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 .
Priority
Acknowledgement is made of the Applicant’s claim of domestic priority to provisional US application 63/391,895 filed 25 July 2022.
Examiner's Note
Applicant's amendments and arguments filed 20 July 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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. In the Applicant's response, filed 20 July 2026, it is noted that claim 1 has been amended. Support can be found in the claims as originally filed.
Election/Restrictions
Applicant has previously elected the following species:
PNG
media_image1.png
200
400
media_image1.png
Greyscale
Applicant’s elected species (above) appears to be free of the art. As such, examination has proceeded to additional species covered by the instant claims.
Status of the Claims
Claims 1-27 are pending.
Claims 9-14 and 24-27 are withdrawn.
Claims 1-5, 7, and 15-23 are rejected.
Claims 6 and 8 are allowable.
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.
Claims 1-5, 7, and 15-23 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Biomedicine & Pharmacotherapy 125 (2020) 109988) in view of Laird et al. (Clin Cancer Res; 24(20) October 15, 2018) in view of Sigalov (US 2013/0045161) in view of He et al. (Anticancer Research 2019, 39: 1711-1718).
Chen teaches a lipid nanoparticle comprising nitroimidazoles (shown below) conjugated to PLA-PEG linkers that are used to form the shell of the nanoparticle (Fig 1, Fig 2). The core of the nanoparticle comprises DDP (cisplatin) (Fig 2).
PNG
media_image2.png
200
400
media_image2.png
Greyscale
The above nitroimidazole reads on the structure of instant claim 1 wherein M is absent, R1 is C6 alkyl substituted by N(R)2, and wherein R is H. Furthermore, it is noted that the instant claims put no limits on using multiple Markush selections for each of M and R1, thus the further conjugation of a PEG molecule onto the imidazole reads on the instant claims wherein M is an alkyl substituted with oxygen atoms. The further conjugation of a DSPE, which would bind via an ether linkage, amide linkage, or a combination of both all of which are found as suitable substitutions of M, reads on Formula III wherein the P(O) group of DPSE read on Q in the instant claims. R3 can an oxygen and R2 is an alkyl group substituted by C(O) and -O- groups as permitted in the instant claims.
Chen teaches that hypoxia targeted drug delivery systems are a promising strategy in cancer therapies (pg 1, ¶2). The above nitroimidiazoles can be incorporated into lipid-polymer hybrid nanoparticles with a polymer core comprising a therapeutic agent (cisplatin) surrounded by a phospholipid layer, which combines the advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes (pg 2, ¶2). The lipid can be DSPE, which is exemplified with a PEG-linked hyaluronic acid (pg 2, sec 2.1-2.2), but can be attached to either HA or NI ligands via PEG linkages (pg 2, sec 2.3). The nanoparticles of Chen can be used to target various cancers including lung cancer (pg 2, ¶3-4). Regarding the amounts of each agent, Chen teaches using 200 mg of the nitroimidazole polymer to 50 mg of the cisplatin (pg 2, sec 2.3).
Chen does not teach combining nitroimidazole with DSPE in the nanoparticle. Chen does not teach additional therapeutic agents, contrast agents, or brain efflux suppressing agents being used in the nanoparticle.
Laird teaches that lung cancer is often treated with chemotherapy of cisplatin and etoposide, however is often met with tumor recurrence (pg 5143, ¶1). Laird teaches the need to complement and enhance current treatments (id) and has found that PARP inhibitors such as talazoparib effectively sensitizes lung cancer cells to irradiation and thus provide a powerful tool to improving lung cancer therapy (abstract).
Sigalov teaches that greater target selectivity and better delivery efficiency are two major goals in the development of imaging contrast agents [0003]. Tumor-targeted contrast agents based on a nanoparticle formulation may offer enhanced sensitivity and specificity for in vivo tumor imaging [0003].
He teaches that downregulation of P-glycoprotein may be a promising strategy to overcome cisplatin resistance (abstract). He tested using dofequidar fumarate, a P-gp inhibitor, and found a synergistic with cisplatin result in vivo indicating that the inhibition of P-gp by dofequidar fumarate enhanced cisplatin efficacy (pg 1714, ¶2).
It would have been prima facie obvious to prepare the nanoparticles of Chen wherein the particle is a lipid-polymer hybrid nanoparticle with a polymer core surrounded by a phospholipid layer. Chen teaches the phospholipid layer may comprise DSCE and can be linked by PEG to the nitroimidazole derivative, above. The inner core can comprise the active agent, cisplatin, and the nanoparticle can be used to treat lung cancer. It would have been obvious to further include an additional therapeutic agent, such as talazoparib, in the core based on its known use for treating lung cancer and enhancing the sensitivity of the cancer cells to irradiation. Moreover, the inclusion of dofequidar fumarate along with cisplatin, in the invention of Chen, to enhance the efficacy of cisplatin and reduce resistance thereof in vivo would have been obvious. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (see MPEP § 2144.07). Moreover, it would have been obvious to further include a contrast agent in the nanoparticle based on the teaching of Sigalov that contrast agents can be used to enhance sensitivity and selectivity of the nanoparticles for in vivo tumor imaging, which would thus enhance the treatment as well.
Regarding the concentration of either the lipid or the therapeutic agent, Chen teaches using 200 mg of the lipid-linked nitroimidazole to 50 mg of the active. While these are not provided in mol%, it can be estimated that the amount of active is greater than 0.025 mol% and less than 95 mol%, and thus reads on instant claim 16.
Regarding instant claim 18, Chen teaches that phospholipids can be used to form the outer shell layer, thus reading on the presence of a hydrophobic therapeutic agent which can be a lipid.
The combination of Chen, Laird, and Sigalov accordingly render obvious instant claims 1-5, 7, and 15-23.
Allowable Subject Matter
Instant claims 6 and 8 are free of the art. The prior art does not teach said ligands in combination with a lipid and therapeutic agent in a nanoparticle formation.
Response to Arguments
Applicant's arguments filed 20 July 2026 have been fully considered but they are not persuasive. The Applicant argues, on pages 15-16 of their remarks, that Chen teaches nitroimdazole conjugated toe PLA-PEG polymers and that the presently claimed nanoparticles do not teach imadazoles conjugated to any group. The Applicant further argues that variable R and R1 exclude any possibility of conjugation in general.
In response, the Markush structure of the instant claims is very broad and includes an infinite number of combinations. Looking to Formula III, as explained above, the structure of Chen comprising a nitroimidazole ligand, PEG linkage, and DSPE lipid tail all fall within the permitted variables. As such, the composition of Chen renders obvious the instant claims. There is no need to exclude the PLA-PEG linker, but rather modify it to be a PEG-DSPE linker, as taught as being a suitable alternative by Chen. Therefore, there is no need to modify Chen so that it is inoperable.
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 ANDREW S ROSENTHAL whose telephone number is (571)272-6276. The examiner can normally be reached M-F 8-5pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613
Prosecution Insights