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 . 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 02/20/2026 has been entered.
Priority
The instant application is a 371 of PCT/US2020/049580 filed on 09/04/2020, which claims domestic benefit to US provisional application no. 62/897,254 filed on 09/06/2019.
Status of the Claims
The claim amendments and remarks filed on 02/20/2026 is acknowledged. Claim 1 is amended. Claims 2, 4, 6, 14-15, and 19-25 are cancelled. Claims 1, 3, 5, 7-13, 16-18, and 26-30 are pending.
Claims 26-29 were previously withdrawn in the office action dated 04/15/2025 from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Accordingly, claims 1, 3, 5, 7-13, 16-18, and 30 are being examined on the merits herein.
Withdrawn Rejections
The 35 USC 102 rejection over Medina-Kauwe for claims 1, 5, 7-9, 11, 17, and 30 is withdrawn because amended claim 1 now requires that the nucleic fragments are a plurality of DNA fragments having a range of sizes, and wherein nanoparticles are formed as a direct result of self-assembly of the one or more therapeutic compounds with the plurality of DNA fragments, which has changed the scope of the claims and requires new search and consideration.
The 35 USC 103 rejection over Medina-Kauwe for claims 1, 3, 10, and 17-18, over Medina-Kauwe in view of Dennig for claim 13, and over Medina-Kauwe in view of Bae for claims 12 and 16 are withdrawn because amended claim 1 now requires that the nucleic fragments are a plurality of DNA fragments having a range of sizes, and wherein nanoparticles are formed as a direct result of self-assembly of the one or more therapeutic compounds with the plurality of DNA fragments, which has changed the scope of the claims and requires new search and consideration.
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) 1, 3, 5, 7-9, 12, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bae et al (US20190247313 in IDS filed on 03/28/2023) in view of Kang et al. (Molecular Pharmaceutics, 2015 in IDS filed 02/22/2023) and Mann et al. (Biosensors and Bioelectronics, 2004 in PTO-892).
Bae et al. discloses particle compositions that contain a therapeutic agent and a bile acid or bile acid conjugate, and further disclose the composition can include a cationic moiety and an anionic polymer, which are coupled through electrostatic interactions (see Abstract).
Bae provides a general illustration of their particle composition as seen in FIG. 1A. Bae discloses that the composition contains a complex of a therapeutic agent and a cationic moiety which are electrostatically connected to an anionic moiety that is further covalently linked to a bile acid (paragraph 0057). The compositions form particles with diameters ranging from about 20 nm to about 5000 nm in size (paragraph 0057).
Bae et al. discloses their compositions provide improved bioavailability for therapeutic agents which are currently administered orally, such as anticancer agents including doxorubicin (see paragraph 0059).
Bae et al. demonstrates in Example 3 the preparation of their therapeutic composition suitable for oral delivery comprising of DOX-loaded particles, a bile acid conjugate taurocholic acid (TCA), and an anionic polymer such as heparin or chondroitin sulfate (see paragraph 0143).
Bae et al. discloses that to prepare heparin-TCA (H-TCA) complex with DOX, the DOX was mixed with sheared salmon sperm DNA to get a negative surface charge on the DNA/DOX complex and then mixed with cationic poly-L-lysine to get a complex (termed DDP) to obtain a positively charged surface. Since the salmon sperm DNA used in Bae is sheared, this would meet the limitation of a plurality of DNA fragments. Bae et al. further discloses that the H-TCA was used to coat the cationic DDP complex to form the final therapeutic particle composition. Bae discloses the formed particle was around 200 nm in size after reconstitution (paragraph 0158).
Bae et al. discloses that the formed therapeutic composition comprising the DNA/DOX complex significantly reduced tumor growth in a HepG2 cancer cell xenograft mouse model (see paragraph 0178 and 0184 and FIG. 23A).
Bae, however, does not teach the recited wt/wt ratio of 2:1 to 10:1 nucleic acid fragments to therapeutic compounds. Furthermore, Bae does not explicitly teach the sheared salmon DNA used has a range of sizes.
Kang discloses DNA polyplexes as combinatory drug carriers of doxorubicin and cisplatin (Abstract).
As seen in the illustration of the Abstract, doxorubicin (DOX) physically intercalates with DNA double helices and is further complexed with a positively charged, endosomolytic polymer (Abstract). Kang discloses that compared to free drug, the polyplexes (100-170 nm in size) delivered more drug into the cytosol and nucleus and demonstrated similar of superior (up to 7-fold increase) in vitro cell-killing activity (Abstract).
Kang demonstrates in Figures 1 and 2 (page 2849) of the optimal molar ratios of doxorubicin and nucleic acid interaction for cell-killing effects.
Kang discloses that the IC50 (the drug concentration that causes 50% growth inhibition) values of DOX-DNA (1:1), DOX-DNA (1:2), and DOX-DNA (1:3) were close to the IC50 (0.96 μM) of free DOX, whereas DOX-DNA (1:4) and DOX-DNA (1:5) had lower IC50 values (∼0.8 μM) (last paragraph left column page 2849). Kang further discloses that DOX-DNA (1:5) was preferred over DOX DNA (1:4) because a higher DNA content in DOX-DNA could be beneficial when the DNA is replaced with therapeutic nucleic acids for the codelivery of DOX and nucleic acids (first paragraph right column page 2849). Specifically, Kang discloses that DOX-DNA (1:5) completely intercalated the added DOX, as the filtrate did not contain any DOX after centrifuging the DOX-DNA (1:5) (first paragraph right column page 2849).
Kang concludes that their polyplexes offers the possibility of versatile combination therapies of genetic materials and small molecule drugs that bind to nucleic acids to treat various diseases (Abstract).
Mann discloses an ultrasonic method to rapidly produce DNA fragments from genomic material (Abstract).
Mann discloses that physical methods such as syringe shearing and ultrasound are rapid and simple means to fragment DNA with ultrasound being more versatile and more readily controlled in terms of energy delivery and selection of environmental conditions (second paragraph left column page 946).
Mann demonstrates their ultrasound method to produce varying bp lengths of DNA fragments using salmon sperm DNA as the starting genomic DNA material (section 2.1 left column page 947). Mann discloses that the salmon sperm DNA used had a starting approximate bp length of 2000 (first paragraph under section 3.5 page 953).
Fig. 3 on page 951 demonstrates the effect of ultrasound exposure times on fragmentation patterns of the genomic DNA. Mann demonstrates that the peaks close to the pixel number 40 are the result of non-fragment genomic DNA (last paragraph left column page 950), and further discloses that pixel number 240 was 100 bp fragments (second paragraph right column page 950). Mann also demonstrates in Fig 4 (page 951) and Table 3 (page 952) that their ultrasound method produces fragment DNAs having lengths ranging from 89 bp to 1280 bp length.
It would have been prima facie obvious before the effective filing date of the claimed invention to have routinely optimize the weight ratio of DNA to DOX for the DOX-DNA complex disclosed in Bae by increasing the amounts of DNA as suggested in Kang and further modify the sheared salmon DNA used in Bae by preparing the sheared salmon DNA using the ultrasound method of Mann to generate fragmented salmon sperm DNA having varying lengths of 100-2000 bp as disclosed in Mann to arrive at the claimed invention.
An ordinary skilled artisan would have performed routine optimization to arrive at the recited wt/wt ratio of DNA:DOX by increasing the amount of DNA based on Kang providing guidance that higher DNA content in the DNA-DOX complex such as 5:1 molar ratio resulted in complete intercalation and may be beneficial for co-delivery of DNA and DOX, which indicates that increasing the amount of DNA in the DNA:DOX ratio is a result effective variable. See MPEP 2144.05 II
One of ordinary skill in the art would have combined prior art elements according to known methods for generating sheared salmon sperm DNA fragments of varying lengths to yield predictable results and would have a reasonable expectation of success in doing so because Bae provides guidance of using sheared (fragmented) salmon sperm DNA to form a DOX-DNA complex that is further associated to polylysine via electrostatic interactions to obtain a positively charged complex and form the particle composition. Furthermore, Mann demonstrates an ultrasound method to fragment 2000 bp salmon sperm DNA into varying bp fragment lengths as low as 89 bp, which suggests the ordinary skilled artisan would have considered that the sheared salmon sperm DNA used in Bae can range from 89-2000 bp and would have used DNA having these lengths or perform methods such as disclosed in Mann to obtain these bp lengths to form the DOX-DNA complex.
Lastly, the nanoparticle composition formed as disclosed by the combined teachings of Bae, Kang, and Mann described above meets the limitation of nanoparticles formed as a direct result of self-assembly of doxorubicin and DNA fragments because the combined references provide guidance of forming a nanoparticle that involves complexing the doxorubicin to sheared salmon DNA. It is also noted that the term “comprising” in the claims is open-ended and does not exclude additional, unrecited elements (MPEP 2111.03 I), which means additional components in the nanoparticle composition such as the carrier polypeptide is within scope of the instant claims.
Claim(s) 10-11 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Bae et al (US20190247313 in IDS filed on 03/28/2023) in view of Kang et al. (Molecular Pharmaceutics, 2015 in IDS filed 02/22/2023) and Mann et al. (Biosensors and Bioelectronics, 2004 in PTO-892), as applied to claim 1 above, and further in view of Medina-Kauwe et al. (US 20190175747 in PTO-892 dated 04/15/2025).
The combined teachings of Bae, Kang, and Mann are as described above and teach the composition of instant claim 1 as discussed above.
The combined references, however, do not teach using other therapeutic compounds such as mitoxantrone recited in instant claim 11. Furthermore, the combined references do not teach further comprising a ligand that targets the nanoparticles to specific cells such as binding to a tumor specific antigen.
Medina-Kauwe et al. discloses compositions comprising nanoparticles comprising a carrier polypeptide and a double-stranded oligonucleotide, wherein the carrier polypeptide comprises a cell-targeting segment, a cell-penetrating segment, and an oligonucleotide-binding segment (see Abstract).
Medina-Kauwe et al. discloses that the carrier polypeptide that comprises a cell-targeting segment can bind to a molecule present on the surface of a cell and that the target molecule can be a cancer antigen (see paragraph 0079). Medina-Kauwe et al. discloses that the carrier polypeptide that comprises an oligonucleotide-binding segment can be polylysine or positively charged (see paragraph 0036). Medina-Kauwe et al. discloses the oligonucleotide-binding segment binds the double-stranded oligonucleotide component of the nanoparticle via electrostatic bonds (see paragraph 0086). Lastly, Medina-Kauwe et al. discloses that their nanoparticles are more effective at killing target cancer cells than liposomal doxorubicin and is also effective at killing cancer cells that are resistant to chemotherapeutic drugs, including antibodies (such as an anti-HER2 antibody, namely trastuzumab) or small molecule chemotherapeutic agents, such as doxorubicin (for example LipoDox) (see paragraph 0064).
Medina-Kauwe et al. discloses in some embodiments, a small molecule compound such as a chemotherapeutic agent doxorubicin is bound to the double-stranded oligonucleotide by electrostatic interactions or by intercalating in the double-stranded oligonucleotide (see paragraph 0090). Medina-Kauwe et al. discloses that other small molecule chemotherapeutic agents such as other anthracyclines (daunorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin), alkylating or alkylating-like agents (such as carboplatin, carmustine, cisplatin, cyclophosphamide, melphalan, procarbazine, or thiotepa), or taxanes (such as paclitaxel, docetaxel, or taxotere) can be used (see paragraph 0090). Medina-Kauwe et al. discloses that in some embodiments, the double-stranded oligonucleotide is DNA or RNA, and in some embodiments, the RNA is synthetically produced (paragraph 0088). Medina-Kauwe also discloses in other embodiments, the double-stranded oligonucleotide is about 10 base pairs to about 100 base pairs in length (see paragraph 0034). Medina-Kauwe et al. discloses that in some embodiments, the molar ratio of the double-stranded oligonucleotide to the small-molecule drug in the nanoparticle composition is about 1:1 to about 1:60 (see paragraph 0013).
Medina-Kauwe et al. demonstrates in Example 1 (see paragraphs 0209-0215) a nanoparticle assembly which comprises of a carrier polypeptide (HerPBK100), 30 base pair double-stranded DNA (dsDNA) oligonucleotide, and doxorubicin (DOX). Medina-Kauwe et al. disclose the nanoparticles formed were about 35 nm in size when molar ratios of 4:1, 5:1, and 6:1 (HerPBK100:dsDNA) were combined (paragraph 0216).
Furthermore, Medina-Kauwe et al. demonstrates that the nanoparticles assembled in Example 1 were incubated with various cancer cell lines including MDA-MB-435 (human cancer) cells, BT474 (human breast cancer) cells, etc. listed in paragraph 0219. Medina-Kauwe et al. discloses the nanoparticles (named “Eos-001”) were effective in decreasing cell survival of these various cancer cell lines (see FIG 4-12 and paragraphs 0223-0232).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the doxorubicin as disclosed by the combined teachings of Bae, Kang, and Mann described above with the mitoxantrone as disclosed in Medina-Kauwe to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (doxorubicin) for another (mitoxantrone) to obtain predictable results and would have a reasonable expectation of success in doing so because Medina-Kauwe provides guidance that either doxorubicin or mitoxantrone are suitable therapeutic agents that can be used to complex to a nucleic acid and form a nanoparticle.
In regards to instant claims 11 and 30, it would have also been prima facie obvious before the effective filing date of the claimed invention to have further modified the nanoparticle composition as disclosed by the combined teachings of Bae, Kang, Mann, and Medina-Kauwe described above by including a carrier polypeptide that comprises a cell-targeting segment can bind to a molecule such as a cancer antigen present on the surface of a cell as disclosed in Medina-Kauwe to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Medina-Kauwe provides guidance of further including this cell-targeting carrier polypeptide in a similar nanoparticle composition that involves the formation of a DNA-DOX complex.
Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over Bae et al (US20190247313 in IDS filed on 03/28/2023) in view of Kang et al. (Molecular Pharmaceutics, 2015 in IDS filed 02/22/2023) and Mann et al. (Biosensors and Bioelectronics, 2004 in PTO-892), as applied to claim 1 above, and further in view of Medina-Kauwe et al. (US 20190175747 in PTO-892 dated 04/15/2025) and Dennig et al. (Plos One, 2011 in PTO-892 dated 04/15/2025).
The combined teachings of Bae, Kang, Mann, and Medina-Kauwe are as described above and teach the composition of claim 1 as discussed above. Furthermore, Medina-Kauwe discloses their oligonucleotides were obtained from Eurofins Operon (see paragraph 0210) and discloses that the DNA oligonucleotides have specific sequences as shown in paragraph 0210.
The combined references, however, do not disclose wherein the nucleic acid fragments comprise chemically synthesized DNA.
Dennig et al. discloses a multiple site saturation mutagenesis method termed “OmniChange” (see Abstract). Dennig et al. discloses using ten oligonucleotides with specific sequences (Table 2 page 4)as PCR-primers for their method (see page 7 right column, section titled “Mutagenic oligonucleotide design”). Lastly, Dennig et al. discloses the oligonucleotides were synthesized by Eurofins MWG Operon (see page 7 bottom left column to top right column).
It would have been prima facie obvious before the effective filing date of the claimed invention to have included in the nanoparticle composition as disclosed by the combined teachings of Bae, Kang, Mann, and Medina-Kauwe described above the DNA oligonucleotides disclosed in Medina-Kauwe and further preparing these DNA oligonucleotides by synthesizing them through Eurofins Operon as disclosed in Denning to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both Bae and Medina-Kauwe disclose that their respective nucleic acids are suitable to form a complex with the doxorubicin that is further associated to polylysine via electrostatic interactions to obtain a positively charged complex and form a nanoparticle. Furthermore, Medina-Kauwe discloses that their DNA oligonucleotides contained specific sequences that were obtained from Eurofins Operon, and Denning provides guidance of synthesizing specific sequences of oligonucleotides through Eurofins Operon.
Response to Arguments
Applicant’s arguments filed on 02/20/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant presents arguments over the 35 USC 102 rejection and the 35 USC 103 rejection over Medina-Kauwe on the basis that the claims recite “a plurality of DNA fragments having a range of sizes” and that the “nanoparticles are formed as a direct result of self-assembly of the one or more therapeutic compounds with the DNA fragments”.
However, these features are rendered obvious by the new rejection using Bae as the primary reference to arrive at the recited nanoparticle composition, rendering Applicant’s argument over Medina-Kauwe moot.
Furthermore, Applicant states that the teachings of Medina-Kauwe require the use of a carrier polypeptide to form nanoparticle, whereas their claimed invention can form the nanoparticle as a result of the nucleic acid fragment – drug complex. Applicant states while the claims recite the open-ended term “comprising”, the claims now also recite “nanoparticles as a direct result of a self-assembly of the one or more therapeutic compounds with the DNA fragments”. Applicant states that the complexing of the double stranded oligonucleotide to the small-molecule drug is optional in Medina-Kauwe and not a necessary feature to form the nanoparticles.
Applicant’s argument described above were not found persuasive because as noted above, the teachings of Medina-Kauwe are not relied upon in forming the claimed nanoparticle composition. However, to the extent the arguments applies to Bae, the carrier polypeptide disclosed in Medina-Kauwe is still within scope of the claims due to the open-ended term “comprising”, which means any additional structural components to form the nanoparticles are within scope of the claims. Furthermore, as discussed in the new rejection above, the nanoparticle composition formed from the new combination of references meets the limitation of nanoparticles formed as a direct result of self-assembly of doxorubicin and DNA fragments because the combined references provide guidance of forming a nanoparticle that involves complexing the doxorubicin to sheared salmon DNA.
Applicant states in regards to instant claim 13 the nucleic acid fragments comprise chemically
synthesized DNA of differing nucleotide lengths and not oligonucleotides of the same length. Applicant
states that Denning teaches a multiple site mutagenesis method to generate libraires of high genetic
diversity in a single PCR step and does not rectify the deficiencies of Medina-Kauwe. Applicant further
states it would be difficult to arrive at the recited molar ratios of nucleic acid fragments and therapeutic
compounds disclosed Medina-Kauwe because the oligonucleotide taught in Medina-Kauwe does not
exceed 100 bp, and the method of Denning is not applicable to oligonucleotides that are 100 bp or
smaller.
Applicant’s argument described above was not found persuasive because the new rejection described above provides guidance of using sheared salmon sperm DNA containing DNA fragments ranging from 89bp-2000bp in length , to form the DNA-DOX complex. Furthermore, the obviousness rationale described above does not rely on whether the method of Denning is capable of producing the oligonucleotides of Medina-Kauwe. Rather, the teachings of Denning were used to establish that the oligonucleotides of Medina-Kauwe were chemically synthesized based on Medina-Kauwe et al. disclosing their DNA oligonucleotides were obtained from Eurofins Operon, and Dennig et al. providing guidance that Eurofins Operon synthesizes oligonucleotides as described above. Lastly, an ordinary skilled artisan would have performed routine optimization to arrive at the recited ratios of DNA:DOX in the instant claims as discussed above.
Applicant states in regards to instant claims 12 and 16 that Bae teaches the use of various polymers and coatings to produce their therapeutic composition and therefore do not rectify the deficiencies of Medina-Kauwe. Applicant states that Bae does not teach the production of nanoparticles by complexing nucleic acid fragments such as naturally occurring DNA. Applicant further states that a skilled artisan would have a hard time achieving the molar ratios disclosed in Medina-Kauwe because the double-stranded oligonucleotide of Medina-Kauwe does not exceed 100 bp, and the likelihood of the sheared salmon sperm DNA fragments disclosed in Bae being less than 100 bp is very low. Therefore, Applicant states that an ordinary skilled artisan would not modify the nanoparticles taught by Medina-Kauwe with the sheared salmon sperm fragments of Bae without violating the requirement that the double-stranded oligonucleotide is 100 bp or smaller.
Applicant’s argument described above was not found persuasive because the new rejection described above provides guidance of using sheared salmon DNA having a range of sizes from 89bp to 2000bp. It is also noted that Bae does teach the production of nanoparticles by first complexing nucleic acid fragments (sheared salmon sperm DNA) to the doxorubicin. Furthermore, an ordinary skilled would have performed routine optimization to increase the amount of DNA present and arrive at the recited ratios as discussed in the new rejection above.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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