DETAILED ACTION
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 .
Acknowledgement of Receipt
Applicant’s Response, filed 12/5/2025, in reply to the Office Action mailed 9/11/2025, is acknowledged and has been entered. Claims 1, 8, 14, 16, 18 and19 have been amended. Claims 1, 3-10, 14 and 16-20 are pending and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterate herein has been withdrawn. Applicant’s arguments that the cited art does not disclose the claim the elements of claim 1 as amended have been fully considered and are persuasive. New grounds of rejection are set forth herein.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-10, 14 and 16-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites the limitation "the liposome" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claims 4 and 6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite the limitation "the drug containing solution.” There is insufficient antecedent basis for this limitation in the claim.
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.
Claim(s) 1, 4-7, 9-10, 14, 16-17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Starmans et al. (PLOS One, 2013, 8(2), p. e57335) in view of Lee (CA 3134257) and de Menezes (Cancer Res., 1998, 58, 3320-30), in further view of Namiki (JP 2010053113).
The instant claims are directed to a method of producing magnetic micelle aggregates comprising the steps of: combining oleic acid coated magnetic nanoparticle with lipids to create a hydrophobic mixture including lipids and the uniform oleic acid coated magnetic nanoparticles, infusing the hydrophobic mixture in chloroform into a hydrophilic drug-containing aqueous phase under ultrasonication, and using functionalized lipids and Cu-free click chemistry for directional conjugation of a targeted antibody to the liposome, wherein the directional conjugation comprises mildly oxidizing the Fc portion of the targeting antibody with sodium periodate.
Starmans teaches iron oxide nanoparticle-micelles (ION-Micelles) for sensitive (molecular) magnetic particle imaging and magnetic resonance imaging.
IONs were obtained through a method based on thermal decomposition of FeO(OH) in the presence of oleic acid.
IONs were phase-transferred by encapsulation of IONs into lipidic micelles according to a similar procedure used to phase transfer quantum dots. In a typical phase-transfer procedure, PEG2000-DSPE (0.20 g, 71.3 mmol) was dissolved in 4 mL chloroform and 1 mL IONs in hexane (6 mg Fe) was added. A 40-fold excess of lipids required to entirely cover the surface of all IONs with a lipid monolayer was used. This suspension was injected into stirred, deionized water at 80 C with an injection-speed of 6 mL/hr. Upon evaporation of the organic solvents, the IONs were encapsulated in the core of phospholipidic micelles, creating iron oxide nanoparticles-micelles (ION-Micelles).
Figure 4A–B shows typical high-resolution cryo-TEM images of ION-Micelles. The ION-Micelles were mostly dispersed in HBS as single particles or as small aggregates of nanoparticles. Occasionally, also larger, worm-like aggregates were observed (Figure 4C). Other lipidic structures, such as liposomes and (empty) micelles, were not observed (page 4).
Starmans does not specifically teach wherein the aqueous solution comprises a hydrophilic drug and wherein the chloroform/aqueous solution is sonicated, as well as conjugation of an antibody comprising mildly oxidizing the Fc portion of the targeting antibody with sodium periodate.
Lee teaches ultrafine iron oxide nanoparticles that are prepared based on a combination of a technique for uniform core synthesis and a technique for surface hydrophilization and have a uniform contrast effect while maintaining their uniform size in vivo, thus being suitable for use in the production of Ti contrast agents that have the potential to replace conventional gadolinium-based contrast agents.
In Example 1, iron oxide nanoparticles comprising oleic acid are taught. In Example 2, the nanoparticles were hydrophilized with the 5-10% (v/v) micelle solution and were uniformly dispersed using a sonicator (Ultra-sonicator). When 100 mg (5 mL) of the 3 nm nanoparticles were dispersed in chloroform to a concentration of 20 mg/mL, added to 40 mL of the 10% (v/v) micelle solution, and sonicated at 60 C for 10 min, the opaque brown (latte color) suspension became clear and turned transparent brown (americano color). At that time, the solution where the reaction was taking place was placed on a stirrer at 60 C, followed by stirring for additional 10 min to completely remove the possibly remaining organic solvent.
Example 3 shows surface modification of the hydrophilized ultrafine iron oxide nanoparticles with click compound. In this example, the hydrophilized ultrafine iron oxide nanoparticles were surface modified with a click compound (DBCO). 1-10 mol% DSPE-PEG2000-DBCO was used for functionalization and surface modification with a click compound and encapsulation with micelles (pages 16-21).
Further, binding a functionalizing material containing a click reactive moiety to the surface of the core particles to modify the surface of the core particles is taught, including disease targeting agents (claims 10, 21).
de Menezes teaches the ability to selectively target liposomal anticancer drugs via specific ligands against antigens expressed on malignant cells could improve the therapeutic effectiveness of the liposomal preparations.
In these experiments, we demonstrate increased targeting and specific cytotoxicity to Namalwa cells by DXR-SIL[anti-CD19] relative to DXR-SL or free DXR (page 3320-1).
For the coupling method used here, the linkage occurs via an oxidized carbohydrate on the Fc portion of the mAb coupled to the terminus of HZ-PEG-DSPE via a hydrazone bond. This orientation of the Ab seems to expose the Fab binding domain, allowing it to recognize the CD 19 epitope on B cells (page 3328).
Namiki teaches magnetic lipid nanoparticles as a drug delivery system. In claim 1, (A) A step of obtaining a fat-soluble magnetic fluid by dispersing magnetic nanocrystals coated with a fat-soluble surfactant in a fat-soluble organic solvent; (B) an amphiphilic drug and a fat-soluble drug in the magnetic fluid; or A step of obtaining a mixture by dissolving only an amphipathic drug or only a fat-soluble drug; (C) After adding water or a water-soluble drug solution to the mixture, it is uniformly dispersed by mechanical dispersion (D) removing the fat-soluble organic solvent from the dispersion mixture, and removing the fat-soluble organic solvent from the hydrophobic group of the fat-soluble surfactant and the hydrophobic group of the amphiphilic drug, or the fat-soluble interface. By promoting self-association due to hydrophobic interaction between the hydrophobic group of the active agent and the hydrophobic group of the fat-soluble drug, the hydrophilic group of the amphiphilic drug or the fat-soluble drug is exposed on the outermost layer of the nanoparticle. Hydrophilic to particles Imparting to method for producing a self-associated magnetic lipid nanoparticles to obtain high self-associated magnetic lipid nanoparticles dispersibility in aqueous solution (translation).
It would have been obvious to one of ordinary skill in the art to provide micelle aggregates comprising iron oxide by sonication of a mixture of lipid and oleic acid coated iron oxide in chloroform and water when the teaching of Starmans is taken in view of Lee. While Lee teaches injection of a chloroform solution of oleic acid coated iron oxide nanoparticle and lipid into water and stirring, sonication is not specifically taught as a means of mixing. However it would have been obvious to one of ordinary skill in the art at the time of the invention to perform sonication as a functionally equivalent means of mixing with a reasonable expectation of success, as it is known from Lee that sonication of a chloroform solution comprising oleic acid coated iron oxide nanoparticles with aqueous micelle solution to provide magnetic micelles.
One would have been motivated to provide a hydrophilic drug in the solution with a reasonable expectation of success, because Namiki teaches adding a water soluble drug solution to a hydrophobic mixture in obtaining lipid nanoparticles for drug delivery followed by mechanical dispersion.
Regarding the limitation directed to Cu-free click chemistry for directional conjugation of a targeted antibody to the liposome, wherein the directional conjugation
of a targeted antibody to the liposome, wherein the directional conjugation comprises mildly oxidizing the Fc portion of the targeting antibody with sodium periodate, Lee teaches click chemistry and incorporation of targeting ligands, and de Menezes teaches directional conjugation of a targeting antibody to phospholipid via periodate oxidized Fc region as suitable for conjugation of a targeting ligand to phospholipid.
With regard to claims 4-10, it would have been obvious to heat the drug containing solution, as taught by Starmans and Lee. It would have been further obvious to provide a probe ultrasonicator as functionally equivalent and to modify power, distance and infusion rate as a matter of routine experimentation in order to provide micelles having optimal properties such as stability and size. Furthermore, with regard to temperature and lipid concentration, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here 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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim(s) 1, 3-7, 9-10, 14, 16-17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Starmans et al. (PLOS One, 2013, 8(2), p. e57335) in view of Lee (CA 3134257) and de Menezes (Cancer Res., 1998, 58, 3320-30), in further view of Namiki (JP 2010053113) and Handi (IN 201641023).
The rejection over Starmans in view of Lee, de Menzes and Namiki is applied as above.
With regard to claim 3, doxorubicin is not specifically taught as the hydrophilic drug.
Handi teaches self-assembled magnetic micelles comprises a nanoparticle complex, which is conjugated with integrin antibody to form an integrin targeted micelles. The self-assembled magnetic micelles exhibit anti-metastatic activity by promoting formation of thicker fibrous capsule to imprison the invasive tumor cells at primary tumor region. The nanoparticle complex is a doxorubicin-superparamagnetic iron oxide nanoparticles (Dox-SPION complex). The nanoparticle complex is encapsulated in the self-assembled magnetic micelles. The integrin antibody is αvβ3. The magnetic micelles are spherical having diameter of 30-45nm. The magnetic micelles has a zeta potential of 37.7± 7.09mV. The integrin targeted micelles demonstrate fluorescence and magnetic resonance T2 contrasting property. The integrin targeted micelles exhibits hyperthermia induced and endosomal delivery of Dox. The Dox-SPION complex is formed by electrostatic interaction. The Dox-SPION complex has optimal ratio of Dox and SPION as 1:100 which is based on the fluorescence intensity. The micelles is formed by hydrophobically modified chitosan. The hydrophobically modified chitosan has a critical micelle concentration (CMC) value of 1μ g/mL. The critical micelle concentration (CMC) is determined by using dye solubilization method. The integrin targeted micelles overcomes the drug resistance and permeates the Dox in cytosol of MDA-MB 231. The integrin targeted micelles demonstrates anti-migratory effect on invasive MDA-MB 231 cell lines. The saturation magnetization (Ms) for integrin targeted micelles is 0.82emu/g. The integrin targeted micelles exhibits the specificity against triple negative cells (MDA-MB 231 cell lines) by magnetizing the α vβ 3 integrin over-expressed triple negative cells. The integrin targeted micelles forms fibrous tissue around the tumor region 450, abstract).
It would have been obvious to provide doxorubicin as the hydrophilic drug in the compositions of Starmans in view of Lee, de Menezes and Namiki, when the teachings of Starmans, Lee and Namiki are taken in view of Handi. One would have been motivated to do so, with a reasonable expectation of success, because Handi teaches doxorubicin to be suitable for delivery with magnetic micelle for use in treatment of tumor.
Claims 1, 4-10, 14 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Starmans et al. (PLOS One, 2013, 8(2), p. e57335) in view of Lee (CA 3134257) and de Menezes (Cancer Res., 1998, 58, 3320-30), in further view of Namiki (JP 2010053113) and Obaid (US 2018/0161272).
The rejection over Starmans in view of Lee, de Menezes and Namiki is applied as above.
With regard to claim 18, HER2 antibodies are not specifically taught.
Obaid teaches a liposome comprising: a) a conjugate comprising a lysophospholipid and a photosensitizer; b) a first derivatized phospholipid comprising a first phospholipid and a strained cyclooctyne moiety; c) a second derivatized phospholipid comprising a second phospholipid and a polyethylene glycol polymer; and d) a cationic or anionic lipid. Also provided herein is a liposome comprising: a) a conjugate comprising a lysophospholipid and a photosensitizer; b) a first derivatized phospholipid comprising a first phospholipid and a targeting moiety; c) a second derivatized phospholipid comprising a second phospholipid and a polyethylene glycol polymer; and d) a cationic or anionic lipid. The liposomes provided herein can be used, for example, in the treatment of cancer or in the imaging of cancer tumors (paragraph 0004). In some embodiments, the targeting moiety comprises an azide moiety prior to conjugating with the first derivatized phospholipid. In some embodiments, the targeting moiety comprises a strained cyclooctyne as provided herein prior to conjugating with the first phospholipid. In some embodiments, the targeting moiety is conjugated to the first phospholipid using Cu-free click chemistry. For example, the azide or strained cyclooctyne on the targeting moiety can react with the strained cyclooctyne or azide, respectively, on the first phospholipid via Cu-free click chemistry. In some embodiments, the first derivatized phospholipid comprises the first phospholipid and the reaction product of a strained cyclooctyne and the targeting moiety comprising an azide (paragraph 0065).
See Figure 6, for example, a schematic representation of a liposome surface bound to cetuximab-protein Z through copper-free click chemistry. Protein Z is site-specifically bound to the Fc region of any IgG molecule (e.g., cetuximab) and is photocross-linked through an unnatural benzoylphenylalanine amino acid. The terminal azide on the peptide-bound protein Z is click conjugated to the optimal surface molar ratio of DSPE-PEG.sub.2000-ADIBO, a strained-cyclooctyne derivatized phospholipid.
HER2 targeting antibodies are taught, paragraph 0095+. The targeting moieties provided herein increase the selectivity of the liposomes provided herein. For example, selective binding and phototoxicity can be achieved for any click-conjugated targeting moiety with its respective target-overexpressing cell line (paragraph 0067).
It would have been obvious to one of ordinary skill in the art at the time of the invention to employ Cu-free click chemistry for directional conjugation of a HER2 targeted antibody to the magnetic micelles when the teachings of Starmans, Lee, de Menezes and Namiki are taken in view of Obaid. Lee and de Menezes teaches the benefit of click chemistry as well as disease targeting agents, i.e. antibody (claim 12), and Handi teaches drug delivery using magnetic micelles comprising another cancer targeting ligand. One would have found it obvious to select another cancer targeting ligand as functionally equivalent with a reasonable expectation of success, as Obaid teaches the Cu-free click chemistry using functionalized lipids to provide the advantage of increased selectivity.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618