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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 24, 2025 has been entered.
Claim Status
Claims 1-3, 6-7, 9, 13, 20-32, and 35 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35
U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of
PCT/US2019/023157, which claims benefit to U.S. Provisional Applications 62/645,613, filed March 20, 2018, and 62/791,481, filed January 11, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is noted that that disclosure of the prior filed application provide adequate support for the limitation of claim 1 directed to a composition that does not include a chemotherapeutic.
The later-filed application must be an application for a patent for an invention which is also
disclosed in the prior application (the parent or original nonprovisional application or provisional
application). The disclosure of the invention in the parent application and in the later-filed application
must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA
35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance
Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, 62/645,613, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The limitations of claims 1 and 7 directed to the p38 MAPK inhibitors AZD7624, ARRY-797, AVE-9940, LY3007113, skepinone-L, UM-164, SCIO 323, SX-011, SK-F860002, SB706504, CHF-6297, RWJ-67657, Org48762-0, ML3403, JX-401, EO-1428, DBM 1285, AMG-548, AL-8697, PD-169316, PF- 3715455, selonsertib, and dilmapimodand are not included in the disclosure of U.S. Provisional Application 62/645,613. Accordingly, the claims are not entitled to the benefit of this application.
Claims 1-3, 6-7, 9, 13, 20-32, and 35 are given an earliest effective filing date of January 11, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 24, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Withdrawn Rejections
Rejection of claims 33-34 under 35 U.S.C. 112(a) as failing to comply with written description requirement is withdrawn; these claims have been canceled.
The rejections of claims 1-3, 6, 9, 13, 20-32, and 35 under 35 U.S.C. 103 as being unpatentable over Goldberg in view of Goldman et al, Carey et al, Yeung et al, and Dubbini et al are withdrawn, and new rejections over Li et al in view of Goldman et al, Qi et al, Dubbini et al, Carey et al, and Yeung et al are set forth below. It is noted that, based upon the earlier effectively filed date of Goldberg, this reference constitutes as prior art under 35 U.S.C. 102(a)(2). In order to avoid reinstatement of the rejection over Goldberg, applicant is encouraged to provide a statement under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A)
New Rejections
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.
Claims 1-3, 9, 20-32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al, published March 16, 2017 (see IDS from 12/17/2020, in view of Qi et al, published February 7, 2018 (see PTO-892 from 6/5/24), Goldman et al, published online December 1, 2017 (see PTO-892 from 6/5/24), and Dubbini et al published July 20, 2015 (instant PTO-892).
The claims are directed to a method of preventing tumor recurrence and/or metastasis comprising intraoperative administration at tumor resection site of a composition comprising a crosslinked hydrogel biomaterial and a p38 MAPK inhibitor.
Li et al teaches a method for delivering an alginate hydrogel system to locally deliver celecoxib to treat tumor-bearing mice; subcutaneous injection celecoxib in the vicinity of a melanoma significantly inhibited tumor growth and extended survival time (pg e1074374-2, column 2; Figures 1A and 2). The COX-2 inhibitor celecoxib is an inhibitor of p38 MAPK, as evidenced by Sperandio da Silva (see PTO-892 from 7/24/25), which meets the p38 inhibitor limitation of claim 1. Li et al so teaches coadministration of the celecoxib composition with an anti-PD-1 antibody (an immune checkpoint inhibitor), which reads on the activator of innate immunity of instant claim 13.
Li et al does not teach any of the specific p38 MAPK inhibitors of instant claim 1.
Goldman et al teaches that p38 MAPK inhibitors represent a novel therapeutic strategy for improving outcomes in those with cancer (pg 630, column 1). Oral administration of the p38 MAPK inhibitor LY3007113 to mice was shown to be effective in xenograft models of human ovarian and kidney cancers as well as leukemia (pg 630, column 1). Clinical development of this p38 MAPK inhibitor for the treatment of patients with cancer, however, was suspended due to toxic adverse event (abstract).
Given that Li et al teaches a method for delivering a composition comprising a hydrogel and a p38 MAPK inhibitor at a tumor site, and further given that Goldman et al teaches the utility of the p38 MAPK inhibitor LY3007113 in the treatment of cancer, it would have been obvious to one of ordinary skill in the art to use the inhibitor of Goldman et al in the composition and Li et al and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within their technical grasp to obtain predictable results. Such would amount to the simple substitution of one functionally equivalent element for another (i.e. LY3007113 for celecoxib) to obtain predictable results. The motivation to do so comes from Goldman et al, which teaches that systemic administration of a p38 MAPK inhibitor is limited clinically because of adverse events; one attempting to prevent cancer recurrence using p38 MAPK pathway inhibitors would look to a method of locally administering p38 MAPK inhibitors.
Li et al in view of Goldman et al do not teach administration of the composition at a tumor resection site, as required by instant claim 1.
Qi et al teaches a method for applying a hydrogel co-assembled with the chemotherapy drug doxorubicin to a tumor resection site (see abstract). A murine model of local cancer recurrence was established by injecting 4T1 tumor cells into the mammary fat pads of female BALB/c mice; when tumor volume reached 200 mm3, the tumors were resected and mice were implanted with the doxorubicin loaded hydrogel at the surgical site (pg 6973, Section 2.4), as in instant claims 1 and 35.
The biomaterial of Qi et al forms a matrix, and the inhibitor is within the biomaterial (pg 6975, column 2, last paragraph), as in claim 20.
Qi et al teaches that the doxorubicin-loaded hydrogel composition is biodegradable in vivo, as in instant claim 22, and is injectable, as in instant claim 28 (pg 6979, column 1, ln 1-2). The doxorubicin-loaded hydrogel was implanted at the resection site (pg 6973, column 2, Section 2.4), as in claim 27.
Primary tumor volume and micrometastases to the lungs were assessed (Section 2.4) by measuring metastatic foci in the lungs (see Figure 5 and pg 6977, Section 3.4), as in instant claims 31 and 32.
Qi et al teaches that 99% of the primary tumor was surgically resected (pg 6976, Section 3.4), as
in the resection site characterized by an absence of gross residual tumor of instant claim 30.
Given that Li et al in view of Goldman et al teach a method for inhibiting tumor growth comprising administration of a composition comprising a hydrogel and a p38 MAPK inhibitor, and further given that Qi et al teaches a method for intraoperatively administering a composition comprising a hydrogel and an anti-cancer agent, it would have been to obvious to one of ordinary skill in the art to substitute the chemotherapeutic of Qi et al with the inhibitor of Goldman et al to treatment at a tumor resection site. One would do so with a reasonable expectation of success because Qi et al teaches the advantages of using localized delivery of anti-tumor drugs. Qi et al teaches that although systemic chemotherapy is used to prevent cancer recurrence, few chemotherapeutic drugs accumulate at the primary tumor site and systemic chemotherapy often has side effects; a strategy to achieve high drug concentration at the tumor site to decrease risk of cancer recurrence is the localized delivery of cytotoxic drugs (pg 6972, column 1, paragraph 1). As systemic administration of a p38 MAPK inhibitor was shown by Goldman et al to be limited clinically because of adverse events, one attempting to prevent cancer recurrence using p38 MAPK pathway inhibitors would look to a method of locally administering anti-cancer agents. Indeed, Qi et al explains because of the ease of preparation, injectability, and local drug delivery capacity, the peptide-based hydrogels for localized chemotherapy may serve as a powerful candidate for the improvement of current clinical therapeutics (pg 6979, column 1, ln 6-11).
The combined teachings of Li et al in view of Goldman et al and Qi et al do not teach a biomaterial that is or comprises hyaluronic acid (as required by claim 1) and thermally induced crosslinks (as required by claim 9) nor do they teach injecting one or more precursor components of the biomaterial and permitting the biomaterial to form at the tumor resection site (as required by claim 29).
Regarding claims 1 and 9, Dubbini teaches injectable hyaluronic acid-based hydrogels for the application of a controlled drug delivery system (abstract). The hydrogel is comprised of cross-linked hyaluro-nic acid (pg 429, Section 3.1), as in claim 1, with thermal gelation at 37 °C (pg 427, ln 1-2). Regarding claim 29, Dubbini teaches that the hydrogel is injectable and that gelation of the hydrogel is accomplished at the site of injection due to its thermosensitivity properties (pg 424, ln 16-21).
Given that Li et al in view of Goldman et al and Qi et al teach a method for delivering a composition comprising a hydrogel and an inhibitor of p38 MAPK to a tumor resection site, and further given that Dubbini et al teaches biomaterials comprised of hyaluronic acid and methods comprised of injecting the hydrogel biomaterial and gelation at the space of injection, it would have been obvious to one of ordinary skill in the art to apply an injectable biomaterial comprising cross-linked hyaluronic acid and have a reasonable expectation of success. The motivation to do so comes from the Dubbini reference, which teaches advantages of using injectable hydrogels, including high moldability, capacity for filling irregular-shaped defects, can be delivered in vivo by minimally invasive administration methods (pg 424, ln 1-3). Further, one would have been motivated to substitute the hydrogel of Qi et al with the hydrogel comprising hyaluronic acid of Dubbini et al because of the art recognized need to develop novel drug delivery systems for cancer treatment, with the goal of having improved outcomes. One of ordinary skill in the art would have easily been able to carry out such a substitution with methods already described in the art, and the results would have been reasonably predictable.
The composition of Li et al in view of Goldman et al, Qi et al, and Dubbini et al does not require: (i) adoptive transfer of T cells to the subject; (ii) administration of a tumor antigen to the subject; and/or (iii) administration of a microparticle to the subject. Therefore, absent evidence to the contrary, the method of the prior art teaches the method of claim 3. Goldberg does not teach an active transport step, and thus the inhibitor is released by diffusion, as in instant claim 21.
While Li et al in view of Goldman et al, Qi et al, and Dubini et al are silent regarding a biomaterial characterized by a storage modulus of about 500 Pa to about 50,000 Pa of claim 2 and a biomaterial characterized by the intended results of claims 23-26, it is clear that the same composition comprising a hydrogel and a PI3K inhibitor would have the same characteristics and effects as the instantly claimed composition since there is no evidence to the contrary. Note that rejections for anticipation are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III). In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not obviously the same.
Claims 1-3, 6, 9, 20-32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Qi et al, Goldman et al, and Dubbini et al, as applied to claims 1-3, 9, 20-32, and 35 above, and further in view of Carey et al, published December 2015 (PTO-892 from 10/23/24).
The teachings of Li et al, Goldman et al, Qi et al, and Dubbini et al are discussed above. This combination of references does not teach a method for intraoperative administration at a tumor resection site a composition comprising p38 MAP kinase inhibitors of quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, pyrazole, quinolinone, and/or naphthridinone core structure, as required by claim 6.
Carey et al teaches a method for treating cancer using the p38 inhibitor ARRY 614 (see entire document), which has a pyrazole core structure, as evidenced by the structure in Product Information sheet for Pexmetinib, synonym ARRY 614 (PTO-892 from 10/23/24), as in claim 6.
Given that Li et al in view of Goldman et al, Qi et al, and Dubbini et al teaches a method of administering a composition comprising a hydrogel and an inhibitor of p38 MAPK to a surgical resection site and further given that Carey et al teaches pyrazole comprising p38 inhibitor ARRY 614 for the treatment of cancer, it would have been obvious to one of ordinary skill in the art to replace the p38 inhibitor of Goldman et al with the p38 inhibitor ARRY 614. One of ordinary skill in the art would have been able to carry out such a substitution, and the results would have been reasonably predictable. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)."
Claims 1-3, 7, 9, 20-32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al, Goldman et al, Qi et al, and Dubbini et al, as applied to claims 1-3, 9, 20-32, and 35 above, and further in view of Yeung et al published February 2018 (PTO-892 from 10/23/24).
The teachings of Li et al, Goldman et al, Qi et al, and Dubbini et al are discussed above; this combination of references does not teach a method for intraoperative administration at a tumor resection site a composition comprising the p38 inhibitor losmapimod, as required by claim 7.
Yeung et al teaches a method for treating cancer using the p38 inhibitor losmapimod (abstract).
Given that Li et al in view of Goldman et al, Qi et al, and Dubbini et al teaches a composition comprising a hydrogel and an inhibitor of p38 MAPK and further given that Yeung et al teaches losmapimod for the treatment of cancer, it would have been obvious to one of ordinary skill in the art to use losmapimod in the injectable hydrogel p38 inhibitor composition of Li et al in view of Goldman et al, Qi et al, and Dubbini et al and have a reasonable expectation of success. This is because one of ordinary skill in the art would have been able to carry out such a substitution, and the results would have been reasonably predictable. As is stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)."
Response to Arguments
Applicant's arguments filed October 24, 2025 with respect to the 35 U.S.C. 103 rejections over Goldberg et al have been considered. Although this rejection no longer relies on Goldberg et al for any specific teaching, arguments regarding celecoxib will be addressed because the new reference Li et al also teaches delivery of celecoxib at tumor sites.
Applicant asserts that there is no basis in fact and/or technical reasoning sufficient to support that the allegedly inherent characteristic necessarily flows from the taught p38 MAP inhibitor of celecoxib (remarks, pg 8). Furthermore, a person of ordinary skill in the art would be motivated to use a different COX-2 inhibitor but not any p38 MAPK inhibitor (remarks, pg 8). The rejection, however, is made over the combined teachings of Li et al, Goldman et al, and Qi et al; especially in view of Goldman et al, which teaches the utility of p38 MAPK inhibitors in the treatment of cancer. As such, it is the combination of references that render the present claims obvious. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s arguments do not show how the combined teachings of the cited references and the knowledge/skills contained therein cannot render the properties of the rejected claims obvious .
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675