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
This office action is a response to applicant’s communication submitted December 26, 2025 wherein the rejections of record in the previous action are traversed. This application is a national stage application of PCT/US2019/040292, filed July 2, 2019, which is a continuation in part of US application 16/367233, now abandoned, filed March 27, 2019.
Claims 4-8, 10, and 119-127 are pending in this application.
Claims 4-8, 10, and 119-127 as amended are examined on the merits herein.
The following rejections of record in the previous action are maintained:
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 4-8, 10, 119, and 121-127 are rejected under 35 U.S.C. 103 as being unpatentable over Raker et al. (PCT international publication WO2013/109732, Reference included with PTO-1449) in view of Alsaab et al. (Reference of record in previous action)
Independent claim 119 is directed to a method of treating a neoplasm comprising administering to a subject a sterile filtered glycated chitosan (GC) and a checkpoint inhibitor, wherein the GC is defined as having a specific molecular weight of below 420kDa and a degree of glycation up to 30% and the checkpoint inhibitor is defined as an anti-PD-1 or anti-PD-L1 antibody. Dependent claims 4 and 122-126 further defines the mw and degree of glycation of the GC. Dependent claims 5-8 further define characteristics of the solution of GC polymer. Dependent claim 121 further specifies that the GC is administered intratumorally. Dependent claim 127 describes the patient as being treated with radiation therapy.
Raker et al. discloses chitosan-derived compositions and methods of using these compositions to treat neoplasms. (p. 3 paragraph 12) In one embodiment the chitosan derivative is glycated chitosan. (p. 3 paragraph 14) The chitosans have a molecular weight less than 1500 kDa and have unexpectedly beneficial viscoelastic properties. (p. 6 paragraph 21) The degree of glycation is preferably 0.1-30%, most preferably 2% (p. 6 paragraph 22) falling within the range recited in present claims 119, 123, and 124. In a preferred example a glycated chitosan having a mw of 250 kDa is shown to be usefully capable of sterile filtration. (pp. 40-41 example 2) In another example a glycated chitosan is disclosed having a mw of 250 kDa, a degree of deacetylation of about 80%, a degree of glycation of about 12.5%, and a structure falling within the structure recited in claim 119. (p. 13 figure 2) These low molecular weight GCs were also found to have improved injectability. (p. 42 last paragraph) Physicochemical properties disclosed as result-effective variables include molecular weight, degree of polymerization, degree of deacetylation, and degree of glycation. (top of p. 13) Therefore one of ordinary skill in the art would have found it to be obvious to adjust the degree of glycation within the range of 0.1-30% disclosed by Raker et al. to arrive at the optimal number. Regarding claims 5-7, a preferred pharmaceutical composition comprising the GC is a viscoelastic aqueous solution having a pH of 5.0-7. (p. 18 paragraphs 71-72) Regarding claim 8, Raker et al. discloses the solution as having a viscosity of about 1-100 centistokes at 25 degrees Celsius. (p. 19 paragraph 77)
These viscoelastic GC compositions are useful as immunoadjuvants, for example in combination with laser-assisted immunotherapy or radiation therapy for cancer. (p. 20 paragraph 85, p. 25 paragraph 105) The immunoadjuvant composition can be locally injected into a tumor mass, and can be conjugated to a tumor or antigen. (p. 20 paragraphs 86-87, pp. 25-26 paragraph 108-109) In such a method a laser is applied to the tumor to release tumor antigens, and the immunoadjuvant enhances the subsequent immune response to the tumor antigens. (p. 24 paragraphs 102-103)
The therapeutic methods described by Raker et al. differs from the claimed invention in that it does not further administering a checkpoint inhibitor such as an anti-PD-1 antibody. However, Raker et al. does disclose that the compositions can be administered along with other cancer therapies. Additionally, Alsaab et al. discloses the use of checkpoint inhibitors of the PD-1/PD-L1 interaction to facilitate an immune response against a tumor. (p. 2 right column last paragraph) Antibodies against PD-1 and PD-L1 have been shown to be useful as antitumor agents for improving an immune response against a tumor. (p. 5 right column)
It would have been obvious to one of ordinary skill in the art at the time of the invention to combine the GC described by Raker et al. with the checkpoint inhibitor antibodies described by Alsaab et al. One of ordinary skill in the art would have found this combination to be obvious because both of these elements are disclosed to be useful individually for the purpose of treating cancer. Furthermore, because Alsaab et al. describes the anri-PD-1 and PD-L1 antibodies as improving the subject’s immune response against a tumor, one of ordinary skill in the art would have additionally considered this to be obvious based on a rationale of applying a known improvement to a prior art method ready for improvement. Specifically, because the immunotherapy described by Raker et al. functions by producing an immune response against the tumor, an additional agent that enhances the antitumor immune response would be expected to improve the effectiveness of the therapy.
With respect to the degree of glycation of 5% recited in present claims 4 and 126, while Raker et al. does not specifically disclose a degree of glycation falling within this range, according to MPEP 2144.05, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” In the present case a range of 0.1-30%, preferably greater than 2% therefore renders obvious the range of 3-6% which falls within this broader range.
Therefore the invention taken as a whole is prima facie obvious.
Claim 120 is rejected under 35 U.S.C. 103 as being unpatentable over Raker et al. in view of Alsaab et al. as applied to claims 4-8, 10, 119, and 121-127 above, and further in view of Lee et al. (Reference of record in previous action)
The disclosures of Raker et al. and Alsaab et al. are discussed above. Raker et al. in view of Alsaab et al. does not specifically disclose wherein the radiotherapy is particle beam irradiation. However, Lee et al. discloses a review of the use of proton beam therapy, which is a form of particle beam irradiation, in combination with cancer immunotherapy. (p. 180 left column – right column first paragraph) Lee et al. further discloses that proton beam irradiation can be calibrated to deliver radiation at a more precisely defined depth, (p. 183 left column first paragraph) and can produce greater immunogenicity and less immunosuppression than photon irradiation. (p. 183 left column last paragraph – p. 184 left column first paragraph) Clinical data so far demonstrates a benefit of proton beam radiotherapy compared to photon radiotherapy. (p. 184 right column last paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to is proton beam irradiation as the radiotherapy in the methods described by Raker et al. One of ordinary skill in the art would have seen the disclosure of Lee et al. as indicating that proton beam irradiation is an improvement over photon radiotherapy, and therefore obvious to apply to a prior art radiotherapy method.
Therefore the invention taken as a whole is prima facie obvious.
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.
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Claims 4-8, 10, 119, and 121-127 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 10-13, and 16 of US Patent No. 12398215 (Cited in PTO-892, issued from previously cited US application 18/237228, herein referred to as ‘215) in view of Raker et al. (PCT international publication WO2013/109732, Reference of record in previous action) in view of Alsaab et al. (Reference of record in previous action).
Claim 1 of ‘215 claims a method of treating a cancer in a subject comprising administering to the subject a glycated chitosan having a mw of 100-300 kDa, a degree of deacetylation of about 75-99%, and a degree of glycation of 0.1-30%. Dependent claim 6 of ‘215 further defines the method as involving administration directly into the neoplasm. Claim 7 further adds a step of ablating the neoplasm. Dependent claims 10-13 define the same features of the GC recited in present claims 2-4. Claim 16 of ‘215 specifies that the GC is sterile filtered. While the material described in claims of ‘215 does not further include a checkpoint inhibitor such as an anti-PD-1 antibody, as described previously under 35 USC 103, Raker et al. discloses that intratumoral GC is specifically useful in cancer immunotherapy, and Alsaab et al. discloses that local administration of an anti-PD1 antibody would be expected to augment the immune response, enhancing the effect of immunotherapy. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to administer an anti-PD-1 antibody along with the glycated chitosan in the method claimed by ‘215, since the prior art provides a rationale for believing that adding this additional component would enhance the effect of the GC.
Claims 4-8, 10, 119, and 121-127 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-9, and 12 of U.S. Patent No. 11773188 (Reference of record in previous action, herein referred to as ‘188) in view of Alsaab et al. (Reference of record in previous action).
Claim 1 of ‘188 claims a method of treating a cancer in a subject comprising administering to the subject a glycated chitosan having a mw of 100-300 kDa, a degree of deacetylation of about 75-99%, and a degree of glycation of 0.1-30%. Dependent claims 2 and 3 of ‘228 further define the method as involving administration directly into the neoplasm. Claim 4 further adds a step of ablating the neoplasm. Dependent claims 7-9 define the same features of the GC recited in present claims 2-4. Claim 12 of ‘188 specifies that the GC is sterile filtered. While the material described in claims of ‘188 does not further include a checkpoint inhibitor such as an anti-PD-1 antibody, as described previously under 35 USC 103, Raker et al. discloses that intratumoral GC is specifically useful in cancer immunotherapy, and Alsaab et al. discloses that local administration of an anti-PD1 antibody would be expected to augment the immune response, enhancing the effect of immunotherapy. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to administer an anti-PD-1 antibody along with the glycated chitosan in the method claimed by ‘188, since the prior art provides a rationale for believing that adding this additional component would enhance the effect of the GC.
Claims 4-8, 10, 119, and 121-127 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11111316 (Reference of record in previous action, herein referred to as ‘316) in view of Alsaab et al. (Reference of record in previous action).
Claim 1 of ‘316 claims a glycated chitosan having a mw of 100-300 kDa, a degree of deacetylation of about 75-99%, and a degree of glycation of 0.1-30%. Dependent claims 2-5 of ‘316 further define the same features of the GC recited in present claims 2-4. Claims 5-11 of ‘316 define the same features of the composition as present claims 6-7. While the material described in claims of ‘316 does not further include a checkpoint inhibitor such as an anti-PD-1 antibody, as described previously under 35 USC 103, Raker et al. discloses that intratumoral GC is specifically useful in cancer immunotherapy, and Alsaab et al. discloses that local administration of an anti-PD1 antibody would be expected to augment the immune response, enhancing the effect of immunotherapy. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to administer an anti-PD-1 antibody along with the glycated chitosan in the composition claimed by ‘316, since the prior art provides a rationale for believing that adding this additional component would enhance the effect of the GC.
Claim 120 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 10-13, and 16 of US Patent No. 12398215 (Cited in PTO-892, issued from previously cited US application 18/237228, herein referred to as ‘215) in view of Raker et al. (PCT international publication WO2013/109732, Reference of record in previous action) in view of Alsaab et al. (Reference of record in previous action) and further in view of Lee et al. (Reference of record in previous action)
The claims of ‘215 are discussed previously. The disclosures of Raker et al. and Alsaab et al. are discussed previously. While the claims of ‘215 in view of Raker et al. in view of Alsaab et al. do not specifically describe or suggest using particle beam irradiation, Lee et al. discloses a review of the use of proton beam therapy, which is a form of particle beam irradiation, in combination with cancer immunotherapy. (p. 180 left column – right column first paragraph) Lee et al. further discloses that proton beam irradiation can be calibrated to deliver radiation at a more precisely defined depth, (p. 183 left column first paragraph) and can produce greater immunogenicity and less immunosuppression than photon irradiation. (p. 183 left column last paragraph – p. 184 left column first paragraph) Clinical data so far demonstrates a benefit of proton beam radiotherapy compared to photon radiotherapy. (p. 184 right column last paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to is proton beam irradiation as the radiotherapy in the methods described by Raker et al. One of ordinary skill in the art would have seen the disclosure of Lee et al. as indicating that proton beam irradiation is an improvement over photon radiotherapy, and therefore obvious to apply to a prior art radiotherapy method.
Claim 120 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-9, and 12 of U.S. Patent No. 11773188 (Reference of record in previous action, herein referred to as ‘188) in view of Alsaab et al. (Reference of record in previous action) and further in view of Lee et al. (Reference of record in previous action)
The claims of ‘188 are discussed previously. The disclosures of Raker et al. and Alsaab et al. are discussed previously. While the claims of ‘188 in view of Raker et al. in view of Alsaab et al. do not specifically describe or suggest using particle beam irradiation, Lee et al. discloses a review of the use of proton beam therapy, which is a form of particle beam irradiation, in combination with cancer immunotherapy. (p. 180 left column – right column first paragraph) Lee et al. further discloses that proton beam irradiation can be calibrated to deliver radiation at a more precisely defined depth, (p. 183 left column first paragraph) and can produce greater immunogenicity and less immunosuppression than photon irradiation. (p. 183 left column last paragraph – p. 184 left column first paragraph) Clinical data so far demonstrates a benefit of proton beam radiotherapy compared to photon radiotherapy. (p. 184 right column last paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to is proton beam irradiation as the ablation in the methods claimed by ‘188. One of ordinary skill in the art would have seen the disclosure of Lee et al. as indicating that proton beam irradiation is effective in combination with cancer immunotherapy, and therefore obvious to include in a prior art immunotherapy method such as that claimed by ‘188.
Claim 120 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11111316 (Reference of record in previous action, herein referred to as ‘316) in view of Alsaab et al. (Reference of record in previous action) and further in view of Lee et al. (Reference of record in previous action)
The claims of ‘316 are discussed previously. The disclosures of Raker et al. and Alsaab et al. are discussed previously. While the claims of ‘316 in view of Raker et al. in view of Alsaab et al. do not specifically describe or suggest using particle beam irradiation, Lee et al. discloses a review of the use of proton beam therapy, which is a form of particle beam irradiation, in combination with cancer immunotherapy. (p. 180 left column – right column first paragraph) Lee et al. further discloses that proton beam irradiation can be calibrated to deliver radiation at a more precisely defined depth, (p. 183 left column first paragraph) and can produce greater immunogenicity and less immunosuppression than photon irradiation. (p. 183 left column last paragraph – p. 184 left column first paragraph) Clinical data so far demonstrates a benefit of proton beam radiotherapy compared to photon radiotherapy. (p. 184 right column last paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to is proton beam irradiation as the ablation in the methods claimed by ‘316. One of ordinary skill in the art would have seen the disclosure of Lee et al. as indicating that proton beam irradiation is effective in combination with cancer immunotherapy, and therefore obvious to include in a prior art immunotherapy method such as that claimed by ‘316.
Response to Arguments
Applicant’s arguments submitted December 26, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that, as evidenced by the declaration of Dr. Lam, the combination of irradiation, intratumoral injection of glycated chitosan, and systemic administration of a nanti-PD1 antibody produces an unexpectedly superadditive effect on survival compared to either irradiation combined with glycated chitosan or systemic anti-PD1 antibody alone.
In particular, Applicant argues that group 3 in the provided figure 1 (MWA + intratumoral glycated chitosan) corresponds to the disclosure of Hode (WO2013/109732, referred to as Raker in the previous obviousness rejection) described above, and that group 4 (Anti-PD1 antibody) corresponds to the disclosure of Alsaab discussed above. Applicant argues that this is a comparison showing unexpected results as compared to the closest prior art. However, as discussed previously, Yin, Abdo, Kudo, and Liu all demonstrate that it was already known in the prior art that combination therapy involving both tumor immunotherapy such as radiofrequency ablation and administration of an anti-PD1 or anti-PDL1 antibody produces a synergistic antitumor effect as compared to either therapy alone. Therefore showing a synergistic therapeutic effect for the combination of microwave ablation and anti-PD1 antibody treatment is not evidence of unexpected results, since any superadditive result would have been expected based on the cited prior art. While Yin, Abdo, Kudo, and Liu do not specifically mention glycated chitosan, Hode/Raker specifically describes one benefit of glycated chitosan being its use as an immunoadjuvant that improves the functioning of cancer immunotherapy, of which the microwave ablation described in the declaration of Lam. (see pp. 20-21 paragraphs 85-88 of Hode) Any reasonable interpretation of the data presented by figure 1 would be that any superadditive effect is due to the known synergism between microwave ablation and the anti-PD1 antibody. No novel unexpected synergistic effect due to the glycated chitosan is needed to explain this result. Therefore the declaration of Dr. Lam provides evidence only of an expected synergistic effect based on the prior art.
Therefore the rejections are deemed proper and maintained.
Conclusion
No claims are allowed in this action. THIS ACTION IS MADE FINAL. 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.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 2/23/2026