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 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.
Priority
The instant application filed, 04/28/2021, claims domestic benefit to US provisional application 63/045,275, filed 06/29/2020.
Status of Application, Amendments, and/or Claims
Applicant’s response of 01/12/2026 is acknowledged. Claims 11, 28, and 33 are amended and claims 1-10, 12-15, 23-24, and 31 are cancelled. Claims 11, 16-22, 25-30, and 32-33 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 09/12/2025,
Claims 11, 28, and 33 were objected to. Applicant’s amended claims with proper markings has overcome the objections and the objections are withdrawn.
Claims 11, 13, 16-18, 22, 24, and 27-28 were rejected under 35 USC 103 over Clift in view of WO’323, and Markoutsa; claims 19-21, 25-26, 29-30, and 32 were rejected under 35 USC 103 over Clift, WO’323, Markoutsa, and Chen; claims 21, 23, and 31 were rejected under 35 USC 103 over Clift, WO’323, Markoutsa, and Shtutman; and claim 33 was rejected under 35 USC 103 over Shtutman, WO’323, Markoutsa, and Clift. Applicant’s amendment to independent claims 11, 28, and 33 to limit the antibody to comprising an anti-PD-L1 or anti-PD-1 antibody has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are new as necessitated by applicant’s amendment to the claims.
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 11, 16-18, 21-22, 27-28, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Wu, Y., et al (2019) PD-L1 distribution and perspective for cancer immunotherapy- blockade, knockdown, or inhibition Frontiers in Immunology 10(2022); 1-15 in view of Clift, D., et al (2017) A method for the acute and rapid degradation of endogenous proteins Cell 172; 1692-1706, WO 2018/231323 (Thayumanavan, S. and J. Zhuang) 20 Dec 2018, and Markoutsa, E., and P. Xu (2017) Redox potential sensitive N-acetyl cysteine-prodrug nanoparticles inhibit the activation of microglia and improve neuronal survival Mol Pharm 14(5); 1591-1600.
Wu teaches that cancer immunotherapy involves blocking the interaction between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, PD-L1 antibody therapy has shown efficiency in blocking membrane PD-L1 and efficiency in treating some advanced carcinomas. However, this therapy has limited effects on many solid tumors, suspecting to be related to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. Wu provides a review summarizing cellular distribution of PD-L1 and the versatile functions of intracellular PD-L1. Wu teaches that the intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity leading to tumor clearance (abstract).
Wu teaches that IHC studies of patient tumor tissues suggest that PD-L1 positive immune responses may appear to be on the tumor cell membrane and in the cytoplasm and has also demonstrated that, in papillary thyroid carcinoma, patients with positive cytoplasmic PD-L1 expression had shorter disease-free survival than those with negative cytoplasmic PD-L1 expression, highlighting the function of cytoplasmic PD-L1. Wu also teaches that the function of cytoplasmic PD-L1 may be related to the promotion of cancer cell growth. By silencing PD-L1 with specific siRNA in SKOV3, an ovarian cell line with negative membrane PD-L1 but positive cytoplasmic PD-L1, inhibition in cell growth and migration was demonstrated. Wu teaches that knockdown of cytoplasmic PD-L1 could benefit cancer immunotherapy (page 3, cellular PD-L1 distribution). Wu further teaches that cytoplasmic PD-L1 results from endogenous translation and that it performs functions such as transfer to membrane, shorten disease-free survival, and cell growth and migration as well as enhancing chemo-resistance. Wu also teaches gene and chemo inhibitor treatments (page 4, Table 2, “cPD-L1”).
Wu also teaches that intracellular PD-L1 may transfer to the cell surface and resume the ability of immune escape and postulates that intracellular PD-L1 may be the reservoir for membrane PD-L1, which may explain some failure in PD-L1 positive cohort as this translated membrane PD-L1 requires more frequent antibody administration and higher dosage for efficient cancer immunotherapy (page 5, right column, paragraph 2). Wu also teaches the potential of intracellular PD-L1 to secrete outside of cells (page 5, right column, paragraph 3).
Wu teaches the use of gene silencing, such as RNA targeting techniques and CRISPR technology to “switch off” PD-L1 expression, resulting in low protein production at any location, but teaches limitations associated with delivery. Wu suggest that methods such as nanoparticles or polymers could be used (page 6, right column, paragraphs 1-2; page 9, right column, paragraph 1).
Wu teaches various PD-1 and PD-L1 antibodies that have been approved by the FDA for cancers including breast cancer (page 3, Table 1; page 9, Table 4), demonstrating the relevance of PD-L1 targeting in these cancers.
Wu, however, does not disclose delivering an anti-PD-L1 antibody to the interior of the cell using the claimed methods.
Clift teaches that traditionally, DNA-modifying methods have been used to knockdown proteins on the gene level, such as with CRISPR/Cas9 technology and RNA-targeting methods. However, in both approaches, protein depletion is indirect and dependent on the inherent turnover of the protein. Consequently, long-lived proteins take more time to deplete, or may be resisting to DNA- and RNA-targeting depletion methods all together. Clift sought to develop a truly posttranslational protein depletion method based on protein targeting antibodies. Antibodies bind to proteins with high affinity and specificity, they are widely available commercially, and can be produced for almost any protein with relative ease. Antibodies are, therefore, ideal as the basis of a protein-targeting method. Clift teaches that a widely applicable protein depletion method that acts exclusively at the protein level is lacking and that such a method would allow for the acute depletion of endogenous proteins (page 1692, left column, paragraph 1 – right column, paragraph 2).
Clift teaches that antibody bound pathogens can be recognized by the cytosolic antibody receptor, TRIM21, and that TRIM21 is an E3 ubiquitin ligase that binds with high affinity to the Fc domain of antibodies. Clift further teaches that TRIM21 is widely expressed in diverse cell types and tissues, which is necessary for its physiological role and that, during infection, TRIM21 recruits the ubiquitin-proteasome system to antibody-bound pathogens, leading to their destruction (page 1692, right column, paragraph 3). In the study performed by Clift, TRIM21 was repurposed to establish a method to degrade endogenous proteins allowing for the degradation of proteins within minutes of application (page 1693, left column, paragraph 1). Clift provides a diagram of the mechanism behind Trim-Away in the graphical abstract which shows that an antibody enters the cell and binds to an endogenous protein. TRIM21 then binds to the Fc region of the antibody and the entire complex is degraded via proteasome.
Clift reasoned that TRIM21 could be used as a tool to drive the degradation of exogenous proteins by using a 3-step strategy, coined “Trim-Away”: First, exogenous TRIM21 is introduced; second, the antibody against the protein of interest is introduced; and third, TRIM21-mediated ubiquitination followed by degradation of the antibody-bound protein of interest (page 1693, right column, paragraph 2; Fig. 1A). To test the Trim-Away strategy, experiments were performed in mammalian cell lines that had been transfected with mCherry-Trim21 vectors (page 1693, right column, paragraph 2; page e5, “transient protein expression” and “stable cell lines”). Clift teaches that Trim-Away performed efficiently when TRIM21 is ectopically overexpressed via transduction or transfection (page 1702, left column, paragraph 4). Clift also teaches that, in some cells, endogenous levels of TRIM21 are sufficiently high for protein degradation (page 1703, right column, paragraph 5).
Clift teaches that aberrant protein expression or activation is a hallmark of many human diseases such as neurodegeneration and cancer. It may become possible to adapt the Trim-Away method to develop novel therapeutics that target disease causing proteins for degradation (paragraph bridging pages 1703-1704).
In studies performed by Clift, antibodies were introduced into the cells via microinjection or electroporation (page 1694, left column, paragraph 4; page 1702, left column, paragraph 3; page e5, paragraphs 5-6.). Clift teaches that in the microinjection studies, antibodies were injected at concentrations including 0.73 mg/mL (anti-GFP), 0.08 mg/mL (anti-Eg5), and 5 mg/mL (anti-polyglutamine 3B5H10) (page e5, paragraph 5). In studies of electroporation, antibodies were diluted to 0.5-1 mg/mL in PBS prior to electroporation (page e5, paragraph 6). All of these reported concentrations were shown to be effective in degrading proteins via TRIM21.
WO’323 teaches that trafficking proteins and other biological macromolecules across a cellular membrane remains a critical component in the realization of effective protein and other biological therapeutics. A robust sustainable delivery strategy demands not only a good protection of the cargo, but also for reversibility in conjugation and activity (page 2, [0006]). Two limiting approaches have been taken to address this need, both of which involve non-covalent self-assembly. The first involves electrostatic binding of proteins to complementarily charged polymers and nanoparticles and the second includes encapsulation of proteins in water-filled compartments, such as liposomes. However, limitations in these methods exist including non-specific fouling of surfaces, toxicities, and low loading capacities (page 2, [0007]). As such, novel strategies, along with novel delivery vehicles and release methodologies are desired (page 2, [0008]).
WO’323 teaches polymers and polymer networks to which biomolecules, including antibodies, can covalently conjugate to and stably encapsulate in, forming nano-assemblies, and be controllably delivered and released, tracelessly, upon degradation of the nano-structures in response to specific microenvironments (page 2, [0009]). WO’323 further teaches that the antibody can be a full-length antibody (page 14, [0088]; page 39, claim 15). The polymer coating traffics proteins across the cellular membrane and releases them into the cytosol. It is the higher redox potential of the cytosol that is being targeted for selective release (pages 11-12, [0074]). WO’323 teaches that cysteine and lysine are two popular handles for conjugating polymers with proteins because of their nucleophilicity. Because of the surface availability of multiple lysines in larger numbers of proteins, lysines are preferred. Lysines, however, present a disadvantage in that it is more difficult to functionalize them where they can be tracelessly liberated in the presence of an intra-cellular environment. WO’323 discloses that, by placing reactive side-chain functionalities, complementary to amines, with responsive self-immolation characteristics in a polymer provides a novel and general system that is capable of encapsulating proteins with high fidelity and tracelessly releasing them upon encountering a target microenvironment. By traceless release, it is meant that the released agent, e.g. protein, does not include any traces of a linker or vehicle, e.g. polymer (page 9, [0063]-[0064]).
WO’323 discloses the chemical structure of polymers and their reaction scheme for protein conjugation, crosslinking to generate the nanoassembly, and its release in the presence of a reducing agent, in scheme 1 in Fig. 1B, which is duplicated below for convenience (Figure page 2/34).
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The scheme shows polymer P1, which includes an NPC moiety side chain (boxed in the scheme 1 above for identification).
Reaction of an amine from the peptide with the NPC moiety in P1 produces the corresponding carbamate shown in P2 with the release of the nitrophenol group from the side chain. The polymer is treated the protein, where multiple lysine moieties are reacted with the p-nitrophenylcarbonate groups in the polymer chains. As shown in P2, this reaction results in the formation of a nanoassembly in which proteins are attached to, and therefore surrounded by, multiple P1 polymers (shown in the scheme as squiggly lines).
Following this, the remaining carbonate moieties are reacted with a diamine crosslinker to complete the polymer network formation around the protein as represented in Fig. 1A and Fig. 1B. WO’323 notes that the disulfide moiety is placed at the beta-position, relative to the carbamate oxygen. The purpose of this placement is to render the polymer responsive to the more reductive environment present inside the cells compared to the extracellular environment. Reductive cleave of the disulfide moiety will result in the thiol intramolecularly cleaving the carbamate moiety to release the original amine. The reaction causes both the polymer being uncrosslinked and the protein being tracelessly liberated from the polymer (pages 9-10, [0066]). WO’323 further teaches that the polymer can be a random copolymer or a block copolymer (page 15, [0095]).
In scheme 1 of WO’323, the polymer already includes the NPC moiety side chain in P1. WO’323 details the Synthesis of P1 in the experimental section, where it is shown that the synthesis of P1 originates from p(PEGMA-co-PDSMA) (pages 24-25). The 1H-NMR spectra for the polymer samples are provided in Fig. 6-8, where p(PEGMA-co-PDSMA) is shown to have the following structure (Fig. 6). The structure disclosed by WO’323 for p(PEGMA-co-PDSMA) is PDA-PEG, comprising a PDA component and a PEG component, as evidenced by Markoutsa (page 16, Figure 1A; comparison included below), demonstrating that WO’323 used a PDA-PEG polymer with an added NPC side chain to form P1.
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To test the design strategy disclosed, WO’323 used cytochrome C (CytC) as a model protein because of its distinct cellular readout in the form of apoptotic cell death. After initially reacting CytC with P1, the polymer-protein conjugate was further secured by crosslinking with ethylenediamine (ED) or tetraethyleneoxide-bis-amine. WO’323 teaches that the reaction between the NPC moiety and an amine produces p-nitrophenol as a byproduct, the distinct absorption of which can be conveniently monitored. Therefore, the protein conjugation step was quantified using the evolution of the absorption spectrum. Encapsulation efficiency and loading capacity were found to be ~47% and 5-7%, respectively.
WO’323 teaches that the results provided demonstrate that the polymer conjugate has better access to the cells compared to the native protein itself (pages 11-12, [0074]).
WO’323 concludes that a versatile strategy for the encapsulation of proteins and their traceless release in response to a specific trigger is demonstrated. The encapsulation is templated by the lysine handles in the protein itself which are then used to wrap the protein with a polymer network in a secondary crosslinking step. The versatility of the approach is highlighted by the facts that (i) it utilizes a functional handle that is abundantly available on the surface of >85% of globular proteins, which renders the strategy broadly applicable; (ii) the target protein is encapsulated with high fidelity, i.e., high load capacity; (iii) the cargo is protected from degradation by proteases; (iv) the protein activity is masked in the encapsulated state; (v) the polymer sheath is removed tracelessly with high efficiency with response to a target intracellular environment; (vi) the native structure and function are retained upon release; (vii) the protein can be delivered with high fidelity into the cytosol; and (viii) activity of the protein is regained in the cytosol (pages 23-24, [00142]).
While WO’323 does not use the term “nanogel”, absent a definition for the term in the instant disclosure to the contrary, an ordinarily skilled artisan would reasonably conclude that WO’323’s teaching of a nanoassembly meets the instant claim limitation of nanogel.
Markoutsa teaches the use of prodrug nanoparticles for the delivery of NAC to the brain to as a means to overcome challenges with low bioavailability and short half-lives (abstract). Markoutsa teaches that previous studies have demonstrated the fabrication of nanoparticles using Poly[(2-(pyridine-2-yldisulfanyl)-co-[poly(ethylene glycol)]] (PDA-PEG), which is sensitive to both high redox potential and acidic pH. In the study disclosed by Markoutsa, a NAC drug-based delivery system based on PDA-PEG polymer conjugated to NAC through disulfide bonds is disclosed. Markoutsa teaches that since disulfide bonds can only be cleaved by elevated GSH level, the stability of the nanoparticles is preserved while promptly releasing the drug intracellularly (page 3, paragraph 2).
Markoutsa teaches that PDA-PEG was used due to the abundance of pyridine-2-thiol groups in the polymer and its amphiphilic properties (page 3, paragraph 2). Markoutsa further teaches that the DTT was used in studies to cleave the payload from the polymer (page 4, paragraph 3).
The following structure is disclosed by Markoutsa for PDA-PEG and the synthesis of NAC-PDA-PEG (page 16, Figure 1A).
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Markoutsa teaches that the nanoparticles were prepared by a crosslinking reaction of NAC polymer via disulfide bond cleavage followed by aerial oxidation and that tris(2-carboxyethyl)phosphine (TCEP) was used in the fabrication to generate free thiol groups in the polymer. Markoutsa teaches that TCEP was added and the mixture was dropped into ddH2O [double distilled water] under stirring conditions to form crosslinking through disulfide bonds by aerial oxidation. The final solution was loaded into a dialysis bag and dialyzed against PBS (page 4, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the gene silencing strategies taught by Wu for targeting intracellular PD-L1 in the treatment of cancer cells, including human breast cancer cells, with the Trim-Away system disclosed by Clift where the antibody delivered to the cytoplasm of the cell is an anti-PD-L1 antibody. It would further have been obvious to transfect the cells to overexpress TRIM21 as disclosed by Clift. It would have also been obvious to substitute the intracellular antibody delivery methods, such as electroporation, taught by Clift with the nanoassembly antibody delivery methods taught by WO’323, which utilizes polymers comprising PDA and PEG components crosslinked with ethylenediamine and to further crosslink the nanoassembly with TCEP as taught by Markoutsa, either through crosslinking of non-NPC functionalized PDA groups in the polymer of WO’323 or by purposefully leaving some PDA groups in the polymer of WO’323 non functionalized for further crosslinking as demonstrated by Markoutsa.
An ordinarily skilled artisan would have been motivated to use the Trim-Away system taught by Clift in place of the gene targeting techniques disclosed by Wu in order to target PD-L1 protein depletion directly in a manner that is not dependent on the inherent turnover of the protein allowing for the targeting of long-lived proteins and avoiding the possibility of resistance to gene targeting depletion methods while allowing for the acute depletion of the endogenous protein. Additionally, the use of the Trim-Away system would assist in overcoming challenges taught by Wu in gene targeting of intracellular PD-L1. An ordinarily skilled artisan would have had a reasonable expectation of success as Wu teaches that PD-L1 is an endogenous intracellularly expressed protein that can be targeted for cancer treatment and Clift teaches methods of depleting endogenous proteins and teaches that the methods disclosed can be used to treat cancer. Additionally, Clift teaches the TRIM-Away system as an alternative to RNA approaches, such as those disclosed by Wu.
An ordinarily skilled artisan would have been further motivated to transfect the cell to overexpress TRIM21 in order to take advantage of the endogenous protein degradation pathway disclosed by Clift in which the antibody binds the target protein, TRIM21 binds the Fc domain of the antibody and the complex is degraded by proteasome in the cell. By using Trim-Away, the PD-L1 protein bound to the PD-L1 antibody would be degraded in the cell. An ordinarily skilled artisan would have had a reasonable expectation of success as Clift teaches studies in which cells were transfected to express TRIM21 (page e5, Stable cell lines). Clift further teaches that Trim-Away performed efficiently when TRIM21 was ectopically overexpressed, demonstrating effective function of transfected TRIM21.
An ordinarily skilled artisan would have been motivated to use the nanoassembly of WO’323 for the intracellular delivery of the PD-L1 antibody as WO’323 teaches that the nanoassembly is able to deliver proteins intracellularly with better access to the cells compared to native proteins alone. Additionally, WO’323 teaches numerous benefits including encapsulation with high load capacity, protection of the cargo from degradation by proteases, masking of the protein activity in the encapsulated state, and traceless release of the protein in the intracellular environment while maintaining function and activity. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’323 teaches the use of the nanoassemblies disclosed for the intracellular delivery of full-length antibodies.
It would have further been obvious to one of ordinary skill in the art to further crosslink the nanoassembly with TCEP as taught by Markoutsa, either through crosslinking of non-NPC functionalized PDA groups in the polymer of WO’323 or by purposefully leaving some PDA groups in the polymer of WO’323 non functionalized for further crosslinking as Markoutsa teaches methods of using PDA-PEG polymers with unfunctionalized PDA crosslinked with TCEP for drug delivery suggesting PDA/TCEP as a potential crosslinking method for the polymers disclosed by WO’323. An ordinarily skilled artisan would have had a reasonable expectation of success as the copolymers used by Markoutsa and WO’323 comprise the same polymer components, specifically PDA and PEG and both WO’323 and Markoutsa teach the formation of nanoassemblies using PDA-PEG for delivering therapeutics intracellularly where the therapeutic is released by the cleavage of disulfide bonds in the intracellular environment.
Claims 19-21, 25-26, 29-30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wu, Y., et al (2019) PD-L1 distribution and perspective for cancer immunotherapy- blockade, knockdown, or inhibition Frontiers in Immunology 10(2022); 1-15 in view of Clift, D., et al (2017) A method for the acute and rapid degradation of endogenous proteins Cell 172; 1692-1706, WO 2018/231323 (Thayumanavan, S. and J. Zhuang) 20 Dec 2018, and Markoutsa, E., and P. Xu (2017) Redox potential sensitive N-acetyl cysteine-prodrug nanoparticles inhibit the activation of microglia and improve neuronal survival Mol Pharm 14(5); 1591-1600 as applied to claims 11 and 28 above, and in further view of Chen, W., et al (2017) Cyclo(RGD)- Decorated reduction-responsive nanogels mediate targeted chemotherapy of integrin overexpressing human glioblastoma in vivo Small 13 (1601997); 1-9.
The combination of Wu, Clift, WO’323, and Markoutsa teach the methods of claim 11 and 28 as discussed above.
The combination of applied references, however, do not disclose that the nanogel further comprises a tumor-targeting ligand on the surface or that the ligand is a peptide and is RGD.
Chen teaches that advanced nanosystems for controlled drug delivery have received tremendous attention because they confer prolonged circulation time, efficient tumor-targeted accumulation via the enhanced permeability and retention effect, reduced side effects, and improved drug tolerance. Chen teaches that various types of biocompatible nanocarriers, including nanogels, have been developed for in vitro and in vivo drug delivery and that nanogels with internally crosslinked 3-D structures are able to stably encapsulate bioactive compounds such as drugs, peptides/proteins, and DNA/RNA. Chen further teaches that nanogels actively participate in the drug delivery process due to their intrinsic properties like stimuli-responsive behavior, welling, and softness to achieve a controlled drug release at the target site (page 1, right column, paragraph 1).
Chen teaches that decorating the nanogel surface with a specific tumor-homing ligand can largely increase retention and accumulation in the tumor vasculature as well as provide a selective and efficient internalization by target tumor cells. Chen further teaches that it has been demonstrated that cRGD peptide has a high affinity with the αvβ3 integrin receptors overexpressed on angiogenic endothelial cells and tumor cells such as malignant glioma cells, breast cancer cells, bladder cancer cells, and prostate cancer cells, which renders cRGD a unique molecular ligand for targeted cancer therapy. In their study, Chen designed cRGD-decorated reduction-responsive PVA nanogels for investigating targeted chemotherapy of human glioblastoma in vivo (page 2, right column, paragraph 1). Chen teaches that cRGD-decorated, reduction-responsive nanogels based on the FDA approved PVA, afford a tumor-targeted and reduction-triggered intracellular release of DOX into human glioblastoma xenografts in mice resulting in efficient inhibition of tumor growth with little adverse effects. Chen teaches that the nanogels exhibited enhanced internalization in the αvβ3 integrin overexpressed cells via receptor-mediated endocytosis to induce cell death of cancer cells compared to nondecorated nanogel counterparts. Chen teaches that cRGD-decorated reducible PVA nanogel systems present a promising platform for targeted and efficient cancer chemotherapy of αvβ3 integrin overexpressed malignant tumors in vivo and that the nanogels are highly versatile and could be used for the delivery of various drugs and proteins to actively treat different malignant tumors with a specific targeting ligand decoration (paragraph bridging left and right columns, page 7).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wu, Clift, WO’323, and Markoutsa to further functionalize the nanoassembly by conjugating cRGD peptides to the surface. An ordinarily skilled artisan would have been motivated to functionalize the surface with cRGD in order to target the nanoassemblies to tumor cells that overexpress the αvβ3 integrin receptor. An ordinarily skilled artisan would have had a reasonable expectation of success in making this combination as WO’323, Markoutsa, and Chen all teach the use of nanoassemblies for the intracellular delivery of therapeutics demonstrating analogous art and Chen teaches cRGD decorated nanogels. Additionally, Chen teaches cancers that cRGD has a high affinity for αvβ3 integrin receptors that are overexpressed on cancer cells that overlap with those taught by the combination of Wu, Clift, WO’323, and Markoutsa, including breast cancer.
Response to Arguments
Applicant’s arguments in the response filed 01/12/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but are not persuasive.
Applicant argues that the cited references, Clift, WO’323, Markoutsa, and Chen are silent to anti-PD-L1 or anti-PD-1 antibodies.
In the new rejections of the instant office action, the reference Wu has been applied to demonstrate that intracellular PD-L1 in cancer cells was known and that targeting of cytoplasmic PD-L1 had been considered in the treatment of cancer. The combination of Wu, Clift, WO’323, Markoutsa, and Chen render obvious the instant claims as discussed in detail in the rejections of the instant office action.
Conclusion
No claims are allowed.
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.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693