds number flow rate was varied from Re 0.5-5000 (page 12, Figure 5), which corresponds to a flow rate range of 0.0472-471.2 mL/min volumetric flow rates for 2-inlet jets and 0.0708-706.8 mL/min for 3-inlet jets, assuming an aqueous solution fluid density of water (1000 kg/m3) and fluid viscosity of water (0.001 Pa·s) (v = (Re * μ) / (ρ * D); ρ = density of the fluid (kg/m³), v = velocity of the fluid (m/s), D = diameter tubing (meters), μ = dynamic viscosity of the fluid (Pa·s); cross-sectional area of one inlet at 1 mm diameter = 7.854 x 10^-7 m2, volumetric flow rate for one inlet = v* cross-sectional area * 60,000,000 (conversion factor m3/s to mL/min), total volumetric flow rate (mL/min) = one inlet x total number of inlets). Thus, the instant claim range flow rate of about 0.2-25 mL/min for a 2-inlet jets and about 0.1-25 mL/min for a 3-inlet jets is within the range disclosed by Han. Further, Han illustrates that varying CIJ mixer flow rates is known in the art as an experimental factor that is modified to produce optimal particle size of nanoparticles.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of Cheng and Hanes, adding the protein to improve drug transport and delivery, with modifying the concentration ranges of composition components as a matter of routine experimentation to optimize nanoparticle production. In addition, it would have also been obvious to change the type of mixing/mixer used and modify the flow rate as a matter of routine nanoparticle fabrication experimentation practices as taught by Han, which moreover encompasses the instant claimed ranges, to arrive at the desired nanoparticle size.
Claims 26-31 are rejected under 35 U.S.C. § 103 as being unpatentable over Cheng (CN108721250A; publication date: 02 November 2018) in view of Hanes (US20140329913A1; publication date: 06 November 2014) and Barnett (US20100080788A1; publication date: 01 April 2010).
Regarding instant claims 26-31, Cheng discloses use of the nanoparticle as a method of treating cancer as, “In the preparation method of the complex of the present invention…boric acid anticancer drugs can be delivered to the tumor efficiently and safely, and at the same time, the good biological phase of natural polyphenols is used capacitance, to ensure the safety of nano-drugs, using the anti-tumor, anti-inflammatory, anti-oxidation and other effects of natural polyphenols and the stabilizing effect of polymer compounds, can give full play to the role of this nano-drug in the treatment of tumors and other related diseases. The preparation method of the complex of the present invention can be used as a reference strategy for the preparation of anticancer drug delivery with the advantages of high efficiency, low toxicity, and low cost.” (page 3, paragraph 14 and Example 2). Cheng does not disclose wherein the cancer is liver cancer or nanoparticle delivery by intratumor injection.
Barnett discloses a nanoparticle to treat liver cancer as, “In a particular embodiment of the method, the alginate based biomaterial comprises one or more anti-cancer agents.” (paragraph [0017]) and “In another embodiment, the targeted area is selected from the group consisting of: liver…” (paragraph [0051]) by intratumor injection as, “Accordingly, the present invention relates to the targeted intratumoral delivery...” (paragraph [0218]).
Barnett further teaches blocking tumor blood vessels feeding the cancer, which include arteries, or transarterial embolization as, “In a further embodiment the methods of the invention are used to embolize the tumors.” (paragraph [0217]) related to targeted intratumor injection delivery (paragraph [0218]). Where, “The term “embolism” is meant to refer to a blockage or clot. An embolism can be the result of a blockage caused by an alginate based biomaterial.” (paragraph [0138]), which would inherently achieve a local retention and release of bortezomib due to the blockage of circulating blood flow to clear and further distribute the active drug more widely from the localized area. Intravascular arterial delivery is specifically described in In Vivo Experiment #1 (paragraph [0341]) and delivery of one or more nanoparticles are delivered by catheter as, “In one embodiment, the device is a syringe, a microcatheter, a bronchoscope and an endoscope a syringe.” (paragraph [0078]).
Cheng and Hanes render the nanoparticle of instant claim 1 obvious for the treatment of cancer. Barnett specifically teaches treating liver cancer by intratumoral injection and transarterial embolization of a nanoparticle to achieve local retention and release of a chemotherapeutic agent. Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of Cheng nanoparticle for the use in treating cancer, as modified by teachings of Hanes (the nanoparticle of instant claim 1), with that of Barnett, for use more specifically in treating liver cancer via catheter-based intratumor and intravascular injection for transarterial embolization, resulting in local retention and release of bortezomib as a site-specific anti-cancer therapy for localized treatment method for liver cancer. A person of ordinary skill, seeking to apply the improved but obvious BTZ nanoparticle of Cheng/Hanes to the treatment of liver cancer, would have been motivated by Barnett to administer it using the established and advantageous localized delivery techniques of intratumoral injection and embolization for tumor site-specific treatment, rather than systemic treatment, thereby reducing the side effects of treatment, with a reasonable expectation of success.
New Rejections
The following new rejections are made from the previous Office Correspondence dated 07 April 2025, as the Applicant's amendment to the claims and the newly added claim necessitated the new grounds of rejection presented below.
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-AlIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AlA) 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:
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 12, 14-16 and 21-25 are rejected under 35 U.S.C. § 103 as being unpatentable over Cheng (CN108721250A; publication date: 02 November 2018) in view of Hanes (US20140329913A1; publication date: 06 November 2014) and Han (Han J, Zhu Z, Qian H, Wohl AR, Beaman CJ, Hoye TR, Macosko CW. A simple confined impingement jets mixer for flash nanoprecipitation. J Pharm Sci. 2012 Oct;101(10):4018-23; publication date 06 July 2012).
Regarding instant claims 14-16 and 21-25, Cheng discloses a method for making a nanoparticle comprising mixing bortezomib and tannic acid simultaneously to form a complex as, “The present invention also proposes a method for preparing a biocompatible boric acid nano drug complex, which includes the following steps: in an organic solvent, first mix boric acid drugs and natural polyphenols to obtain boric acid drugs and natural polyphenols compound, and then mix the complex obtained above with a high molecular compound [polymer PVP, PVA, F127 or PEO of a molecular weight between 10,000-360,000] to obtain the biocompatible boric acid nano drug complex containing boric acid drugs, natural polyphenols and high molecular compounds.” (page 3, paragraph 3) and “In another specific embodiment, in the dimethyl sulfoxide solution, bortezomib and tannic acid are mixed according to (1:1.443), and then respectively mixed with polyvinyl alcohol and polyoxyethylene polyoxypropylene ether block copolymer mixed aqueous solution to prepare the biocompatible boric acid nano drug complex of the present invention.” (page 3, paragraph 10), and where the complex and polymer are mixed in a solution comprising DMSO and 0% acetonitrile at a volume ratio of about 0 to about 1 as, “In a specific embodiment, in the organic solution dimethyl sulfoxide, bortezomib, tannic acid and polyvinylpyrrolidone are mixed according to a mass ratio of 1:1.476:1.754 to obtain a compound, and then the compound is added dropwise Add it into an aqueous solution, and drop it into a total volume of 168 microliters to obtain the biocompatible boric acid nano drug complex of the present invention.” (page 3, paragraph 9).
Additionally, Cheng teaches nanoparticle preparation with the mass ratio of: 1 bortezomib (boric acid drug): 0.696-1.476 tannic acid (natural polyphenol): 1.248-1.754 polymer (PVP); 1 bortezomib (boric acid drug): 0.880-1.443 tannic acid (natural polyphenol): 1.248-1.754 polymer (PVA); and 1 bortezomib (boric acid drug): 0.880-1.443 tannic acid (natural polyphenol): 0.997-2.540 polymer (F127). Further, one embodiment has a mass ratio of 1 bortezomib: 1.476 tannic acid: 1.754 polymer (PVP) and the next embodiment presented 1 bortezomib: 1.443 tannic acid (page 3, paragraphs 2-3 and 6-10). Thus, showing that the concentration range of tannic acid used for nanoparticle preparation constitutes a component modified by routine experimentation to arrive at optimal formulations.
Cheng does not describe wherein the BTZ and TA are mixed by simultaneously injecting the BTZ (2-10% DMSO/80-95% water with or without up to 10% acetonitrile) and TA (1-20 mg/mL aqueous solution) into a 2-inlet confined impinging jet (CIJ) mixer to form the BTZ/TA complex, mixing protein(s)/peptide(s) (e.g., albumin) in an aqueous suspension as in step (b) with that complex from step (a) by simultaneously injecting the BTZ/TA complex and protein(s)/peptide(s) into a second 2-inlet CIJ mixer to form the BTZ/TA complex to form the BTZ/TA/protein(s) or peptide(s) complex, nor the use of a non-water-soluble polymer as in step (c) mixed with the complex formed by step (b) by simultaneously injecting the BTZ/TA/protein(s) or peptide(s) complex and the non-water-soluble polymer into a 3-inlet CIJ mixer, to form a nanoparticle wherein the bortezomib is released in vitro from the nanoparticle from about 2-60 days. A DMSO/acetonitrile mixture at a volume ratio of about 0 to about 1, reads on the use of no DMSO/acetonitrile or a ratio from about >0-1, therefore the inclusion as the instant claim is written is not required.
Hanes teaches a therapeutic active agent encapsulation within a nanoparticle (paragraph [0132]) in a non-water-soluble polymer matrix as PLGA-PEG MPP (poly(lactic-co-glycolic acid)-polyethylene glycol-maleimide polypropylene glycol mucus-penetrating nanoparticles); paragraph [0147]) capable of encapsulating hydrophobic or hydrophilic drugs efficiently. Where PLGA is a biodegradable polyester, PEG is a block copolymer, and PLGA-PEG refers to the same di-block copolymer as PEG-b-PLGA and the nanoparticle comprises the addition of a protein to form a protein complex (i.e., albumin; paragraph [0084]). Hanes discloses adding a protein to the complex where “Examples of the surface-altering agents include, but are not limited to, proteins, including anionic proteins (e.g., albumin)…” (paragraph [0084]) and further as, “Examples of preferred natural polymers include proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate.” (paragraph [0076]).
Hanes, in an example, uses BSA as a representative hydrophilic molecule in preparing nanoparticles, where tannic acid is also hydrophilic, and teaches dissolving BSA in 0.2 mL 16% w/v aqueous solution (paragraph [0316]). Using the emulsification nanoparticle preparation steps outlined in paragraph [0316] the hydrophilic molecule concentration range would start at 160 mg/mL and end at 0.693 mg/mL, encompassing the concentration range of the instant claim for using hydrophilic tannic acid in the preparation of nanoparticles (where 16% w/v is 160 mg/mL, where the total solution is 0.2 mL therefore the total BSA content is 32 mg (160 mg/mL x 0.2 mL). Subsequently for the primary emulsion the 0.2 mL of BSA is added to 1 mL of PLGA-PEG5k in DCM solution, therefore the BSA concentration for the primary emulsion is 26.67 mg/mL (32 mg / 1.2 mL). The primary emulsion is then added to 5 mL of 1% saponin solution resulting in a BSA concentration of 5.16 mg/mL (32 mg / 6.2 mL) for the double emulsion. A final dilution of the double emulsion was made by transferring it to 40 mL of a 1% saponin solution to give a final dilution concentration of 0.693 mg/mL (32 mg / 46.2 mL) BSA.
Hanes teaches “In a particular embodiment, the nanoparticles are prepared using an emulsification in method. In general, the particles are prepared by either o/w single emulsion or w/o/w double emulsion method as described in R. C. Mundargi et al, J. Control. Release 125, 193 (2008), M. Li et al., Int. J. Pharm. 363, 26 (2008), C. E. Astete and C. M. Sabliov, J. Biomater. Sci. Polymer Ed. 17, 247 (2006), and R. A. Jain, Biomaterials, 21, 2475 (2000). In this procedure, the polymer is dissolved in an organic solvent, such as dichloromethane, to form an oil phase.” (paragraph [0273]).
Hanes describes the use of acetonitrile for nanoprecipitation of nanoparticles as, “PLGA45k-PEG5k solution in acetonitrile at concentration of 25 mg/ml was slowly injected into DI water under magnetic stirring (700 rpm).” (paragraph [0274]). Hanes teaches the use of DMSO as, “Suitable classes of penetration enhancers are known in the art and include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-methyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols).” (paragraph [0229]), where DMSO was also used in experimental procedure to dissolve nanoparticles as, “The encapsulation efficiency of curcumin in nanoparticles was measured by dissolving the freeze-dried nanoparticles in DMSO…” (paragraph [0324]).
Hanes does not explicitly disclose mixing the tannic acid and the bortezomib by simultaneously injecting into a 2-inlet confined impinging jet (CIJ) mixer, wherein the BTZ/TA complex and the protein are mixed by simultaneously injecting the BTZ/TA complex and the protein into a second 2-inlet CIJ mixer, or simultaneously injecting the BTZ/TA/protein complex and the non-water-soluble polymer into a 3-inlet CIJ mixer to form a nanoparticle wherein the bortezomib is released in vitro from the nanoparticle from about 2-60 days.
Han teaches the preparation of nanoparticles using a closed impinging jet (CIJ) mixer with 2-4 inlet jet streams for mixing aqueous solutions/suspensions, where flow rate of inlet streams is an experimental factor modified to vary nanoparticle size by varying the flow rate (page 4, paragraph 3, see also as described above). Han illustrates using varying inlet jet streams for mixing using a CIJ mixer and varying flow rates is known in the art as an experimental factor that is modified to produce optimal particle size of nanoparticles.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of Cheng and Hanes and arrive at the instant claimed bortezomib-tannic acid complex nanoparticle taught by Cheng, and replacing the water soluble PVP polymer with the use of non-water-soluble polymer matrix encapsulation and adding albumin to the core complex as taught by Hanes, achieving the tannic acid concentration range through routine experimentation, as it is known that hydrophilic active ingredients and more specifically tannic acid concentration is a factor modified in the method of making nanoparticles to arrive at an optimal composition, and a method of making nanoparticles comprising the use of bortezomib in a solution comprising 0-10% acetonitrile, 2-10% dimethyl sulfoxide and 80-96% water. The use of these percent concentration ranges, in the absence of unexpected results, would be a matter of routine experimentation in methods of making nanoparticles. One would be motivated to make changes to the concentrations and ratios to that of the instant claim to optimize the nanoparticles produced by the method of making to optimize the nanoparticles to achieve the most desirable stability and release profile, with a reasonable expectation of success. “Where 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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Variations are predictable to one of ordinary skill in the art.
It would have been obvious to one of ordinary skill to utilize the CIJ mixing techniques of Han, a known and efficient method for nanoparticle formation, to manufacture the obvious nanoparticle formulation from Cheng and Hanes. The specific sequential steps and flow rates represent routine process optimization to control the assembly of the obvious components. The specific use of the instant claimed closed impinging jet (CIJ) mixer and inlet jet streams is routine in the art of nanoparticle production as evidence by Han. It would have also been obvious to change the type of mixing/mixer used in the inventions of Cheng and Hanes and modify the flow rate as a matter of routine nanoparticle fabrication experimentation practices (as taught by Han), to arrive at the desired nanoparticle of the instant invention. Combining the prior art elements according to known methods or known techniques to improve nanoparticle production in the same way to yield predictable results is obvious. The selection of the performance of the specific instant claimed process steps is prima facie obvious in the absence of new or unexpected results (see In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)).
Regarding the further limitation of instant claim 12, Cheng discloses the in vitro release profile of bortezomib from the bortezomib-tannic acid PVP polymer matrix nanoparticle under different pH values as Specification Example 3 embodiment, detected by high performance liquid chromatography (page 4, Example 3) with drawing of release curve (Drawings, Figure 5), where under normal physiological conditions (pH=7.4), drug release microenvironment (pH=6.5) and tumor cells/endosomes conditions (pH=5.0), the release of bortezomib was stable and sustained after ≤6 hours for up to 2 days (24 hours). However, bortezomib release from the nanoparticles was not provided for time periods beyond 2 days.
Hanes teaches encapsulation of one or more active agent in the composition of the nanoparticles to allow for sustained release of the agent per desired application (paragraph [0040]) with an embodiment of the nanoparticle using delayed release dosage formulations of a 45 kDa PLGA having lactic acid to glycolic acid ratio of 50:50, 6 wt % 5 kDa PEG, a nanoparticle size range of 100-500 nm (Specification, Detailed Description of the Invention, Examples section- summarized example embodiments). Based on the details disclosed by Hanes and typical behavior of PLGA-based nanoparticles, the nanoparticles will likely have a biphasic drug release in vitro with ~20-30% of the drug being released within the first 1-2 days and the remaining drug released over a period of ~10-60 days, with the smaller nanoparticle sizes in the range having faster release times and the larger, slower release times. Thus, using bortezomib as the active agent in the nanoparticle taught by Hanes including an albumin protein complex, bortezomib release from the nanoparticle in vitro would be expected to be encompassed in over a period of time ranging from the instant claim range of about 2 to about 60 days. Mixing the BTZ/TA/protein complex or the BTZ/TA/protein complex and the non-water-soluble polymer in a 3-inlet CIJ mixer at a flow rate of about 0.1 to about 25 mL/min is not expected to alter the release time, in the absence of evidence from the Applicant to the contrary.
Further, Hanes teaches “Delayed release dosage formulations may be prepared as described in standard references such as “Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), “Remington—The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6th Edition, Ansel et al., (Media, PA: Williams and Wilkins, 1995). These references provide information on excipients, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.” (paragraph [0253]), where it is known in the art that a drug release profile can be tuned as a matter of routine experimentation by adjusting the molecular weight and composition of PEG and PLGA, as well as by adjustments to the PLGA lactic acid to glycolic acid ratios, and nanoparticle size range adjustments. Therefore, modifying the time range of bortezomib release from the nanoparticle to arrive at the instant claim range would also be a matter of routine experimentation.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teaching of the bortezomib-tannic acid complex nanoparticle by Cheng with the use of the tunable drug release PLGA-PEG polymer matrix nanoparticle with albumin taught by Hanes, incorporating routine experimentational modifications known in the art, if required, to achieve the optimal nanoparticle desired bortezomib-tannic acid sustained release profile of the instant claim, and improve biocompatibility with the use the biodegradable PLGA-PEG polymer and reduce potential long-term risks associated with PVP polymer bio-persistence and accumulation in the body, with a reasonable expectation of success.
Claim 32 is rejected under 35 U.S.C. § 103 as being unpatentable over Cheng (CN108721250A; publication date: 02 November 2018) in view of Hanes (US20140329913A1; publication date: 06 November 2014).
Claim 1 is previously rejected under 35 U.S.C. § 103 as being unpatentable over Cheng in view of Hanes as described above.
Further, Hanes teaches the use of wherein the one or more proteins or peptides are selected from ovalbumin (¶[0279]), collagen, gelatin, and protamine (¶[0076]). Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teaching of the bortezomib-tannic acid complex nanoparticle by Cheng with the use of surface-altering stabilization proteins or peptides, including ovalbumin, collagen, gelatin, and protamine, as taught by Hanes to achieve a more stable nanoparticle.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 07 October 2025, have been fully considered. The Applicant's arguments are not persuasive for the reasons outlined below.
The Applicant's arguments center on the assertion that the cited prior art does not teach or suggest a nanoparticle with the specific "core-shell" structure or the specific three-step CIJ mixing process now claimed. The Examiner acknowledges that the cited references do not explicitly disclose the exact final structure or process as claimed. However, for a prima facie case of obviousness, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference, nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art (see In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The prior art need not suggest the precise claimed invention, but rather must provide a motivation to combine its teachings to arrive at the claimed invention with a reasonable expectation of success (see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007)).
Regarding the rejection of claims 1-13 and 32 under 35 U.S.C. § 103 (Cheng in view of Hanes) the Applicant argues that Cheng does not disclose a core comprising a complex of TA, BTZ, and one or more proteins or peptides, nor a coating of a non-water-soluble polymer matrix. The Examiner maintains that it would have been obvious to one of ordinary skill to modify Cheng with the teachings of Hanes to arrive at the claimed invention. Cheng discloses BTZ–TA complexes in polymer matrices. Hanes teaches protein-complexing nanoparticles, including albumin and other proteins, teaches combining protein complexes with polymers, and suggests performance-modifying shell coatings. One skilled in the art would be motivated to add proteins or peptides (as taught by Hanes) to improve stability, drug loading, dispersibility or release characteristics by incorporation into the BTZ–TA complex of Cheng and use coating comprising a non-water-soluble polymer matrix taught by Hanes.
The formation of a complex between the protein and the pre-formed BTZ/TA complex via hydrogen bonding and other non-covalent interactions is the natural and expected result of such a combination, leading to the claimed "core" structure. Hanes further provides specific examples with BSA incorporated into PLGA-PEG nanoparticles at weight percentages (11.4%, 11.5%, 16.7%) falling within the claimed 5-20 w/w% range. Hanes teaches that biodegradable, non-water-soluble polymers like PLGA and its PEG block copolymers (e.g., PLGA-PEG, i.e., PEG-b-PLGA) are superior for creating nanoparticles with tunable, sustained drug release profiles and improved biocompatibility. Replacing Cheng's water-soluble PVP with Hanes well-known, biodegradable, non-water-soluble polymer matrix (e.g., PLGA-PEG) to achieve a more desirable, sustained release profile and to avoid potential bio-persistence issues would have been a predictable and obvious design choice. The result is a nanoparticle with a core (BTZ/TA/protein) encapsulated within a shell of a non-water-soluble polymer, i.e., the core-shell structure. The combination of Cheng and Hanes provides a clear motivation to create a stable, biodegradable nanoparticle for sustained release of BTZ, arriving at the product of claim 1. Dependent claims 3-13 and 32 merely recite optimization parameters (concentrations, specific proteins, specific polymers) that are either explicitly disclosed in Hanes or would have been arrived at through routine experimentation (see In re Aller, 220 F.2d 454, 456 (CCPA 1955)).
The Applicant’s argument of “core-shell structure” is insufficient to establish nonobviousness because Cheng already shows PVP embedding of BTZ–TA aggregate structures, Hanes teaches core polymer/protein layers, and core-shell architectures are routine in drug-delivery nanoparticle art, thus, the claims remain obvious.
Regarding the rejection of claims 14-25 under 35 U.S.C. § 103 over Cheng in view of Hanes and in further view of Han, the Applicant argues that Han does not teach sequential 2-inlet / 2-inlet / 3-inlet CIJ use. However, Han teaches general CIJ principles, variable inlet numbers (2–4 inlets), altering inlet numbers to control mixing speed, supersaturation, and particle morphology and multiple CIJ stages for sequential complexes were known in FNP literature (e.g., Han’s Figure 1 and text describing staged addition). The claimed flow rates fall squarely within the operational range demonstrated by Han.
As established above, the composition produced by the process of claim 14, a nanoparticle with a BTZ/TA/protein core and a non-water-soluble polymer shell, is itself obvious over Cheng and Hanes. Han teaches that CIJ mixers are effective tools for flash nanoprecipitation to form nanoparticles and that process parameters can be adjusted. The claimed sequential steps—first forming the BTZ/TA complex, then adding the protein, and finally adding the polymer—logically follow from the components being combined. One skilled in the art, familiar with the principles of complex formation and encapsulation, would understand that sequential addition can help control assembly and would be motivated to use the efficient CIJ mixing technique taught by Han to carry out these steps. The use of specific solvent mixtures (aqueous suspension, DMSO/acetonitrile) is a matter of routine formulation, as both Hanes and Cheng teach the use of such solvents in nanoparticle preparation.
Therefore, while the cited art does not spell out the exact three-step CIJ process, it would have been obvious to a skilled artisan to use this known, high-throughput mixing technique to manufacture the obvious nanoparticle formulation in a controlled manner. The claimed process yields no unexpected results, only the expected product. Dependent claims 15-25 add no non-obvious limitation, as they recite concentrations, specific proteins, and specific polymers that are either disclosed in the prior art or are products of routine optimization. Further, Applicant has not provided evidence that the ordered sequence of mixing steps is critical, and unexpected results flow from using 2-inlet then 2-inlet then 3-inlet mixers. Without evidence of criticality, choosing inlet numbers and staging is a routine optimization, and optimization of mixing steps is well within the skill of an ordinary artisan, thus, claims 14–25 remain obvious.
Regarding the rejection of claims 26-31 under 35 U.S.C. § 103 over Cheng in view of Hanes and in further view of Barnett, Cheng teaches BTZ–TA nanoparticles, Hanes teaches polymer-coated nanoparticles with controlled release and Barnett teaches tumor-localized intratumor injection of nanoparticles, including polymeric nanoparticles, for controlled release. The Applicant argu