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 .
Claim Status
Claims 1-3, 6-7, 9, 13, 20-32, and 35 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 13, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Modified Rejections Necessitated by Amendment
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 Goldman et al, published online December 1, 2017 (see PTO-892 from 6/5/24), Qi et al, published February 7, 2018 (see PTO-892 from 6/5/24), Lei et al, published 2012 (see instant PTO-892), and Dubbini et al published July 20, 2015 (PTO-892 from 1/12/2026).
The claims are directed to a method of preventing tumor recurrence and/or metastasis comprising intraoperative administration at a tumor resection site 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 of 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 administration of 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 events (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 2 days after the resection (pg 6973, Section 2.4; Figure 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.
Amended claim 1 requires the new limitation wherein the p38 MAPK-loaded hydrogel is injected during the resection. Although Qi et al teaches implantation at 2 days after surgical resection, Qi et al does not teach implantation during tumor resection surgery. Lei et al teaches a method for the prevention of cancer recurrence in the mouse model of 4T1 breast cancer by applying a thermosensitive hydrogel comprising the chemotherapy drug paclitaxel at a resection site (abstract). This composition was injected immediately after the surgery at the tumor site on day 0 (pg 5687, column 2, para 1).
Because Qi et al teaches the desirability of delivering the therapeutic composition to the tumor resection site to treat residual tumor cells and Lei teaches implantation of a hydrogel at the time of surgery, in the absence of evidence that administration at the time of resection achieves a different or unexpected result compared with administration 2 days after resection, selection of the precise time of administration would have been an obvious matter of routine optimization. Given the teachings of Qi et al and Lei et al, modifying the timing of implantation from 2 days after surgery to during the surgical procedure would have represented the use of a known treatment at a known location according to its established purpose and would yield predictable results.
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 and Lei et al teach a method for intraoperatively administering a composition comprising a hydrogel and an anti-cancer agent, it would have been 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 hyaluronic 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, Qi et al, and Lei 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, and 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 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 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 April 13, 2026 with respect to the rejection under 35 U.S.C. 103 have been considered but are not persuasive.
Applicant asserts that the cited documents do not suggest the combination of their teachings or suggest the reasonable expectation of success (remarks, pg 8). Regarding the obviousness rejections over Li et al in view of Goldman et al, Qi et al, Dubbini et al, and Carey et al and Li et al in view of Goldman et al, Qi et al, Dubbini et al, and Yeung et al, applicant argues that these combinations can only occur by the impressible use of hindsight reasoning (remarks, pg 8). Further, there is no suggestion in Goldman et al that a p38 MAPK inhibitor could be effective if administered as a crosslinked hydrogel biomaterial (remarks pg 8) or that alternatives to systemic administration would result in less toxicity (remarks, pg 9).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
It is the examiner’s position that the combination of cited reference makes obvious the claimed method. The prior art teaches that p38 MAPK inhibitors kill tumor cells (Goldman et al); systemic administration of p38 MAPK inhibitors causes significant toxicity (Goldman et al); residual tumor cells remain at tumor resection sites (Qi et al); methods for local administration of anticancer agents at resection sites (Li et al, Qi et al, and Lei et al); local administration is an art-recognized method for reducing systemic toxicity while maintaining sustained high drug concentration at the target site (Li et al); injectable hyaluronic acid-based hydrogels for the application of a controlled drug delivery system (Dubbini et al). Because of the appreciated systemic toxicity of p38 MAPK inhibitors when administered orally, local administration may be viewed as an obvious alternative strategy. As taught by Li et al, localized delivery is a commonly used approach to increase drug concentration at the target site and to reduce systemic exposure and related systemic toxicity (pg 8, column 1). There is no evidence to suggest that any of the claimed p38 MAPK inhibitors would not remain active to inhibit residual tumor growth when delivered locally. In the absence of unexpected results, the claims are obvious over the cited prior art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results; the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. Applying a known technique to a known product or method ready for improvement and substituting one known element for another to obtain predictable results are obvious to one of ordinary skill in the art. Here, the claims are drawn to administering a known agent via a known technique to reduce systemic exposure, i.e. local drug delivery; the local administration is a known technique and the reduced systemic toxicity is the predictable result.
Claim 1 has been amended to include the limitation wherein the hydrogel is administered during tumor resection surgery. Applicant points out that Qi et al teaches injection of the chemotherapy-loaded hydrogel after surgery (i.e. resection is on day 7 and injection of hydrogel is on day 9) (remarks pg 11) and, therefore, does not teach the new limitation. As stated in the modified rejection above, because Qi et al teaches the desirability of delivering the therapeutic composition to the tumor resection site to treat residual tumor cells and Lei teaches implantation of a hydrogel comprising a chemotherapy at the time of surgery, in the absence of evidence that administration at the time of resection achieves a different or unexpected result compared with administration 2 days after resection, selection of the precise time of administration would have been an obvious matter of routine optimization. Given the teachings of Qi et al and Lei et al, modifying the timing of implantation from 2 days after surgery to during the surgical procedure would have represented the use of a known treatment at a known location according to its established purposed and would yield predictable results.
Conclusion
No claim is 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.
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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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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