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 10/7/2025, in reply to the Office Action mailed 7/9/2025, is acknowledged and has been entered. Claims 19-29 and 32-35 have been amended. Claims 37-39 are newly added. Claims 19-39 are pending and are examined herein on the merits for patentability.
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) 19-26, 29-31, 36, 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (CN 107802844) in view of Laurent et al. (Nanoscale, 2016, 8, 12054).
Shi teaches a hybrid sodium alginate nano-gel preparation method of loaded double contrast elements. A load-element hybrid sodium alginate nano-gel preparation method is taught, comprising the following steps: the AG dissolved in ultra-pure water, adding EDC and NHS activation, then gradually adding to AOT dissolved with DCM solution, stirring, obtain W/O emulsion, then super-pure water solution is added dropwise to the PVA, continuously stirring to obtain the W/o/w polymer emulsion, the aqueous solution of PEI-Au-Gd NPs into the W/O/W emulsion, stirring overnight, continuously reacting, separating and purifying, and obtaining the AG/PEI-Au-Gd NGs. The invention is easy to operation and separation, the raw material source is wide, the cost is low; the prepared AG/PEI-Au-Gd NGs with uniform grain diameter distribution, good X-ray attenuation performance, and can obviously improve the r1 relaxation rate, has good water solubility, colloid stability, cell compatibility, has no bad effect to the organism (abstract).
The invention claims a load-element hybrid sodium alginate nano-gel preparation method, comprising the following steps: (1) dissolving the sodium alginate AG in ultra-pure water, adding 1 - (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC and N-hydroxyl succinimide NHS activated; then gradually adding into solution with dioctyl sodium sulfosuccinate in AOT dichloromethane DCM solution, stirring to obtain W/O emulsion; then ultra pure water on the polyvinyl alcohol PVA solution is added, continuously stirring to obtain W/O/W emulsion, wherein AG, the mol ratio of EDC and NHS is 1:2: 2~1: 5:5; (2) the polyethylene imine-modified gold composite nano particle PEI-Au-Gd NPs aqueous solution as crosslinking agent in the step (1) to obtain a W/O/W emulsion, stirring overnight, continuously reacting; separating and purifying to obtain the mass ratio of AG load-element hybrid sodium alginate nano-gel AG/PEI-Au-NGs; Gd, wherein PEI-Au-Gd NPs in the step (1) is 0.5:1 to 4:1 (page 3).
AG/PEI-Au-Gd-NGs exhibits a surface potential of turnover of -16.3mV and increased hydrodynamic diameter 167.7 nm.
In Example 2, through TEM observation in Example 1 to prepare PEI-Au-Gd NPs and AG/PEI-Au-Gd-NGs shape, as shown in FIG. 5, the results show that PEI-Au-Gd NPs are spherical, the average grain diameter is 4.0 nm, after cross-linking of AG/PEI-Au-Gd NGs is approximately spherical, can observe obvious phenomenon, the size of nanoparticle clusters is uniform, the average diameter is about 83.3 nm, there is no obvious agglomeration phenomenon.
Shi does not specifically recite wherein a metal ion is complexed by a macrocyclic chelating agent.
Laurent teaches that three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar (abstract).
The clinical application of these promising nanosized radiosensitizing MRI contrast agents can be impeded because the use of gadolinium complexes as contrast agents is questionable in the case of bisamide derivatives of linear chelators such as DTDTPA (the dithiolated form of diethylenetriaminepentaacetic acid (DTPA)). We recently demonstrated that DTDTPA-Gd complexes are 1000-fold more stable when they are anchored onto the gold core in comparison with unbound DTDTPA-Gd complexes in aqueous solutions. Nevertheless the corresponding stability is not higher than that of DTPA-Gd. Although the DTPA-Gd complex is a common contrast agent for clinical MRI examination, its use has been restricted owing to fatal cases of nephrogenic systemic fibrosis (NSF) observed in patients suffering from kidney failure. The partial dissociation of DTPA-Gd chelates leading to the release of highly toxic gadolinium ions has been suspected to be at the origin of NSF. For limiting the presence of gadolinium ions in the organism, the content of gadolinium in the organic shell was fixed at a ratio of one gadolinium ion for three DTDTPA chelating units. However, the replacement of linear chelators by macrocyclic chelators appears to be a safer alternative since the latter form more stable but also much more inert complexes with gadolinium ions. For this purpose, three chelators containing both a DOTAtype macrocycle and two sulfur atoms were developed: DTDOTA, TADOTA and TADOTAGA (Scheme 1). The opposite extremities of the chelators (macrocycle and sulfur atoms), separated by a flexible spacer (a chain containing amide functions), are expected to play important roles. The highly hydrophilic DOTA-like moiety should ensure the colloidal stability and the entrapment of ions for MRI (Gd3+) and nuclear imaging (radioisotopes), while the two sulfur atoms should impact the growth of the gold nanoparticles and therefore their size. Indeed, they should favor the adsorption of the ligands onto the growing gold nanoparticles owing to the great affinity of sulfur for gold atoms. Although these ligands exhibit only minor differences in their structures, they induce drastic changes in the properties of the resulting gold nanoparticles. The biodistribution and therefore the radiosensitization efficiency of the macrocycle-coated gold nanoparticles are particularly affected (page 12055).
The reduction of gold salt in the presence of DOTA-like macrocycles functionalized by two sulfur atoms leads to the formation of gold nanoparticles whose properties depend on the structure of the ligands. Although the three chelators (DTDOTA, TADOTA and TADOTAGA) exhibit only minor structural differences, they exert an important influence on the physical and biological behavior of each type of macrocycle-coated gold nanoparticle (Au@DTDOTA, Au@TADOTA, Au@TADOTAGA).
Among the three chelators, TADOTAGA is finally the best suited ligand for producing gold nanoparticles characterized by promising potential for MRI-guided radiotherapy (page 12062).
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute a macrocyclic chelator for a linear chelator in the compositions taught by Shi comprising a when the teaching of Shi is taken in view of Laurent. One would have been motivated to do so, with a reasonable expectation of success, because Laurent teaches that the replacement of linear chelators by macrocyclic chelators appears to be a safer alternative since the latter form more stable but also much more inert complexes with gadolinium ions, and that although these ligands exhibit only minor differences in their structures, they induce drastic changes in the properties of the resulting gold nanoparticles. The biodistribution and therefore the radiosensitization efficiency of the macrocycle-coated gold nanoparticles are particularly affected. TADOTAGA is finally the best suited ligand for producing gold nanoparticles characterized by promising potential for MRI-guided radiotherapy.
With regard to the amended limitation wherein the polycation c/ being proximate to the gold nanoparticles b/ due to electrostatic interaction with said gold nanoparticles b/ so that said polycation c/ is encapsulated with the gold nanoparticles b/ in the polymer particle a/ and/or adsorbed on the surface of the polymer particle a/, it is noted that the claimed components are consistent with those of Shi/Laurent. Absent evidence to the contrary it is interpreted that the particles taught by Shi/Laurent would necessarily be capable of the claimed electrostatic interaction, because the particles feature the same components, i.e. gold nanoparticles having on their surface chelating agent (i.e. having carboxylate moieties) which would be capable of the same interaction with polyethyleneimine, as claimed.
Claim(s) 19-27, 29-31, 36, 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (CN 107802844) in view of Laurent et al. (Nanoscale, 2016, 8, 12054), in further view of Tang et al. (US 9,603,944).
The rejection over Shi in view of Laurent is applied as above.
Shi and Laurent do not teach PLGA as the biodegradable polymer.
Tang teaches exemplary polymers that can be reversibly linked to proteins and/or used to form nanostructures (e.g., nanocapsules, nanogels, hydrogels) include, without limitation, aliphatic polyesters, poly (lactic acid) (PLA), poly (glycolic acid) (PGA), co-polymers of lactic acid and glycolic acid (PLGA), polycarprolactone (PCL), polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof, including substitutions, additions of chemical groups such as for example alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. Other polymers are contemplated and may be used in accordance with the disclosure.
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute PLGA as a functionally equivalent polymer to polyalginate in the nanoparticles taught by Shi when the teaching of Shi is taken in view of Tang. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143.
In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known degradable polymeric nanocarrier for another, and the results of the substitution would have been predictable, that is preparation of degradable polymeric nanoparticles comprising gold nanoparticles.
Claim(s) 19-26, 28-31 and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (CN 107802844) in view of Laurent et al. (Nanoscale, 2016, 8, 12054), in further view of Nie et al. (WO 06/042146).
The rejection over Shi and Laurent is applied as above.
Shi and Laurent do not specifically teach a targeting ligand such as RGD peptide.
Nie teaches conjugates comprising a nanocarrier, a therapeutic agent or imaging agent and a targeting agent. Also disclosed herein are compositions comprising such conjugates and methods for using the conjugates to deliver therapeutic and/or imaging agents to cells. Also disclosed are methods for using the conjugates to treat particular disorders, such as proliferative disorders (abstract).
The polymeric nanoparticle may comprise alginate and imaging agents (page 11).
In one embodiment, nanocarrier conjugate compounds include, in addition to a targeting agent, a hydrophilic nanocarrier, such as a polycationic or polyanionic polymer, and a hydrophobic component, such as a hydrophobic chemotherapeutic or imaging agent.
The targeting agent can be any ligand moiety, such as an antibody, growth factors, cytokines, cell adhesion molecules, their receptors, peptide, protein or small molecule, such as a receptor agonist, antagonist or enzyme inhibitor that binds to a cell, typically a particular cellular receptor. It is understood that when a particular targeting agent is referred to, fragments, residues and derivatives thereof also are intended. hi one embodiment, the compounds include plural targeting agents, which can be the same or different. For example, a compound can present an effectively multivalent display of plural targeting agents, to enhance affinity, avidity or selectivity of a nanocarrier therapeutic.
In one embodiment the disclosed compounds employ anti-angiogenic factors as targeting agents… such as RGD peptide (page 23-26).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a targeting agent, such as RGD peptide, on the polymeric nanoparticles taught by Shi and Laurent when the teachings of Shi and Laurent are taken in view of Nie. One would have been motivated to do so, with a reasonable expectation of success, because Nie teaches that doing so allows for enhanced affinity, avidity or selectivity of a nanocarrier therapeutic.
Claim(s) 19-27 and 29-39 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (CN 107802844) in view of Laurent et al. (Nanoscale, 2016, 8, 12054), in further view of Fessi et al. (International Journal of Pharmaceutics, 55 (1989) R1-R4).
Shi teaches a hybrid sodium alginate nano-gel preparation method of loaded double contrast elements. A load-element hybrid sodium alginate nano-gel preparation method is taught, comprising the following steps: the AG dissolved in ultra-pure water, adding EDC and NHS activation, then gradually adding to AOT dissolved with DCM solution, stirring, obtain W/O emulsion, then super-pure water solution is added dropwise to the PVA, continuously stirring to obtain the W/o/w polymer emulsion, the aqueous solution of PEI-Au-Gd NPs into the W/O/W emulsion, stirring overnight, continuously reacting, separating and purifying, and obtaining the AG/PEI-Au-Gd NGs. The invention is easy to operation and separation, the raw material source is wide, the cost is low; the prepared AG/PEI-Au-Gd NGs with uniform grain diameter distribution, good X-ray attenuation performance, and can obviously improve the r1 relaxation rate, has good water solubility, colloid stability, cell compatibility, has no bad effect to the organism (abstract).
The invention claims a load-element hybrid sodium alginate nano-gel preparation method, comprising the following steps: (1) dissolving the sodium alginate AG in ultra-pure water, adding 1 - (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC and N-hydroxyl succinimide NHS activated; then gradually adding into solution with dioctyl sodium sulfosuccinate in AOT dichloromethane DCM solution, stirring to obtain W/O emulsion; then ultra pure water on the polyvinyl alcohol PVA solution is added, continuously stirring to obtain W/O/W emulsion, wherein AG, the mol ratio of EDC and NHS is 1:2: 2~1: 5:5; (2) the polyethylene imine-modified gold composite nano particle PEI-Au-Gd NPs aqueous solution as crosslinking agent in the step (1) to obtain a W/O/W emulsion, stirring overnight, continuously reacting; separating and purifying to obtain the mass ratio of AG load-element hybrid sodium alginate nano-gel AG/PEI-Au-NGs; Gd, wherein PEI-Au-Gd NPs in the step (1) is 0.5:1 to 4:1 (page 3).
AG/PEI-Au-Gd-NGs exhibits a surface potential of turnover of -16.3mV and increased hydrodynamic diameter 167.7 nm.
In Example 2, through TEM observation in Example 1 to prepare PEI-Au-Gd NPs and AG/PEI-Au-Gd-NGs shape, as shown in FIG. 5, the results show that PEI-Au-Gd NPs are spherical, the average grain diameter is 4.0 nm, after cross-linking of AG/PEI-Au-Gd NGs is approximately spherical, can observe obvious phenomenon, the size of nanoparticle clusters is uniform, the average diameter is about 83.3 nm, there is no obvious agglomeration phenomenon.
Synthesis of the particles is taught in Example 1: (1) taking 2 mL concentration of aqueous solution of 1wt %AG (20 mg), firstly with 35.48 mg EDC and 21.3 mg NHS activated 3h, then gradually adding to 4 mL in DCM solution of AOT (34 mg/mL), stirring for 30 min to form W/O emulsion, then adding the W/O emulsion dropwise to 30 mL concentration is 2wt % PVA aqueous solution (20 mg/mL), stirring for 30 min. obtain a W/O/W emulsion. (2) adding DTPA (0.02 mmol) with an equimolar amount of Gd (NO3) 3-6H2O (0.02 mmol) was mixed and dispersed in 10 mL ultra pure water, stirring and reacting for 24h, to obtain the DTPA-Gd complex, MPEG5000-MAL) (0.06 mmol) dispersed in 10 mL of ultra-pure water, then gradually adding into the aqueous solution of 20 mL PEI (0.002 mmol), stirring and reacting for 24h, distilled water dialysis 3d, freezing and drying to obtain the mPEG-PEI-NH2 powder, mPEG-PEI NH2 powder is dispersed in ultra-pure water (1 mg/mL). adding HAuCl4 * 4H2O (0.4 mmol) aqueous solution, 0.5h stirring, then adding ice water solution of NaBH4 (2 mmol) as a reducing agent, continuously stirring and 3h, then adding the obtained DTPA-Gd complex aqueous solution. continuously stirring and 1d, finally 3d dialysis with distilled water, freezing and drying to obtain PEI-Au-Gd NPs powder. (3) taking the workpiece in the step (2) to obtain the PEI-Au-Gd NPs aqueous solution of (10 mg/mL) 2 mL as a crosslinking agent into the W/O/W polymer emulsion obtained in the step (1), stirring overnight. continuously open 24h reaction, evaporating to remove organic solvent, then using dialysis bag with interception molecular weight of 100000 to the reaction solution in the dialysis for 2 days (2 L per time, 3 times per day), at 13000 rpm, 15 min centrifugal washing with water for 3 times, to obtain the load-element hybrid sodium alginate nano-gel AG/PEI-Au-Gd NGs.
Shi does not specifically recite wherein a metal ion is complexed by a macrocyclic chelating agent. With regard to the method claims, Shi does not specifically teach contacting an aqueous suspension of gold nanoparticles b/ with an aqueous solution of polycation, in order to obtain an assembly of gold nanoparticles b/ and polycation; contacting the assembly of gold nanoparticles b/ and polycation as defined in the preceding step with a mixture of biodegradable polymer and water-miscible organic solvent, said organic solvent optionally being mixed beforehand with at least one active principle, in order to obtain a mixture of gold nanoparticles b/, polycation, biodegradable polymer. Rather, a W/O emulsion is formed from addition of aqueous polymer to dichloromethane, followed by addition of gadolinium chelate complex, mPEG-PEI NH2, gold chloride and reduction to form alginate nano-gel AG/PEI-Au-Gd NGs.
Laurent teaches that three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar (abstract).
The clinical application of these promising nanosized radiosensitizing MRI contrast agents can be impeded because the use of gadolinium complexes as contrast agents is questionable in the case of bisamide derivatives of linear chelators such as DTDTPA (the dithiolated form of diethylenetriaminepentaacetic acid (DTPA)). We recently demonstrated that DTDTPA-Gd complexes are 1000-fold more stable when they are anchored onto the gold core in comparison with unbound DTDTPA-Gd complexes in aqueous solutions. Nevertheless the corresponding stability is not higher than that of DTPA-Gd. Although the DTPA-Gd complex is a common contrast agent for clinical MRI examination, its use has been restricted owing to fatal cases of nephrogenic systemic fibrosis (NSF) observed in patients suffering from kidney failure. The partial dissociation of DTPA-Gd chelates leading to the release of highly toxic gadolinium ions has been suspected to be at the origin of NSF. For limiting the presence of gadolinium ions in the organism, the content of gadolinium in the organic shell was fixed at a ratio of one gadolinium ion for three DTDTPA chelating units. However, the replacement of linear chelators by macrocyclic chelators appears to be a safer alternative since the latter form more stable but also much more inert complexes with gadolinium ions. For this purpose, three chelators containing both a DOTAtype macrocycle and two sulfur atoms were developed: DTDOTA, TADOTA and TADOTAGA (Scheme 1). The opposite extremities of the chelators (macrocycle and sulfur atoms), separated by a flexible spacer (a chain containing amide functions), are expected to play important roles. The highly hydrophilic DOTA-like moiety should ensure the colloidal stability and the entrapment of ions for MRI (Gd3+) and nuclear imaging (radioisotopes), while the two sulfur atoms should impact the growth of the gold nanoparticles and therefore their size. Indeed, they should favor the adsorption of the ligands onto the growing gold nanoparticles owing to the great affinity of sulfur for gold atoms. Although these ligands exhibit only minor differences in their structures, they induce drastic changes in the properties of the resulting gold nanoparticles. The biodistribution and therefore the radiosensitization efficiency of the macrocycle-coated gold nanoparticles are particularly affected (page 12055).
The reduction of gold salt in the presence of DOTA-like macrocycles functionalized by two sulfur atoms leads to the formation of gold nanoparticles whose properties depend on the structure of the ligands. Although the three chelators (DTDOTA, TADOTA and TADOTAGA) exhibit only minor structural differences, they exert an important influence on the physical and biological behavior of each type of macrocycle-coated gold nanoparticle (Au@DTDOTA, Au@TADOTA, Au@TADOTAGA).
Among the three chelators, TADOTAGA is finally the best suited ligand for producing gold nanoparticles characterized by promising potential for MRI-guided radiotherapy (page 12062).
Fessi teaches that indomethacin-loaded nanocapsules were prepared by deposition of poly-(D,L-lactide) polymer at the o/w interface following acetone displacement from the oily nanodroplets. An attempt was made to elucidate the mechanism of formation in terms of interracial turbulence between two unequilibrated liquid phases involving flow, diffusion and surface tension decrease (Marangoni effect).
The subject of this communication is the presentation of a novel and simple procedure for the preparation of nanocapsules by interfacial deposition of a preformed, well-defined, and biodegradable polymer following displacement of a semi-polar solvent miscible with water from a lipophilic solution.
Nanocapsules of poly-(D,L-lactide) containing indomethacin as a drug model were prepared..125 mg of poly-(D,L-lactide) polymer (PLA) are first dissolved in acetone (25 ml). Eventually, a mixture of phospholipids is also dissolved in acetone by increasing the temperature close to the boiling point. 0.5 ml of benzyl-benzoate containing 12.5 mg of indomethacin are then added to the acetonic solution. The resulting organic solution is poured in 50 ml of water containing 250 mg of poloxamer under moderate magnetic stirring. The aqueous phase immediately turns milky with bluish opalescence as a result of the formation of nanocapsules, the wall of which is mainly constituted by the PLA polymer, and the oily core by the indomethacin benzyl-benzoate solution. The acetone, which rapidly diffused towards the aqueous phase, is then removed under reduced pressure. The colloidal suspension is concentrated to the desired final volume by removal of water under the same conditions (page R1-2).
In addition, other polymers and drug models were tested for the purpose of confirming that this simple method can be applied to a wide range of polymers and drugs (page R3).
The nanocapsule preparation process, apparently simple, may involve complex interfacial hydrodynamic phenomena. Addition of the acetonic-oily solution resulted in spontaneous emulsification of the oily solution in the form of nanodroplets, due probably to some kind of interface instability arising from rapid diffusion of the acetone across the interface and marked decrease in the interfacial tension.
Thus, it can be deduced from the overall results that the rapid diffusion of acetone from the organic phase to the aqueous phase led to the formation of oily nanodroplets as result of interfacial tension decrease and migration of the insoluble PLA towards the o/w interface where it is deposited, forming the nanocapsule membrane. This interpretation of the observed phenomenon apparently agrees with the observations made during this study regarding the influence of surfactants on the nanocapsule properties. It was possible to prepare nanocapsules in the absence of any surfactant, but the poloxamer, a highly aqueous soluble surfactant, was needed for physical stability of the nanocapsule suspension. The main advantage of this one-step manufacturing process is the instantaneous and reproducible formation of nanometric, monodisperse nanocapsules exhibiting a high drug loading capacity (page R3-4).
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute a macrocyclic chelator for a linear chelator in the compositions taught by Shi comprising a when the teaching of Shi is taken in view of Laurent. One would have been motivated to do so, with a reasonable expectation of success, because Laurent teaches that the replacement of linear chelators by macrocyclic chelators appears to be a safer alternative since the latter form more stable but also much more inert complexes with gadolinium ions, and that although these ligands exhibit only minor differences in their structures, they induce drastic changes in the properties of the resulting gold nanoparticles. The biodistribution and therefore the radiosensitization efficiency of the macrocycle-coated gold nanoparticles are particularly affected. TADOTAGA is finally the best suited ligand for producing gold nanoparticles characterized by promising potential for MRI-guided radiotherapy.
It would have been further obvious to provide a biodegradable polymer (e.g. alginate or polylactide in an aqueous miscible organic solvent (e.g. acetone) for preparation of the polymer nanoparticles when the teaching of Shi is taken in view of Fessi. One would have been motivated to do so, with a reasonable expectation of success, because Fessi teaches that the one-step manufacturing process is an instantaneous and reproducible formation of nanometric, monodisperse nanocapsules exhibiting a high drug loading capacity. With regard to the order of addition of reaction components, see MPEP 2144. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
With regard to the amount of encapsulated gold nanoparticles, it would have been obvious to one of ordinary skill in the art to optimize the yield as means of maximizing the amount of retained gold in the nanoparticles. Furthermore, 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).
Response to arguments
Applicant argues that Shi fails to teach or suggest a metal ion that is complexed by a macrocyclic chelating agent and that Laurent fails to remedy all of the deficiencies of Shi. Applicant asserts that Shi relates to sodium alginate nanogels loaded with dual contrast elements. These nanogels comprise a linear DTPA chelator and gold nanoparticles that are grafted inside the alginate nanogels. Applicant asserts that Shi mentions that PEI, which is conjugated with polyethylene glycol (PEG), allows the attachment of the PEG-PEI copolymer onto the gold nanoparticles. Furthermore, the PEI described in Shi is conjugated with polycthylene glycol (PEG) to allow the attachment of the PEG-PEI copolymer onto the gold nanoparticles. Applicant asserts that, in Shi, the PEI is covalently bonded to the gold nanoparticles and forms an organic layer around the gold nanoparticles, which does not correspond to the structure described in the amended claim 19 of the present application, wherein the polycation is proximate to the gold nanoparticles due to electrostatic interaction with the latter, said polycation being thus encapsulated in the polymer particle or adsorbed at the surface of the polymer particle.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Shi teaches the following on page 3-4 of the translation:
The present invention chelates trivalent gadolinium ions with the metal chelating agent DTPA to obtain a DTPA-Gd complex; using NaBH4 as a reducing agent, a one-step reduction method is used to synthesize mPEGylated PEI-stabilized Au nanoparticles mPEG-PEI NH2-(Au0)200, reacted with DTPA-Gd complex to obtain PEI-Au-Gd nanoparticles; the aqueous solution of AG was activated by EDC/NHS and double emulsified to obtain W/O/W emulsion; then PEI-Au-Gd nanoparticles were used as a cross-linking agent was added to the W/O/W emulsion, and a hybrid sodium alginate nanogel loaded with dual contrast elements was prepared through a chemical cross-linking reaction. Accordingly, it is respectfully submitted that Shi teaches that mPEGylated PEI-stabilized Au nanoparticles mPEG-PEI NH2-(Au0)200 are reacted with DTPA-Gd complex, and that PEI-Au-Gd nanoparticles were used as a cross-linking agent and a hybrid sodium alginate nanogel loaded with dual contrast elements was prepared through a chemical cross-linking reaction, but does not necessarily teach that PEI is covalently bonded to the gold nanoparticles and forms an organic layer around the gold nanoparticles, as asserted by Applicant.
Applicant asserts that the currently amended independent claim 19 differs from Shi notably by the presence of macrocyclic chelating agents on the surface of the gold nanoparticles and the proximity of the polycation to the gold nanoparticles. According to the present application, the presence of macrocyclic chelating agents allows the complexation of elements of interest for medical imaging to the gold nanoparticles, thus enabling the tracking of the gold nanoparticles by imaging. Applicant notes that the presence of the polycation allows the formation of an electrostatic interaction between said polycation and the gold nanoparticle, which facilitates the encapsulation of the gold nanoparticle in the biodegradable polymer particle or its adsorption on the surface of the biodegradable polymer particle ((e.g., in paragraph [0021] of specification as filed).
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the amended limitation wherein the polycation c/ being proximate to the gold nanoparticles b/ due to electrostatic interaction with said gold nanoparticles b/ so that said polycation c/ is encapsulated with the gold nanoparticles b/ in the polymer particle a/ and/or adsorbed on the surface of the polymer particle a/, it is noted that the claimed components are consistent with those of Shi/Laurent. Absent evidence to the contrary it is interpreted that the particles taught by Shi/Laurent would necessarily be capable of the claimed electrostatic interaction, because the particles feature the same components, i.e. gold nanoparticles having on their surface chelating agent (i.e. having carboxylate moieties) which would be capable of the same interaction with polyethyleneimine, as claimed. Laurent is included to show obviousness of substitution of a macrocyclic chelating ligand for DTPA as the ligand employed by Shi.
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new 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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618