DETAILED ACTION
This Office action details a first action on the merits for the above referenced application No. Claims 1-20 are pending in this application.
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 .
Priority
This application is a 35 USC 371 National Stage filing of international application No. PCT/CN2022/119469 filed on 16 Sep. 2022 and claims benefit under 35 USC 119(a)-(d) to foreign application No. CN 202210072699.7 filed on 21 Jan. 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21 Mar. 2024 has been considered by the examiner.
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.
Claim 13 is 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. Instant claim 13 is indefinite because the claim omits molecular weight units such as Da, kDa, and amu and so the recited molecular weight range is unclear.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
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.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 104758956 A-English translation; published 2015; see attached 892), in view of Horák et al. (US 2009/0309597 A1; published 17 Dec. 2009; see attached 892).
Chen et al. teach a tumor targeted t1-t2 dual nuclear magnetic resonance imaging contrast agent and its preparation method and application (see title). Chen et al. teach contrast agent includes ferric iron tetraoxide composite magnetic nanoparticles coated with hyaluronic acid (see abstract). The contrast agent comprises coated ferrosol-ferric oxide composite magnetic nanoparticle of hyaluronic acid have a particle diameter between 2-10 nm and the hydration particle diameter of the composite is 10-100 nm (claim 1; pg. 3). Hyaluronic acid is a natural; polymer with good water solubility and HA with different molecular weights play different roles in the living body (pg. 2). The ferric salt in step (2) is FeCl3.6H2O and the ferrous salt in step (2) is FeCl2-4H2O or FeSO4-7H2O. The alkali is ammonia water. The molecular weight of the HA is 6,640-110,000 Da. The preparation method comprises the following steps: (1) dissolving HA in deionized water placed in an oil bath and heated to 80-120oC to obtain reaction system A; (2) dissolving the ferric salt of the ferrous salt in a strong acid to obtain solution B; the mole ratio of ferric salt to ferrous salt is 2; the concentration of the strong acid is 0.5-3 mol/L; (3) inject solution B into reaction system A, adjust the pH to pH=8-11 with ammonia water with a mass fraction of 25-28% and then reflux at 80-120oC for 40-120 min to obtain reaction system C; and (4) cool the reaction system C to room temperature and dialyze at 20-35oC for 60-75 h to obtain the contrast agent (pg. 4; e.g. example 2, pg. 6). (Preparation method for the magnetic ferroferric oxide nanoparticle comprising the step coprecipitating ferrous ions and ferric ions to form the magnetic ferroferric oxide nanoparticle by using hydrophilic macromolecule as a stabilizer wherein the preparation method comprises heating hydrophilic macromolecule solution then mixing the hydrophilic macromolecule solution after being subjected to heating with an iron ion mixed solution comprising ferrous ions and ferric ions for a coordination reaction and then adding an alkali liquor (ammonia water) for coprecipitation reaction to obtain magnetic ferroferric oxide nanoparticle; magnetic ferroferric oxide nanoparticle comprising ferroferric oxide and a hydrophilic macromolecule wherein the ferroferric oxide and hydrophilic macromolecule is in at least the following relationship and the magnetic ferroferric oxide nanoparticle has the following properties: 1) average particle size of greater than 2 nm and less than 5 nm; 2) an electrokinetic potential less than -10 mV; and 3) the hydrodynamic diameter is less than 20 nm.
The contrast agent of the present invention has superparamagnetism and outstanding T1 and T2 relaxation enhancement effects and the linear relationship between T1 and T2 relaxation time reciprocal changes with iron concentration in a large range is good wherein R1 reaches 10.751 mM-1s-1 significantly higher than the R1 value of commercial contrast agents (generally around 4 mM-1s-1) (pg. 4). Fig. 3 is the surface potential figure of the particle prepared in embodiment 1, it can be seen that the particle surface potential is a negative value and the peak is prominent indicating that HA has been successfully coated on Fe3O4 nanoparticles (pg. 4). Chen et al. teach Fig 3
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(electrokinetic potentialmax = ~25 nm). Fig. 2 shows a hydrate particle size distribution with diameters less than 20 nm.
Chen et al. do not teach a magnetic ferroferric oxide nanoparticle having a longitudinal magnetic relaxation rate r1 value under a magnetic field intensity of 3.0 T is greater than 5 mM-1s-1 and a longitudinal magnetic relaxation rate or1 value under a magnetic field intensity of 1.0 T is greater than 10 mM-1s-1. Chen et al. do not teach a hydrophilic macromolecule comprising a carboxylic acid containing macromolecule such polyglutamic acid or polyaspartic acid or an amine containing macromolecule such as polylysine or a hydroxyl containing molecule such as polyserine or an amide containing molecule such as polyglutamine. Chen et al. do not expressly teach a method that in the iron ion mixed solution a concentration of ferrous ions is 30 mM to 500 mM and a concentration of ferric ions is 60 mM to 1,000 mM.
Horák et al. teach superparamagnetic nanoparticles based on iron oxide with modified surface, methods of their preparation and application (see title). Horák et al. teach superparamagnetic nanoparticle probes based on iron oxide coated with polysaccharides or with poly (amino acids) such as aspartic acid, glutamic acid, lysine, glutamine which form a colloid consisting of particles with narrow distribution with polydispersity index smaller than 1.3, the average size amounts to 0.5-30 nm. The superparamagnetic probes can be used for labeling cells used in MRI for monitoring their movement (see abstract). The nanoparticles are modified with agents based on poly(amino acids) such as polyalanine ([0013]). Horák et al. teach the treatment of superparamagnetic iron oxide nanoparticles with poly(amino acids) (example 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Chen et al. (magnetic ferroferric oxide nanoparticle and their methods of synthesis comprising ferroferric oxide and a hydrophilic hyaluronic acid molecule wherein the ferroferric oxide and the hydrophilic molecule are in a relationship such that the hyaluronic acid is adsorbed on the surface of the ferroferric oxide and the magnetic ferroferric oxide nanoparticle simultaneously has 1) an average particle size greater than 2 nm and less than 5 nm, 2) an electrokinetic potential less than or equal -10 mV, 3) a hydrodynamic diameter less than or equal to 20 nm, and 4) wherein R1 reaches 10.751 mM-1s-1) so that a longitudinal magnetic relaxation rate r1 value under a magnetic field intensity of 3 T is greater than 5 mM-1s-1 and a longitudinal magnetic relaxation rate r1 value under a magnetic field intensity of 1 T is greater than 10 mM-1s-1 as taught by Chen et al. because those r1 values would have been expected to advantageously enable optimally enhanced positive contrast effect. MPEP 2144.05.II. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chen et al. by substituting the hyaluronic polysaccharide coating with poly (amino acid) coating such polyglutamic acid, polylysine, polyglutamine, and polyserine as taught by Horák et al. because those poly(amino acids) coatings would have been expected to provide equivalent hydrophilic coatings suitable for MR imaging movement and localization and advantageously enabling functionalization and enhanced cell targeting. Regarding polyserine, polythreonine, and polytyrosine, there are 22 natural proteinogenic amino acids, a person of ordinary skill in the art readily envisaged those poly(amino acids) in view of Horák et al. The zeta potential of the ferroferric oxide nanoparticle is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill would have arrived at a zeta potential less than -30 mV in order to arrive at an optimal surface potential and coating. The hydrodynamic diameter is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a hydrodynamic diameter of less than or equal to 20 nm in order to arrive at small size and good penetrability. Differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). A person of ordinary skill in the art would have been arrived at a molecular weight of the hydrophilic macromolecule from 1,000 and 10,000 since Chen et al. teach a molecule weight of 6,640 Da as being a suitable molecular weight for the hydrophilic macromolecule. A person of ordinary skill in the art would have arrived at following concentrations in the preparation method preparation in order to arrive at effective concentrations for nanoparticle preparation and coating: ferrous ions, 30 mM to 500 mM; ferric ions, 60 mM-1,000 mM; and hydrophilic molecule, 0.1 mg/mL- 20 mg/mL.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (CN 104758956 A-English translation; published 2015; see attached 892), in view of Horák et al. (US 2009/0309597 A1; published 17 Dec. 2009; see attached 892), in further Brenneisen et al. (US 2013/0337070 A1; published 19 Dec. 2013; see attached 892).
Chen et al. teach as discussed above.
Chen et al. do not further teach the claimed hydroxyl containing macromolecule comprising polyserine.
Horák et al. teach as discussed above.
Brenneisen et al. coated nanoparticle therapy for skin cancer. Brenneisen et al. teach the polymer coating on the cerium nanoparticles may include polyhydroxylated polymers such as polyserine ([0020]).
It would have been further obvious to a person of ordinary skill in the art before the effective filing date to further modify Chen et al. so that the hydrophilic macromolecule comprising a hydroxyl-containing macromolecule such as polyserine as taught by Horák et al. and Brenneisen et al. because the polyserine would have been expected to advantageously the hydroxy-functionalized poly-amino acid coating capable of conjugation and increasing hydrophilicity.
Conclusion
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Robert A Wax/ Supervisory Patent Examiner, Art Unit 1615
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