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 (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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/27/2026 has been entered.
Priority
The instant application is a 371 PCT/GB2021/050345 filed on 02/12/2021 and claims foreign priority to British application no. GB2001963.4 filed on 02/13/2020. The certified copy of the foreign priority application GB2001963.4 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/27/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The claim amendments and remarks filed on 01/27/2026 is acknowledged. Claim 2 is amended. Claims 1, 3-18, 20-22, and 24-26 are cancelled.
The declaration by Melinda Jane Duer filed on 01/27/2026 is acknowledged, and the contents are discussed in the response to argument section below.
Accordingly, claims 2, 19 and 23 are pending and being examined on the merits herein.
Withdrawn Rejections
The 35 USC 103 rejection over Fourniols in view of Ahani for claims 2, 17-19, and 22-26 are withdrawn in view of claims 17-18, 22, and 24-26 being cancelled and claim 2 being amended to recite that the crosslinking agent is genipin in a concentration of 2.2 mM to 44 mM, which has changed the scope of the instant claims.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Page 40 line 2 contains the link “[https://pubchem.ncbi.nlm.nih.gov]”.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The following grounds of rejections are new as necessitated by Applicant’s amendments.
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.
Claim(s) 2, 19 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Kelly et al. (WO2019092049 in PTO-892) and as evidenced by Satio-Diaz et al. (bioRxiv, 2023 in PTO-892 dated 06/17/2025).
Kelly discloses a thermo-responsive hydrogel for intratumoral administration as a treatment in solid tumor cancers (see Abstract).
Kelly discloses that systemic chemotherapy for cancer treatment is generally associated with a range of toxic, off-site side effects, and therefore there is interest in developing drug delivery systems which can facilitate retention within the tumor and controlled release of chemotherapeutics from inside the tumor (see page 1 lines 15-35 and page 2 lines 6-15). Kelly discloses that intratumoral administration of chemotherapeutics incorporated in thermo-responsive hydrogels can confer a localized and sustained release of drug directly within the tumor, potentially negating the need for repeated dosing (page 2 lines 6-15). Kelly discloses that since such hydrogels are directly implantable in the target tissue, they may help to circumvent tumor microenvironment (TME) barriers to tissue penetration and reduce non-target tissue exposure and rapid drug clearance associated with systemic delivery and IT instillation (page 2 lines 6-15).
Kelly discloses that current hydrogel formulations suffer from inaccessibility to treatment of sites, inability to image after delivery, along with challenges related to their often-rapid disintegration at their site of action, and poor ability to solubilize non-aqueous drug systems (page 2 lines 15-20). Kelly discloses that current drug delivery formulations such as Gliadel wafers, which are used to deliver chemotherapeutic drug carmustine to the resection site of glioblastoma patients, are markedly different from their hydrogels (page 2 lines 20-35 through page 3 lines 1-5). Therefore, Kelly proposes their hydrogel formulations to overcome at least one of the aforementioned problems with their thermo-responsive hydrogels (page 3 line 31).
Kelly discloses that their room temperature injectable thermos-responsive hydrogel comprises 15-25% (w/w) poloxamer polymer, 0.1-1.0% (w/w) chitosan, 5-20% inclusion complexer (w/w), and 0.05-0.20% (w/w) genipin, and an aqueous base (see Abstract and claim 1 page 36). Here 0.05-0.20% (w/w) genipin converts to 2.2mM to 8.85 mM based on genipin having a molecular weight of 226 g/mol and a solution density of 1 g/mL. Furthermore, Table 2 in Example 1 on page 23 provides specific gel formulations that contain the recited amounts of genipin.
Kelly discloses that their hydrogel can be administered intratumorally to the subject or administered to a tumor resection site to inhibit solid tumor growth in a subject (claim 15 page 37). Kelly discloses that the chitosan and genipin form an interpenetrating scaffold within the hydrogel in which the chitosan is crosslinked with genipin (see Abstract) Kelly discloses that the tumor resection site is from a post-surgical resection (page 9 lines 1-5). Kelly discloses that intratumoral administration means delivery to an existing cavity formed as a result of surgical resection of all or part of a solid tumor, and that administration generally involves injection using a suitable syringe (see page 15 lines 26-30). Kelly discloses the cancer selected for treatment can include glioma, oligodendroglioma, and among others (page 14 lines 22-35 through page 15 lines 1-3).
Kelly demonstrates in Example 17 (pages 31-35) that their hydrogels from Example 1 as well as their hydrogels loaded with chemotherapeutic drugs (Examples 4 and 5) were effective for tumor treatment in in vivo mouse xenograft models. Here, the hydrogels were injected into the tumor of the mice and allowed to gelate (page 32 lines 25-35 through page 33 lines 1-2). Figs 14A-C shows that both the blank loaded hydrogel and drug loaded hydrogel facilitated localized gelation at site administration with retention for at least 14 days. Figs 15A-B show that both blank and drug loaded hydrogels were effective in significantly reducing tumor volume increase in two different types of solid tumors over a period of 14 - 28 days. Figs 16A-D demonstrates that both hydrogels did not induce acute off-site toxicity.
Lastly, as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins (see Abstract on page 3 and first paragraph on page 14 in Satio-Diaz). Therefore, the genipin disclosed in Kelly is also capable of cross-linking extracellular matrix in and/or around the site of the resected tumor.
Here, even though Kelly does not demonstrate administering their hydrogels to the site of a resected primary brain cancer tumor, it would have been prima facie obvious before the effective filing date of the claimed invention to have administered the hydrogels of Kelly to a primary brain tumor cavity that is formed after surgical resection as disclosed in Kelly. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Kelly demonstrates that their hydrogels are effective in inhibiting tumor growth in vivo, and further discloses that glioma and oligodendroglioma can be selected for treatment using their hydrogels. Additionally, Kelly discloses that their hydrogels can be administered via syringe to an existing cavity formed as a result of surgical resection of all or part of a solid tumor.
Furthermore, the teachings of Kelly suggest that the genipin in the hydrogel impedes the movement and/or proliferation of cancer cells, thus inhibiting migration of cancer cells away from the site of the resected tumor because Kelly discloses that their hydrogel can be administered to a resected tumor site to inhibit solid tumor growth, and further discloses that their hydrogels are allowed to gelate at the resected site, in which the genipin and chitosan form an interpenetrating scaffold via crosslinking. Furthermore, as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins (see Abstract on page 3 and first paragraph on page 14 in Satio-Diaz). Therefore, the genipin disclosed in Kelly would necessarily crosslink within the hydrogel matrix as well as crosslink ECM components in/around the resected tumor site thereby impeding migration of cancer cells away from the site of the resected tumor.
Additionally, even though Kelly suggests that their genipin in the hydrogel has the described mechanism of action against cancer cells, this mechanism would also flow naturally from the teachings of Kelly because Kelly teaches administering a composition comprising the same concentrations of genipin to the resected site of a primary brain cancer tumor, and as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins as described above.
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claim 23, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administered the hydrogel of Kelly described above to the resected site of a glioblastoma multiforme (GBM) tumor as suggested in Kelly to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Kelly suggests that their hydrogels are an alternative to current drug delivery systems such as Gliadel wafers, which are used to deliver chemotherapeutic drug carmustine to the resection site of glioblastoma patients. Furthermore, Kelly discloses that their hydrogels can be administered to treat glioma and oligodendroglioma as well as to the cavity of a surgical resected tumor. Therefore, an ordinary skilled artisan could have predictably considered administering the hydrogel to a GBM resected site with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments and declaration under 35 CFR 1.132 filed on 01/27/2026 have been fully
considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant presents several arguments over the teachings of Fourniols and Ahani. However, the new rejection does not cite Fourniols or Ahani. Therefore, Applicant’s arguments over these references are rendered moot.
Applicant states that the instant invention is based upon the technical effect of physically impeding the movement of cancer cells by cross-linking the ECM which surrounds the cancer cells. Applicant states that this mechanism of action was new at the effective filing date of the application.
Applicant’s argument described above was not found persuasive because the new rejection over Kelly suggests their genipin has the described mechanism of action against cancer cells. Specifically, Kelly discloses that the genipin in their hydrogels form an interpenetrating scaffold when the chitosan is crosslinked with genipin (see Abstract), and that these hydrogels are allowed to gelate at the site of the resected tumor. Furthermore, as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins. Therefore, the genipin disclosed in Kelly would necessarily crosslink within the hydrogel matrix as well as crosslink ECM components in/around the resected tumor site thereby impeding migration of cancer cells away from the site of the resected tumor. Additionally, this mechanism would also flow naturally from the teachings of Kelly because Kelly teaches administering a composition comprising the same concentrations of genipin to the resected site of a primary brain cancer tumor, and as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins (see Abstract on page 3 and first paragraph on page 14 in Satio-Diaz).
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Applicant further filed a declaration from Melinda Jane Duer on 01/27/2026, which discloses that the claimed concentration range of genipin is an essential and non-obvious feature of the instant invention. Applicant points to Figure 7, section 16 of the Declaration, in which the level of crosslinking, by different concentrations of genipin, of the model protein poly-lysine, and of commercial Matrigel, which mimics tumor ECM. Applicant states that in the case of both target materials, genipin induces insignificant crosslinks at 0.5 mM and 1 mM (outside of the claimed concentration) even after several hours of exposure. Therefore, Applicant states that a 0.5 mM or 1 mM would not be a feasible option.
Here, while Applicant has demonstrated that lower concentrations of genipin outside of the recited concentration range does not induce the crosslinking mechanism against cancer cells, Applicant has not provided a proper comparison to the closest prior art.
As stated in MPEP 716.02(e), “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness”.
Here, the closest prior art is Kelly, and as described above, Kelly discloses hydrogel compositions comprising 0.05-0.20% (2.2mM to 8.85 mM) genipin and additional components (also see Table 2 on page 23 for specific formulations). It is noted that the method recites administering a composition “comprising” the genipin, which means additional, unrecited elements such as the other components disclosed in the hydrogels of Kelly are within scope of the instant claims, see MPEP 2111.03 I. Therefore, Applicant has not provided a proper comparison to these hydrogel formulations.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2, 19, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 12-13, 15-17, 19, and 21-23 of copending Application No. 18/682,559 (‘559) in view of Kelly et al. (WO2019092049 in PTO-892) and as evidenced by Satio-Diaz et al. (bioRxiv, 2023 in PTO-892 dated 06/17/2025).
Claim 1 of ‘559 recites “An in vivo method of killing brain tumour cells in a brain tumour or at a site of a resected brain tumour in a subject, the method comprising the step of: (a) directly contacting brain tumour cells in the brain tumour or at the site of the resected brain tumour with a composition comprising a cytotoxic agent, wherein the cytotoxic agent is a polyamine, and wherein has the structure: NH2—[(CH2)a—NH]—[(CH2)b—NH]x—[(CH2)c—NH]y—H, wherein a, b and c are each independently 3, 4 or 5; and x and y are each independently 0 or 1; wherein the concentration of the cytotoxic agent in the composition if 100 micromolar to 50 millimolar”. Claim 17 of ‘559 recites that the brain tumour is a glioblastoma multiforme (GBM). Claim 19 of ‘559 recites that the cytotoxic agent additionally comprises a target moiety which is specific for the brain or brain tumor to be targeted. Claim 21 of ‘559 recites the composition is applied to some or all of the brain tumor cells in all or part of: (i) the brain tumor; (ii) the vicinity of the brain tumor; (iii) the site of the resected brain tumor; and/or (iv) vicinity of the site of resected brain tumor. Claim 22 of ‘559 recites the composition is applied by spraying or by swabbing, Here, claims 21-22 of ‘559 meet the limitations “(iv) the composition is applied after a surgical step to remove all or part of the tumor” recited in instant claim 17, and “(iii) the composition is applied after a surgical step to remove all or part of the tumor, wherein the composition is administered topically in to the tumor cavity after removal of the tumor” recited in instant claim 22.
The difference between the claims of ‘559 and the claimed invention is that the claims of ‘558 do not recite administering genipin at 2.2 to 44 mM concentration.
The independent teachings of Kelly and Satio-Diaz et al. are as described above.
It would have been prima facie obvious to combine the claims of ‘559 and Kelly before the effective filing date of the claimed invention by substituting the composition comprising the cytotoxic agent recited in the claims of ‘559 with the hydrogels of Kelly compressing genipin at 2.2mM to 8.85 mM to arrive at the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because both the claims of ‘559 and Kelly recite the use of their respective composition for treating the same resected brain tumors. See MPEP 2144.06 section II.
Furthermore, even though the combination of the claims of ‘558 and Kelly suggests that genipin impedes the movement and/or proliferation of cancer cells, thus inhibiting migration of cancer cells away from the site of the resected tumor, this functional limitation would also flow naturally from this combination because the combination teaches administering a composition comprising the same concentrations of genipin to the resected site of a primary brain cancer tumor, and as evidenced by Satio-Diaz, genipin is a known agent for crosslinking ECM proteins (see Abstract on page 3 and first paragraph on page 14 in Satio-Diaz). Furthermore, Kelly discloses that the genipin in their hydrogels form an interpenetrating scaffold when the chitosan is crosslinked with genipin (see Abstract), and that these hydrogels are allowed to gelate at the site of the resected tumor. Therefore, the genipin disclosed in Kelly would necessarily crosslink within the hydrogel matrix as well as crosslink ECM components in/around the resected tumor site.
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant proposes to evaluate the present claims as well as the pending claims in the ‘559 application when the instant claims are placed in allowable condition.
Since no allowable claims have been found, the double patenting rejection over ‘559 is maintained.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693