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 .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 9/5/25. Claims 1-20 are pending and examined herein.
The terminal disclaimer filed on 9/5/25 disclaiming the terminal portion of any patent granted on this application, which would extend beyond the expiration date of US Patents 11/534,445 and 12,350,275 have been reviewed and accepted. The terminal disclaimers have been recorded. The obviousness double patenting rejections are hereby withdrawn.
Applicant’s arguments with respect to the 103 rejection have been fully considered but found not persuasive, therefore maintained for reasons of record and repeated below for Applicant’s convenience.
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 1-20 are rejected under 35 U.S.C. 103 as being obvious over King et al. (US 9,724,395 B2, of record) in view of Bosch et al. (US 2015/0202291 A1, of record), Lee et al. (US 2012/0087913 A1, of record), and Tsochatzis et al. (Seminars in Oncology, 2010, vol. 37, issue 2, pp. 89-93, of record).
King et al. teach a method of treating cancer comprising administering an effective amount of at least one immune stimulator and one or more additional anti-cancer agents (see abstract). Immune stimulators include PD-1 inhibitors (see column 2, lines 8-20; addresses claim 9). Cancers treated include gastric, breast, colorectal, bladder, ovarian cancer, hepatocellular (liver) cancer, and lung cancer, for example (see column 6, lines 32-50). Metastatic and other late-stage cancers are also taught (col. 5, lines 60-61).
However, King et al. does not specifically teach an immune checkpoint inhibitor; administering the hypoxia-activated bioreductive agent, tirapazamine, and inducing trans-arterial embolization.
Bosch et al. teach a combination treatment regimen including one or more cycles and/or doses of a checkpoint inhibitor and a therapeutic either sequentially, substantially or simultaneously which is more effective in treating cancer to increase enhance or prolong the activity and/or number of immune cells, the efficacy of anti-tumor immune responses or medically beneficial response by a tumor (see abstract). Checkpoint inhibitors also include antibodies, such as nivolumab (paragraph 0097).
Lee et al. teach a method for enhancing the ability of hypoxia-activated bioreductive agents to kill tumor cells within solid tumors comprising administering tirapazamine and one or more vascular disrupting agents and anti-angiogenic agents (see abstract and claims 1 and 2). Vascular disrupting agents include stilbene 5c for example (see claims 7 and 9). Hypoxia can be performed by mechanical embolization with administration of one or more embolizing agents (see claims 12 and 13), such as Lipiodol (paragraphs 0015, 0033-0035, 0052), which can be administered intra-arterial (see paragraphs 35, 43 and 49). Synergy was observed with the combination of tirapazamine and stilbene 5c more than either alone, wherein there was an increase of 70-80% (see paragraph 40). Tirapazamine is administered first before the administration of the vascular disrupting agent (see paragraph 41).
It would have been obvious and one would be motivated for one of ordinary skill in the art before the effective filing date of the claimed invention to teach a method of treating cancer by administering an immune checkpoint inhibitor because King et al. teach the same claimed immune checkpoint inhibitors to stimulate the immune system.
It would have been obvious and one would be motivated for one of ordinary skill in the art before the effective filing date of the claimed invention to further administer a hypoxia-activated bioreductive agent such as tirapazamine (claims 1 and 2) and an embolizing agent (claims 1 and 8), such as Lipiodol, because of the following teaching:
1) King et al. teach the treatment of tumors with the combination of at least one immune stimulator and one or more additional anti-cancer agents (see abstract);
2) Bosch et al. teach a combination treatment regimen including one or more cycles and/or doses of a checkpoint inhibitor and a therapeutic either sequentially, substantially or simultaneously which is more effective in treating cancer to increase enhance or prolong the activity and/or number of immune cells, the efficacy of anti-tumor immune responses or medically beneficial response by a tumor (see abstract);
3) Lee et al. teach a method for enhancing the ability of hypoxia-activated bioreductive agents to kill tumor cells within solid tumors comprising administering tirapazamine and one or more vascular disrupting agents and anti-angiogenic agents (see abstract and claims 1 and 2); and
4) Lee et al. teach vascular disrupting agents include stilbene 5c for example (see claims 7 and 9) and that hypoxia can be performed by embolization with administration of one or more embolizing agents (see claims 12 and 13), such as Lipiodol.
Thus, one skilled in the art would be motivated to combine treatments of King et al. and Lee et al. with the claimed components to enhance the treatment of a tumor. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992); and In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987). One skilled in the art would reasonably expect the combination of methods would enhance the treatment of tumors.
It would have been obvious and one would be motivated for one of ordinary skill in the art before the effective filing date of the claimed invention to perform the claimed method steps because Lee et al. teach that tirapazamine (i.e. HABA; step (a)) is administered first before the administration of the vascular disrupting agent (i.e. step (b); see paragraph 41). Further, Bosch et al. teach a combination treatment regimen including one or more cycles and/or doses of a checkpoint inhibitor and a therapeutic either sequentially, substantially or simultaneously which is more effective in treating cancer to increase enhance or prolong the activity and/or number of immune cells, the efficacy of anti-tumor immune responses or medically beneficial response by a tumor (see abstract). Thus, it is well within the skill of the art to determine the method steps through routine experimentation to provide the best treatment of the tumor.
Furthermore, Tsochatzis teach that transarterial chemoembolization (TACE) is a validated treatment for unresectable hepatocellular carcinoma (see abstract). TACE has been shown to be effective in prolonging survival in comparison to standard supportive care in randomized controlled trials and meta-analyses. Therefore, it is considered as the treatment of choice in patients with multinodular disease, for whom surgical resection or liver transplantation is not an option (see page 89, last paragraph).
It would have been obvious and one would be motivated for one of ordinary skill in the art before the effective filing date of the claimed invention wherein inducing hypoxia comprises trans-arterial embolization because of the following teachings: 1) Lee et al. teach hypoxia can be performed by embolization with administration of one or more embolizing agents (see claims 12 and 13) which can be administered intra-arterial (see paragraphs 35, 43 and 49); and 2) Tsochatzis teach that transarterial chemoembolization (TACE) is a validated treatment for unresectable hepatocellular carcinoma (see abstract), and has been shown to be effective in prolonging survival in comparison to standard supportive care in randomized controlled trials and meta-analyses. Thus, one skilled in the art would reasonable expect that TACE would be effective in administering the embolizing agent to treat tumors.
Response to Arguments
Applicant argues that none of the additional anticancer agents in King nor Bosch include administering tirapazamine and inducing trans-arterial embolization of one or more blood vessels supplying a solid tumor. Applicant argues that Lee does not disclose or teach the inclusion of another therapeutic modality, much less administering immune checkpoint inhibitors. Furthermore, there is nothing in the cited prior art that provides a reasonable expectation of success that the combination as claimed would be effective in treating cancer.
This is not persuasive because based on the rejection above, all the limitations of instant claims are clearly taught by the cited prior art references. Applicant’s arguments are not persuasive because one of ordinary skill in the art would have had a reasonable expectation of success because all the active agents are taught to be useful for treating cancer, in general. In response to applicant’s arguments against the references, one cannot show nonobviousness by attacking references individually where the rejections are based on the combination 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).
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).
The Lee Declaration under 37 CFR 1.132 filed 9/5/25 is insufficient to overcome the rejection of claims 1-20 based upon King et al. (US 9,724,395 B2, of record) in view of Bosch et al. (US 2015/0202291 A1, of record), Lee et al. (US 2012/0087913 A1, of record), and Tsochatzis et al. (Seminars in Oncology, 2010, vol. 37, issue 2, pp. 89-93, of record), as set forth in the last Office action because: the data is not commensurate with the scope of the claims.
In the HCC study, administration of tirapazamine and the immune checkpoint inhibitor, anti-PD-1 antibody, in patients with advanced hepatocellular carcinoma (HCC) produced an overall response rate of 50% as compared to the clinical benchmarks of 5.9-20% for the standard care of outcome for advanced HCC patients with prior immunotherapy failure.
In the Liver Metastasis study, patients with liver metastasis previously failed chemotherapy plus at least one immunotherapy with very poor prognosis. Under the current treatment options, four patients had an overall response rate of 50%, including one patient with a complete response. This result is well beyond the expectations in the field.
This is not persuasive because Applicant has failed to explain how the claimed method is related to the standard care of outcome for advanced HCC patients with prior chemotherapy and immunotherapy failure. Specifically, it remains to be seen if the aforementioned standard care includes the use of tirapazamine or an immune checkpoint inhibitor. In the absence of these correlations, a comparison of the overall response rate cannot be made.
The declaration also argues unexpected results in a patient with large tumor lesion in the liver’s left lobe and multiple lesions in the right lobe. The skilled artisan would not expect any noticeable therapeutic effect from the first round in the right lobe, multiple tumor lesions were observed to have disappeared, which is attributed to the combination of the first round of localized embolization, tirapazamine, and immune checkpoint inhibitor in the left lobe. Since the right lobe is anatomically and a functionally distinct site than the left lobe, the skilled artisan would not expect to see the substantial disappearance of multiple tumor lesions in the right lobe. This same unexpected effect was observed in the right adrenal gland when treatment was performed on the left adrenal gland. Similarly, the B.2. Patient’s left lobe tumor reduced by 60%, which was primarily attributed to the combination of localized embolization with tirapazamine and immune checkpoint inhibitor administration.
This is not persuasive because these results are not commensurate with the scope of the claims. Applicant is reminded that claim 1 recites a method of treating any and all tumors by administering any and all immune checkpoint inhibitors, regardless of structure. The data in the declaration is limited to: 1) tumors in the liver; and 2) the specific immune checkpoint inhibitor, anti-PD-L1. Since the data is limited to a single type of tumor and a single immune checkpoint inhibitor, it is insufficient to support the full scope of the claims.
Finally, even if the data was commensurate with the scope of the claims, it remains to be seen if there are actual unexpected results. The data mentions that previous administration of immune checkpoint inhibitors failed, but there is no mention of any specific chemotherapeutic, let alone tirapazamine. It remains to be seen what effect on right lobe or adrenal gland can be attributed to tirapazamine alone. In the absence of this information, it is difficult to claim unexpected results.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Regarding the establishment of unexpected results or synergism, a few notable principles are well settled. The Applicant has the initial burden to explain any proffered data and establish how any results therein should be taken to be unexpected and significant. See MPEP 716.02 (b). It is applicant’s burden to present clear and convincing factual evidence of nonobviousness or unexpected results, i.e., side-by-side comparison with the closest prior art in support of nonobviousness for the instant claimed invention over the prior art. The claims must be commensurate in the scope with any evidence of unexpected results. See MPEP 716.02 (d). With regard to synergism, a prima facie case of synergism has not been established if the data or result is not obvious. The synergism should be sufficient to overcome the obviousness, but must also be commensurate with the scope of the claims. Further, if the Applicant provides a DECLARATION UNDER 37 CFR 1.132, it must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See MPEP 716.02 (e).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623