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 .
Status of the Claims
Claims 1-12, 14, 15 and 17-22 are pending in a preliminary amendment dated 03/27/2025.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/06/2024 was filed before the mailing date of the instant first action on the merits. The submission thereof is in compliance with the provisions of 37 CFR 1.97. It is noted that the foreign references have only been considered to the extent that an English language abstract, translation or statement of relevance has been provided to the examiner. Accordingly, information disclosure statement has been considered by the examiner, and signed and initialed copy is enclosed herewith.
Claim Objections
Claim 6 is objected to a minor informality.
Claim 6 recites “an ionizable group …”, but which would be better to recite “the weak acid ionizable group …”
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 1-12, 14, 15 and 17-22 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 “a therapeutic nanoparticle” in line 1, “a nanoparticle comprising an amphiphilic polymer” in step c., and “nanoparticle formulation” in step f. It is not clear whether those nanoparticles are the same as the therapeutic nanoparticle. Clarification requested.
Claim 9 recites trademark “Tween”, but which is indefinite according to MPEP § 2173.05(u), using a trademark in a claim to describe a material usually renders the claim indefinite. A patent claim must establish clear boundaries. Because product formulations or features can change over time without public notice while keeping the same trademark and thus the scope of your patent claim would improperly shift over time.
Further, the following claims lack antecedent basis:
Claim 5 recites “the water solubility” in line 1 and “the load of the active ingredient” in line 2;
Claim 17 recites “the hydrodynamic diameter” in line 1;
Claim 18 recites “the zeta potential” in line 1; and
Claim 19 recites “the surface of the polymeric nanoparticle” in line 2; and also claim 19 recites “the polymeric nanoparticle” in lines 1-2, but which lacks sufficient antecedent basis because a nanoparticle comprising an amphiphilic polymer of base claim 1 could comprise non-polymer ingredients.
The remaining claims are also rejected due to the rejection of base claim 1.
Appropriate correction is requested.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
As indicated above, the present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 4 and 6-20 are rejected under 35 USC 103 as being obvious over Figueiredo et al. (US2014/0249158A1, IDS of 03/27/2025) in view of and Shilubhai (US2018/0092857A1, IDS of 03/27/2025).
Applicant claims including the below claim 1 filed on 03/05/2025:
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Determination of the scope and content of the prior art (MPEP 2141.01); Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness Rational and Motivation (MPEP 2142-2143)
Figueiredo teaches therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same (title); the nanoparticles are prepared by mixing an organic phase with an aqueous phase at about 1:5 ([0150] and [0161]) wherein the organic phase is composed of an organic solution, a mixture of a protonatable nitrogen-containing therapeutic agent, and polymer (homopolymer, co-polymer, and co-polymer with ligand), and the polymer or copolymer can be amphiphilic ([0106]) such as amphiphilic polymer including a diblock poly(lactic) acid-poly(ethylene)glycol copolymer (PLA-PEG) or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer having Mw of about 15,000 to about 20,000 Da ([0120]) which reads on the instant amphiphilic polymer and the said Mw overlaps the instant range of 2,000 to 60,000, and the organic solution for the organic phase includes such as toluene, acetonitrile, ethyl acetate, Tween, acetone, dichloromethane, tetrahydrofuran, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide (DMSO), etc., ([0143]) which reads on the instant organic solvent in organic phase, and the organic solvent by evaporation may be necessary to complete the extraction of the solvent and solidify the particles; the aqueous phase comprises a surfactant consisting of sodium cholate, ethyl acetate, benzyl alcohol and dissolved solvent ([0150]) which reads on the instant surfactant and the aqueous phase may have a pH equal to a pKa and the pH is between about 1-3, about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, or about 8-10 which overlaps the basic pH ranges of instant claims 1 and 4; the therapeutic agent includes anti-cancer agents such as sunitinib, imatinib, dasatinib which are weak base and water-insoluble biologically active ingredient, and the therapeutic nanoparticle comprises a hydrophobic ion-pair comprising a hydrophobic acid and the therapeutic agent having at least one ionizable amine moiety which reads on the instant ionizable amino group; and active agent e.g., sunitinib having ionizable amino group is used in an amount of 35% (Table 1) which overlaps the instant range of at least 4% or at least 6% or at least 9%; and the nanoparticle size ranges about 111 to about 136 nm or about 60 to about 150nm (Table 1 and claim 7 of prior art) which overlaps the instant range of between 20-300nm (see e.g., [0008], [0012], [0023], [0106], [0120], [0142], [0143], [0149], [0150], [0154], [0156], [0161], [0171], and the Examples). Further, the applied references teach species of solvent, surfactant or stabilizer, organic solvent, ionizable group, active ingredients as noted above, and species of instant claims 7-11 other than those of the applied references would be an obvious variation, devoid of evidence to the contrary (instant claim 1 (in part), claims 4, 7-11, 14, 15, and 17); the therapeutic nanoparticle is prepared by further emulsification comprising combining a first organic phase with a first aqueous solution to form a second phase, emulsifying the second phase to form an emulsion phase, wherein the emulsion phase comprises a first polymer, a basic therapeutic agent having a protonatable nitrogen, and a substantially hydrophobic acid, quenching of the emulsion phase thereby forming a quenched phase, and filtering the quenched phase to recover the therapeutic nanoparticles ([0039]) (instant claim 12); and the nanoparticles comprises at least one, e.g., two or three protonatable nitrogen-containing functional groups ([0069]); the therapeutic agent can be associated with the surface of polymer matrix and loaded ([0101] and [0213]); and combination of two or more therapeutic agents can be used in the nanoparticle formulation ([0031]) (instant claim 20).
Figueiredo in view of Shilubhai does not expressly teach exact orders of instant preparation steps a-f of instant claim 1. In particular, Figueiredo teaches the organic phase comprising the water insoluble active agent, the organic polymer, and the amphiphilic polymer and thus fails to add the active agent after mixing the organic phase with the aqueous phase and partially removing the organic solvent, and also fails to adjust the pH of the aqueous phase before mixing with the organic phase.
However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the preparation steps of the therapeutic nanoparticle of Figueiredo and produce the claimed invention.
One of the ordinary skill in the art would have been motivated to do this because the claimed ingredients must be mixed to produce the final therapeutic nanoparticle. The order to perform the instant steps a-e is irrelevant or insignificant absent unexpected results. See MPEP 2144.03 IV: “See also In re Burhans, 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 re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).” Further, the prior art discloses either solvent evaporation or dilution may be necessary to complete the extraction of the solvent and solidify the particles ([0154]). The examiner would interpret "solvent evaporation" as needed to complete the extraction of the solvent and solidify the particles by the ordinary artisan to mean one would evaporate off enough solvent to get the particles to solidify and therefore it reads on "partial removing of the organic solvent" as instantly claimed. Further it would be obvious to remove the remaining organic solvents to avoid undesired reaction to occur (instant claim 1 steps a)-f).
Although Figueiredo was discussed e.g., weak base drug, Figueiredo does not expressly teach weak acid active agent of instant claim 1; and zeta potential of instant claim 18. The deficiencies are cured by Shilubhai.
Shilubhai teaches compositions comprising dactinomycin and additional active agents, formulated for delivery by nanoparticle, and methods for treating a myelodysplastic syndrome (MDS) or cancer, for example, NPM1-mutated acute myeloid leukemia (AML), by administration of the compositions of the disclosure (abstract); the nanoparticle is prepared by mixing organic phase containing dactinomycin, polymer in organic solvent with a water phase containing PVA to form a nanoparticle emulsion ([0074]-[0076]); the composition comprising active ingredient encapsulated in nanoparticles comprising PLA-mPEG, wherein the nanoparticles have an average size of about 100nm to about 200nm ([0006] and [0023]) which overlaps the instant range of between 20-300nm; the composition comprises the additional active agents such as sunitinib and dasatinib ([0310]), imatinib ([0087]), vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic derivatives, e.g., Mg valproate, mocetinostat, abexinostat, entinostat, SB939, resminostat, givinostat, quisinostat ([0390]) which reads on the claimed HDAC inhibitor that is weak acid or has weak acid group (instant claim 1, weak acid ionizable drug); and the composition has zeta potential of -11.90±2.18, -23.63±0.49 which overlaps the instant range between -35 and +10mV (instant claim 18).
Although Figueiredo teaches cancer therapeutic agent, it does not expressly teach weak acid active agent of instant claim 1. However, it would be obvious from the standpoint of the ordinary artisan that most anticancer active agents are either weak base or weak acids. Therefore, it would have been obvious to select weak acid ionizable among various cancer agents as a matter of choice or design depending on the intended therapeutic purpose, type of tumor/cancer to be treated, co-anticancer agent, etc. (instant claim 1: weak acid active agent).
Further, all of the applied references do not expressly teach the exact ranges of instantly claimed, and but as noted above, the ranges of the applied art, Mw, diameter, amount of active agent and zeta potential overlap the instant ranges. It would have been prima facie obvious to one of the skilled in the art before the effective filing date of the claimed invention to adjust or optimize the prior art ranges with the claimed ranges without undue experimentation because the prior ranges as noted above are inside or overlap the claimed ranges, in the absence of criticality evidence. MPEP 2144.05 states that [I]n the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Further, Figueiredo/Shilubhai do not expressly teach the active ingredient comprising an ionizable group with a partition coefficient of logP>0 of instant claim 6, and at least 30% partial loading of active ingredient on polymeric nanoparticle having a surface of instant claim 19. However, the properties of these claims would be implicit because the prior art teaches similar method and the same active ingredients and ionizable group. Thus, devoid of evidence to the contrary, the properties of active ingredients would be implicit (instant claims 6 and 19).
In light of the foregoing, claims 1, 4 and 6-20 are obvious over Figueiredo in view of Shilubhai.
Claims 2 and 5 are rejected under 35 USC 103 as being obvious over Figueiredo et al. (US2014/0249158A1, IDS of 03/27/2025) in view of Shilubhai (US2018/0092857A1, IDS of 03/27/2025) and further in view of Sareen et al., “Improvement in solubility of poor water-soluble drugs by solid dispersion”, Int J Pharm Investig. 2012 Jan-Mar; 2(1): 12–17 (IDS of 03/27/2025).
Figueiredo/Shilubhai do not expressly teach water solubility of the active agent increases in basic pH e.g., 8-14, or 10 or more of instant claims 2 and 5. The deficiencies are cured by Sareen.
Sareen teaches that poor water-soluble drug may potentially dissolve in water by applying a pH change, and to access the solubility of this approach, the buffer capacity and tolerability of the selected pH are important to consider. Solubilized excipients that increase environmental pH within the dosage form to a range higher than pKa of weakly acidic drugs increase the solubility of that drug, and those excipients that act as alkalizing agents may increase the solubility of weakly basic drugs. That is, pH of aqueous solution can be raised to the basic range by using of alkalizing agent which leads to enhance water solubility of weekly basic drugs (instant claims 2 and 5- pH).
It would have been prima facie obvious to modify the teachings of Figueiredo/Shilubhai with changing pH of the aqueous solution, as taught by Sareen.
One of the ordinary artisan would have been motivated to do so because Figueiredo/Shilubhai in view of Sareen teaches the active agent has ionizable amino group, and aqueous phase has alkaline pH, and as taught by Sareen, changing pH of the aqueous solution to the basic pH range would enhance water solubility of poor water-soluble drug in the aqueous solution, which would also increase drug loading.
In view of the foregoing, instant claims 2 and 5 are obvious over Figueiredo/Shilubhai in view of Sareen.
Claims 3 and 21-22 are rejected under 35 USC 103 as being obvious over Figueiredo et al. (US2014/0249158A1, IDS of 03/27/2025) in view of Shilubhai (US2018/0092857A1, IDS of 03/27/2025); and further in view of Berg et al., Biochemistry, 5th edition, New York, W H Freeman 2002 (IDS of 03/27/2025).
Figueiredo in view of Shilubhai teaches the active agent has ionizable amino group or weak acid group as noted above.
However, Figueiredo/Shilubhai do not expressly teach the active ingredient is at least 70% ionized in the aqueous phase and the active ingredient and the nanoparticle electrostatically interact of instant claim 3; and the active ingredient is at least 90% ionized in the aqueous phase of instant claims 21-22. The deficiencies are cured by Berg.
Berg teaches amino ionization in the aqueous phase and in acid solution (e.g., pH 1) where the amino group is protonated (-NH3+) and the carboxyl group is not dissociated (-COOH). As the pH is raised, the carboxylic acid is the first group to give up a proton, inasmuch as its pKa is near 2 (see Figure 3.5 section).
Thus, when pH is between pKa+2 and raised pH, e.g., pH 14 as taught by Berg, the active agent having ionizable amino group would have about 99% ionized in the aqueous phase, as supported by instant publication at [0123], and thus, it would be implicit to electrostatically react nanoparticle with the active agent due to pH change (instant claims 3 and 21-22).
It would have been prima facie obvious to further define ionization of the active agent of Figueiredo/ Shilubhai with the teachings of Berg and such definition would have yielded no more than the predictable result, in the absence of evidence to the contrary.
In light of the foregoing, instant claims 3 and 21-22 are obvious over Figueiredo in view of Shilubhai and further in view of Berg.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-12, 14, 15 and 17-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of patent no. 10,952,967B2.
Although the claims at issue are not identical, they are not patentably distinct because both claims require similar steps (a)-(e) and same pH, active ingredient having weak acid ionizable group, surfactant, organic solvent, water-miscible solvent, additional emulsification steps, nanoparticle diameter and zeta potential, load rate. The difference between them is that the instant invention further requires step (f) while patent ‘967 does not. However, step f. of “removing the remaining organic solvent by evaporation” would be non-inventive because undesired reaction to occur should be avoided from the standpoint of ordinary artisan, devoid of evidence to the contrary.
Consequently, the ordinary artisan would have recognized the obvious variation of the instantly claimed subject matter over the patent ‘967 subject matter.
Claims 1-12, 14, 15 and 17-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of patent no. 12,233,164B2.
Although the claims at issue are not identical, they are not patentably distinct because both claims require similar steps (a)-(f) and same pH, active ingredient having weak acid ionizable group, surfactant, organic solvent, water-miscible solvent, additional emulsification steps, nanoparticle diameter and zeta potential, load rate. The difference between them is that patent ‘164 requires specific active agent (HDAC), while the instant active agent requires active agent comprising weak acid ionizable group. Taking certain active agent(s) vary depending on the intended purpose and/or condition to be treated. Consequently, the ordinary artisan would have recognized the obvious variation of the instantly claimed subject matter over the patent ‘164 subject matter.
Conclusion
All claims examined are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYUNG S CHANG whose telephone number is (571)270-1392. The examiner can normally be reached M-F 8-5.
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/KYUNG S CHANG/Primary Examiner, Art Unit 1613
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