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
Claims 1-14, 16, 17, 19, and 20 are pending.
Claims 15 and 18 are canceled.
Claim 1 is 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Claim 20 is withdrawn.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Rejections Withdrawn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The claim rejections under 35 U.S.C. 103 have been withdrawn in view of the claim amendments, dated 01/20/2026. Applicant is referred to the new grounds of rejection under 35 U.S.C. 103 detailed below.
Response to Arguments
In Applicant Arguments, dated 09/18/2025, Applicant points out that the claims have been amended to recite a hydrogel formed of a self-assembled prodrug comprising a cytotoxic agent conjugated to a hydrophilic moiety by a linker, and each of Surahaga et al., Peng et al., Goldberg et al., and Cheetham et al. fail to teach a hydrogel. With respect to the teachings of Sun et al., Applicant asserts that “Sun teaches hydrogels that comprise camptothecin. In particular, Sun teaches hydrogels as vehicles that are formed to provide a scaffold for encapsulation of a drug within the scaffold and thus to act as a drug delivery platform. Sun does not teach or suggest a hydrogel that is formed of a drug (or prodrug) itself. Sun does not teach or suggest a hydrogel formed of a self-assembled prodrug comprising a cytotoxic agent conjugated to a hydrophilic moiety by a linker; and an immunomodulator, wherein the linker comprises a matrix metalloproteinase-2 (MMP-2)-cleavable peptide and a disulfide linker.”
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 detailed below, 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., Peng et al., Goldberg et al., and Cheetham et al. to develop a composition useful for treating cancer comprising (a) a prodrug comprising a cytotoxic agent (paclitaxel) 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., 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., and Cheetham et al.
New Grounds of Rejection
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), 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 abraxanes. 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 hydrogel formed of a self-assembled prodrug comprising a 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. These deficiencies are remedied by Peng et al., Goldberg et al., 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.
PNG
media_image1.png
519
784
media_image1.png
Greyscale
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.
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., and Cheetham et al. to develop a composition comprising (a) a hydrogel formed of a self-assembled prodrug comprising a 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. 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 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). 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., 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., and Cheetham et al. comprises (a) a prodrug comprising a cytotoxic agent (paclitaxel) 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., 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., and Cheetham et al. The invention of Surahaga et al., Peng et al., Goldberg et al., 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.
These 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:
PNG
media_image2.png
292
598
media_image2.png
Greyscale
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.
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 extension fee 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 NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642