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 .
Applicant’s arguments, filed 02/27/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 16-25, 27-35, and 37-62, are pending.
Claims 39-62 are withdrawn.
Claim Objections
Claim 32 is objected to because of the following informalities: “multidentate organic ligand is” should read “multidentate organic ligands are”, in order to be consistent with the terminology of newly amended claim 31. Appropriate correction is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16-25, 28-34, 37, and 38, are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al (US 20170231903 A1, cited on IDS dated 07/26/2023), in view of Giliopoulos et al (Molecules, Jan 2020, 25(1), 185, pp. 1-28, hereinafter “Giliopoulos”), Wang et al (Adv Mater, 2018, 30, 1800202, pp. 1-14, hereinafter “Wang”), and Tromsdorf et al (US 20120201760 A1), as evidenced by Weberding (Outpatient Oncology Drug Series: Doxorubicin Is the Infamous Red Devil, 2015, pp-1-6) and Burggraef et al (Nat Commun, 2024, 15:9814, pp. 1-12).
Lin et al teach metal-organic framework (MOF) nanoparticles, including TBP-Hf@DOTAP/DSPE-PEG nanoparticles, coated with DSPE-PEG (phosphate functionalized polymer) (¶¶ 3, 290-394, ex. 17, claim 23). The MOF is loaded with a drug such as INCB24360 or doxorubicin (ex. 13, claim 22). As evidenced by Weberding, doxorubicin in a cytotoxic chemotherapy drug. The nanoparticles have a particle size of less than about 1,000 nm, such as than about 500 nm, with particular embodiments having a Z-average diameter ranging from 102.3 to 110.4 (¶ 173, table 8). The PEG used in ex. 17 was PEG 2k (¶ 394). The coating layers surround or partially surround the nanoparticle core (¶ 175). The TBP ligand is 5,10,15,20-tetra(p-carboxylphenyl)porphyrin (¶ 217, fig. 29). The organic ligand is a bridging polydentate (¶ 167). Suitable metals for the MOFs include Hf ions, Zn ions, etc. (¶¶ 210, 216-217). Other suitable disclosed MOFs include UiO-66, etc. (¶ 201). In embodiments, drug loading was calculated to be 9.4 wt% (¶ 371). Hydrophilic polymers, including PEG can be used (¶ 225).
Lin et al do not appear to teach a phosphate terminated polymer disposed over the MOF.
Giliopoulos teaches it was known that MOF nanoparticles contain superficial metal ions that are coordinatively unsaturated, therefore, they can be exploited for the coordination for polymer bearing functional groups with a high affinity to metal ions such as amines or phosphate groups (3.3 1st ¶). It was known that PEGylating the surface of MOF nanoparticles prevents the aggregation of pure MOF nanoparticles in aqueous media without affecting the therapeutic results (pg 16 3rd ¶).
Giliopoulos do not specifically teach that the PEG are phosphate terminated.
Likewise, Wang teaches MOF surface functionalization with hydrophilic PEG prevented nanoparticle aggregation, improved colloidal stability in water, prevented burst release, etc. (pg 8 2nd col 2nd ¶, pg. 9 1st col 1st ¶).
Wang do not specifically each that the Peg are phosphate terminated.
Tromsdorf et al teach metal oxide nanoparticles coated with phosphorylated mPEG (abs, fig. 6). The phosphate functionalized PEG chain length is adjusted in order to prevent aggregation of nanoparticles under physiological conditions and to minimize cytotoxicity and unspecific cell uptake into macrophages (¶ 15). The chain length is adjusted by using a poly(ethylene glycol) with different molecular mass, such as in the range of 400 to 2000 g/mol (claim 9). As evidenced by Burggraef et al, methoxy PEG 2,000 has 45 ethylene glycol repeating units (pg. 2 1st col 3rd ¶).
Regarding the active agent of claim 16, it would have been obvious to encapsulate a drug within the MOF, such as INCB24360 or doxorubicin, as taught by Lin et al.
Regarding the phosphate terminated polymer of claim 16, it would have been obvious to modify the MOF nanoparticles of Lin et al by using other known phosphate functionalized polymers suitable for disposition over MOFs, including phosphate functionalized PEG, where Giliopoulos teaches MOF nanoparticles can be functionalized by polymers bearing phosphate functional groups, and teaches PEG as a suitable polymer. The skilled artisan would have motivation to include a PEG polymer bearing phosphate functional groups, where MOF PEGylation was known to prevent aggregation compared to pure MOF nanoparticles without affecting therapeutic results, as taught by Giliopoulos and Wang, as well as improve colloidal stability in water, prevent burst release, etc., as taught by Wang.
Further, it would have been obvious to select from phosphate containing polymers that were known to be suitable for functionalizing metal containing nanoparticles in order to prevent aggregation, such as phosphorylated mPEG, as taught by Tromsdorf et al, a phosphate terminated hydrophilic polymer (see instant claim 24).
Regarding claim 17, it would have been obvious to formulate the MOF nanoparticles made obvious above within the size range taught by Lin et al, such as less than about 1,000 nm, less than about 500 nm, or 102.3 to 110.4 nm from the working embodiments. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 18, it would have been obvious to attach the phosphate polymer made obvious above to one or more metal ions, where Giliopoulos teaches the phosphate groups of polymers can be functionalized to the MOF nanoparticles via the superficial metal ions, thereby appearing to meet the claimed limitation.
Regarding claims 19-21, the phosphate terminated mPEG polymer made obvious above appears to be linear, as taught by Tromsdorf.
Regarding claims 22-24, it would have been obvious to linear phosphate terminated methoxy PEG 2000 (45 repeating ethylene glycol units) of Tromsdorf et al, for the same reasons discussed above.
Further, while an ethylene glycol repeating unit of 45 is made obvious above, it would have also been well within the relative skills of the skilled artisan to routinely optimize the polymer chain length and molecular weight of the polymer within the ranges instantly claimed in order to achieve desired optimal physical properties. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A).
Regarding claim 25, it would have been obvious to use known PEG molecular weights taught to be suitable for disposition over MOF nanoparticles, such as PEG 2k (i.e., 2,000 g/mol), as taught by Lin et al, falling within the claimed range.
Regarding claims 28 and 29, the plurality of metal ions in the MOF made obvious above comprise hafnium atoms.
Regarding claim 30, it would have been obvious to modify the MOF made obvious above by substituting zinc ions for hafnium ions, which are taught to be suitable by Lin et al.
Regarding claims 31, 32, and 34, it would have been obvious to modify the MOF made obvious above by substituting the TBP-Hf framework for other MOFs taught to be suitable, such as UiO-66 (Zr ions and 1,4-benzenedicarboxylate), as taught by Lin et al.
Regarding claim 33, the TBP ligand in the MOF made obvious above appears to be a multidentate organic ligand comprising two or more nitrogen atoms, as shown in fig. 29 of Lin et al.
Regarding claim 37, it would have been obvious to select from doxorubicin as the API, as taught by Lin et al, a cytotoxic API as evidenced by Weberding above.
Regarding claim 38, it would have been obvious for the skilled artisan to start with known amounts of active agent suitable for MOFs, such as 9.4 wt%, and adjust from there in order to achieve desired therapeutic activity for various treatments and different active agents. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A).
Response to Arguments
Applicants arguments over the previously cited combination of Lin et al in view of Wang et al (Nat Commun, 2020, 11, 2495, pp. 1-8) are moot, as Wang et al is no longer cited as necessitated by amendment.
Applicants assert the MOF nanoparticles as instantly claimed have surprising and unexpected properties, where the nanoparticles “do not agglomerate significantly.”
Respectfully, this argument is not persuasive. Where surface functionalization of MOFs with phosphate containing PEGs were known from Giliopoulos and Tromsdorf to prevent aggregation of MOF nanoparticles, and it was known from Wang that MOF surface functionalization with hydrophilic PEG prevents nanoparticle aggregation, improves colloidal stability in water, etc., it would have been reasonably expected, that upon disposing the phosphate terminal PEG polymer over the MOF for the same reasons discussed above, that agglomeration would be limited, as agglomeration is associated with aggregation and colloidal stability.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Lin et al (US 20170231903 A1, cited on IDS dated 07/26/2023), Giliopoulos et al (Molecules, Jan 2020, 25(1), 185, pp. 1-28, hereinafter “Giliopoulos”), Wang et al (Adv Mater, 2018, 30, 1800202, pp. 1-14, hereinafter “Wang”), and Tromsdorf et al (US 20120201760 A1), as applied to claims 16-25, 28-34, 37, and 38 above, and further in view of Horcajada-Cortes et al (US 20100226991 A1).
The references are discussed above but do not specifically teach the weight percent of the polymer relative to the total weight of the nanoparticle.
Horcajada-Cortes et al teach metal-organic framework (MOF) nanoparticles that are surface modified with a surface active agent that may be a phosphate-containing surface agent, such as polyethylene glycol (abs, ¶¶ 29, 73, 85, 935, table 16 ). The PEG surface coatings on MOF nanoparticles were known to be included from 3.8-18.5 wt% of the nanoparticles (table 25, ¶ 950).
It would have been obvious to modify the combination made obvious above by including known amounts of phosphate modified PEG suitable for MOF nanoparticles, such as from 3.8-18.5 wt%, overlapping the claimed range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Lin et al (US 20170231903 A1, cited on IDS dated 07/26/2023), Giliopoulos et al (Molecules, Jan 2020, 25(1), 185, pp. 1-28, hereinafter “Giliopoulos”), Wang et al (Adv Mater, 2018, 30, 1800202, pp. 1-14, hereinafter “Wang”), and Tromsdorf et al (US 20120201760 A1), as applied to claims 16-25, 28-34, 37, and 38 above, and further in view of Mirkin et al (WO 2019032241 A1, cited on IDS dated 06/26/2025).
The references are discussed above but do not specifically teach PCN-222.
Mirkin et al are discussed above and further teach it was known that PCN-222, UiO-66, etc., were suitable for attachment via the phosphate termination and active encapsulation (abs, ¶ 142, claim 3).
It would have been obvious to modify the MOF nanoparticle made obvious above by substituting the PCN-222 for the MOF, which was known to be suitable for phosphate terminated attachment of polymers, and are suitable for encapsulating an active agent, as taught by Mirkin et al.
Conclusion
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 JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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