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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/01/2026 has been entered.
Claims 1-14, 16, 17, 19, and 20 are pending.
Claims 1-4 are currently amended.
Claim 20 is withdrawn.
Claims 1-14, 16, 17, and 19 are under examination on the merits.
Rejections Withdrawn
35 U.S.C. 103
The rejection of claims 1-14, 16, 17, and 19 under 35 U.S.C. 103 as being unpatentable over Surahaga et al. (Cancer Cell, 16(6): 510-520, pages 1-25, 2009), in view of Peng et al. (J. Am. Chem. Soc., 137: 6726-6729, 2015), Goldberg et al. (WO 2018/045058, international publication date: 03/08/2018), and Cheetham et al. (Chem. Commun. (Camb.), 50(45): 6039-6042, pages 1- 10, 2014) is withdrawn in view of the claim amendments, dated 07/01/2026.
Claim Rejections
35 U.S.C. 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 1-14, 16, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Surahaga et al. (Cancer Cell, 16(6): 510-520, pages 1-25, 2009), in view of Peng et al. (J. Am. Chem. Soc., 137: 6726-6729, 2015), Goldberg et al. (WO 2018/045058, international publication date: 03/08/2018), Saif (J Pancreas, 14(6): 686-688), and Cheetham et al. (Chem. Commun. (Camb.), 50(45): 6039-6042, pages 1-10, 2014).
Surahaga et al. teach that “[p]oor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that employs a tumor homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a 3-step process: The RGD motif mediates binding to αv integrins on tumor endothelium, a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor imaging agents and enhanced the activity of an anti-tumor drug.” See Summary. Surahaga et al. also teach that “[t]he ability of iRGD to deliver anti-cancer drugs was investigated by treating mice bearing orthotopic 22Rv1 tumors with iRGD-coated abraxane [albumin-embedded paclitaxel]… In vitro, iRGD-abraxane inhibited the proliferation of 22Rv1 cells more efficiently than abraxane conjugated with a cyclic RGD peptide without a CendR motif (CRGDC; Koivunen et al., 1993) or abraxane alone (Figure S12A). Intravenously injected iRGD-abraxane spread more within tumor tissue than the other abraxane formulations… We next tested the efficacy of iRGD-abraxane in a tumor model unrelated to 22Rv1. We chose orthotopic tumors generated with the BT474 human breast cancer cell line, which expresses both αv integrins and neuropilin-1 at the cell surface (Figure S14). In addition, the BT474 cells are more resistant to abraxane (paclitaxel) than 22Rv1 as shown in cytotoxicity assays (Figure S15). When injected intravenously into the tumor mice, the iRGD-abraxane accumulated in the tumor 11-fold more than non-targeted-abraxane…” See p. 6. At p. 10 and 11, Surahaga et al. detail the preparation of iRGD peptide-conjugated Abraxane. It is noted that iRGD is a hydrophobic moiety according to claim 14, and paclitaxel is a cytotoxic agent according to claim 4.
Although Surahaga et al. teach a prodrug comprising a cytotoxic agent conjugated to a hydrophilic moiety. Surahaga et al. do not teach a composition comprising (a) a self-supporting hydrogel formed of a self-assembled prodrug comprising a first cytotoxic agent and a second cytotoxic agent conjugated to a hydrophilic moiety by a linker and (b) an immunomodulator, wherein the linker comprises a matrix metalloproteinase-2 (MMP-2)-cleavable peptide and a disulfide linker, and wherein the prodrug self-assembles into a one-dimensional nanostructure that forms the self-supporting hydrogel. These deficiencies are remedied by Peng et al., Goldberg et al., Saif, and Cheetham et al.
Peng et al. teach that “[p]oor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that employs a tumor homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a 3-step process: The RGD motif mediates binding to αv integrins on tumor endothelium, a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor imaging agents and enhanced the activity of an anti-tumor drug.” See Summary. Peng et al. also teach that “[i]n this study, a stimuli-responsive drug delivery system with iRGD conjugated to a HPMA copolymer-DOX conjugate via an MMP-2 cleavable spacer was developed. The chemistry for preparing MA-GG-PLGLAG-iRGD can be applied for iRGD derivatization. Conjugation of iRGD to a drug carrier via a PLGLAG spacer enhanced the accumulation and penetration of our DOX conjugate in both monolayer and multicellular spheroid models of prostate cancer, as evidenced by enhanced cell cycle arrest and cell death.” See p. 6729. At p. 6727, Peng et al. teach that “[b]ecause iRGD requires the exposure of C-terminus to preserve its activity, we prepared the monomer MA-GGPLGLAG-iRGD by conjugation starting from the N-terminus of iRGD using solid-phase synthesis (Figure 2). The synthesis of MA-GG-PLGLAG-iRGD started from manual attachment of the Fmoc-Cys(Acm)-OH to 2-chlorotrityl chloride resin. After the active group on the resin was capped with methanol, protected amino acids (Fmoc-Asp(OBut)-OH, Fmoc-Pro-OH, Fmoc-GlyOH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OBut)-OH, Fmoc-GlyOH, Fmoc-Arg(Pbf)-OH, Fmoc-Cys(Acm)-OH, Fmoc-GlyOH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Gly-OH, FmocLeu-OH, and Fmoc-Pro-OH) or MA-GG-OH were loaded to resin sequentially via classic peptide coupling reactions.”
An illustration of the polymer conjugate P-DOX-PLGLAG-iRGD is depicted below.
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Goldberg et al. teach drug delivery compositions that provide for the local administration of therapeutic agents, such as activators of the innate and activated immune system, for use in treating cancer, see [0002]. At [000257] - [000258], Goldberg et al. teach that activators of the immune system include anti-PD-1 antibodies, such as pembrolizumab, nivolumab, and atezolizumab. At [000255], Goldberg et al. teach that activators of the adaptive immune system also include anti-CD47 antibodies. At [000196] - [000202], Goldberg et al. teach that activators of the immune response include various species of cGAMP, a STING agonist.
Saif teaches that Abraxane can be used in combination with gemcitabine for the treatment of metastatic adenoma of the pancreas, see p. 686.
Cheetham et al. teach that “[c]ovalent linkage of anticancer drugs to a carrier presents an effective strategy to improve the drug’s solubility, to enhance the drug targeting efficiency, and to help circumvent multidrug resistance. Such a prodrug strategy has been used to create peptide-drug conjugates, polymer-drug conjugates, dendrimer-drug conjugates nanoparticle-drug conjugates, and most recently drug-based molecular hydrogelators and self-assembling drug amphiphiles.” See Abstract. At p. 3, last full paragraph, Cheetham et al. teach that chemotherapeutic drugs, such as camptothecin, may be linked to carriers via an etcSS linker that allows for the release of camptothecin to yield a free drug.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Surahaga et al. with the teachings of Peng et al., Goldberg et al., Saif, and Cheetham et al. to develop a composition comprising (a) a self-supporting hydrogel formed of a self-assembled prodrug comprising a first cytotoxic agent and a second cytotoxic agent conjugated to a hydrophilic moiety by a linker and (b) an immunomodulator, wherein the linker comprises a matrix metalloproteinase-2 (MMP-2)-cleavable peptide and a disulfide linker, and wherein the prodrug self-assembles into a one-dimensional nanostructure that forms the self-supporting hydrogel. One of ordinary skill in the art would have been motivated to do so, because Surahaga et al. teach a prodrug comprising a cytotoxic agent conjugated to a hydrophilic moiety. Furthermore Peng et al. teach that the activity of anti-tumor drugs may be improved by preparing a drug delivery system comprising iRGD (a hydrophilic moiety) linked to a chemotherapeutic agent via an MMP-2 cleavable spacer (linker). Based upon these teachings, one of ordinary skill in the art would have been motivated to prepare a drug delivery system comprising iRGD (a hydrophilic moiety) linked to a chemotherapeutic agent, such as Abraxane (paclitaxel), via an MMP-2 cleavable linker. One of ordinary skill in the art would have been motivated to do so, because the resultant drug delivery system would be useful for improving the delivery of paclitaxel to cancer cells. Goldberg et al. teach various activators of the immune system that may be used in the treatment of cancer, such as anti-PD-1 antibodies (pembrolizumab, nivolumab, and atezolizumab), anti-CD47 antibodies, and STING agonists, such as cGAMP. One of ordinary skill in the art would have been motivated to combine the invention of Surahaga et al. and Peng et al. to comprise one of the immune activators of Goldberg et al., because the resultant invention would be useful in the treatment of cancer by providing two anti-cancer medicaments (prodrug and immunomodulator). Further in view of the teachings of Saif, one of ordinary skill in the art would have been motivated to modify the invention of Surahaga et al., Peng et al., and Goldberg et al., which comprises iRGD peptide-conjugated Abraxane, to comprise a second cytotoxic moiety, such as gemcitabine, because there would have been a reasonable expectation that the resultant invention may be used in the treatment of metastatic adenoma of the pancreas. Additionally Cheetham et al. teach that chemotherapeutic drugs may be linked to carriers via an etcSS linker that allows for the release of chemotherapeutic drugs to yield a free drug that provides an anti-cancer effect. As such one of ordinary skill in the art would have been motivated to modify the invention of Surahaga et al., Peng et al., Saif, and Goldberg et al. to comprise an etcSS linker, because such a linker would ensure the release of a chemotherapeutic drug. The invention of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al. comprises (a) a prodrug comprising a first cytotoxic agent (Abraxane) and a second cytotoxic agent (gemcitabine) conjugated to a hydrophilic moiety (iRGD) by a linker (MMP-2 cleavable spacer and a disulfide linker that comprises etcSS) and (b) an immunomodulator. Example 1 of the specification details the production of a self-assembling prodrug hydrogel and states that “[t]he amphiphilic prodrug, diCPT-PLGLAG-iRGD, was first synthesized by conjugating a hydrophilic iRGD (a cyclic peptide known to facilitate tumor tissue penetration of anticancer agents) to two hydrophobic CPT molecules through a matrix metalloproteinase 2 (MMP-2) responsive linker (PLGLAG (SEQ ID NO: 4) peptide) (FIGS. 7A-C). The two CPT moieties were attached to the PLGLAG (SEQ ID NO: 4) peptide through a reducible etcSS linker that forms disulfide bonds with the cysteine residues of the peptide sequence. This CPT prodrug spontaneously assembles into supramolecular nanotubes (P-NT) tens of micrometers in length in aqueous environments (FIG. 1B).” The invention of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al. includes all the components of the prodrug of Example 1, which self-assembles into a hydrogel in aqueous environments, and as such, the hydrogel of claim 1 is prima facie obvious over the teachings of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al. The invention of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al. meets the limitations of claims 1-12, 14, and 17.
With respect to claim 13, iRGD meets the limitations of a peptide.
With respect to claim 16, as indicated in the figure above, the MMP-2 cleavable spacer of Peng et al. comprises the amino acid sequence PLGLAG.
The cited references teach or suggest a composition useful for treating cancer comprising a hydrogel comprising a prodrug comprising a cytotoxic agent (camptothecin) conjugated to a hydrophilic moiety (iRGD) by a linker that comprises PLGLAG, which is an MMP-2 cleavable spacer, and an etcSS disulfide linker. Absent evidence to the contrary, a hydrogel comprising these elements meets the limitations of the following structure, as recited in claim 19:
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Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Response to Arguments
In Applicant Arguments, dated 09/18/2025, Applicant asserts that “the amended claims are not obvious. Amended claim 1 recites a self-assembled prodrug comprising a first cytotoxic agent and a second cytotoxic agent conjugated to a hydrophilic moiety by a linker, wherein the prodrug self-assembles into a one-dimensional nanostructure that forms a self-supporting hydrogel… The cited references, alone or in combination, do not teach or suggest these features.”
These arguments have been fully considered but are not deemed persuasive. As indicated in the rejection of the claims under 35 U.S.C. 103 articulated above, in view of the teachings of Saif, one of ordinary skill in the art would have been motivated to modify the invention of Surahaga et al., Peng et al., and Goldberg et al., which comprises iRGD peptide-conjugated Abraxane (first cytotoxic moiety), to comprise a second cytotoxic moiety, such as gemcitabine, because there would have been a reasonable expectation that the resultant invention may be used in the treatment of metastatic adenoma of the pancreas.
Applicant further asserts that “[t]o the extent the rejection rested on the premise that the components of the proposed combination would inherently self-assemble into a hydrogel, that premise does not support rejection of the amended claim. Whether a prodrug self-assembles into a one: dimensional nanostructure and forms a self-supporting hydrogel depends on the amphiphilic balance of the particular two-drug construct, a property the cited references neither disclose nor recognize. Obviousness cannot rest on a property unknown in the prior art. See In re Spormann, 363 F.2d 444, 448 (CCPA 1966) (‘That which may be inherent is not necessarily known. Obviousness cannot be predicated on what is unknown.’); Cytiva BioProcess R&D AB V. JSR Corp., 122 F.4th 876, 890 & n.15 (Fed. Cir. 2024) (where a claim limitation requires prior knowledge of the inherent property, a reasonable expectation of success must still be shown). The Office states that it relied on the specification only as evidence that the prior-art combination would result in a self-assembled molecule. But ‘[b]oth the suggestion and the expectation of success must be founded in the prior art, not in the applicant's disclosure.’ In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988). The cited references do not disclose that the recited two-drug construct self-assembles into a one-dimensional nanostructure or forms a self-supporting hydrogel, and Applicant's disclosure of that behavior cannot supply what the prior art lacks. Here, the self-assembling one-dimensional nanostructure and the self-supporting hydrogel are affirmative features of amended claim 1, not latent properties of an otherwise-taught composition… The cited art also provides no reasonable expectation that a prodrug bearing two cytotoxic agents conjugated to a hydrophilic moiety would self-assemble into a one: dimensional nanostructure and form a self-supporting hydrogel. See MPEP § 2143; Amgen Inc. V. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1362 (Fed. Cir. 2009) (‘An obviousness determination requires that a skilled artisan would have perceived a reasonable expectation of success in making the invention in light of the prior art.’); In re O'Farrell, 853 F.2d at 903 (a result reached by a ‘general approach’ is not obvious ‘where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it’). The references disclose no data or guidance indicating that the recited two-drug construct would assemble as claimed.”
These arguments have been fully considered but are not deemed persuasive. The Office does not disagree with Applicant’s assertion that prior art cannot be supplemented by the applicant's disclosure; however in this situation, Applicant’s specification was not used as prior art. Applicant’s specification was used as evidence that the invention of the prior art would result in a self-assembled molecule, which is not an improper use of Applicant’s specification. As detailed above Example 1 of the specification details the production of a self-assembling prodrug hydrogel and states that “[t]he amphiphilic prodrug, diCPT-PLGLAG-iRGD, was first synthesized by conjugating a hydrophilic iRGD (a cyclic peptide known to facilitate tumor tissue penetration of anticancer agents) to two hydrophobic CPT molecules through a matrix metalloproteinase 2 (MMP-2) responsive linker (PLGLAG (SEQ ID NO: 4) peptide) (FIGS. 7A-C). The two CPT moieties were attached to the PLGLAG (SEQ ID NO: 4) peptide through a reducible etcSS linker that forms disulfide bonds with the cysteine residues of the peptide sequence. This CPT prodrug spontaneously assembles into supramolecular nanotubes (P-NT) tens of micrometers in length in aqueous environments (FIG. 1B).” The invention of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al. includes all the components of the prodrug of Example 1, which self-assembles into a self-supporting hydrogel in aqueous environments, and as such, the hydrogel of claim 1 is prima facie obvious over the teachings of Surahaga et al., Peng et al., Goldberg et al., Saif, and Cheetham et al.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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