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 .
Response to Amendment
The Amendment filed 07/16/2026 in which claims 5, 8, and 9 were amended has been entered. Claim 12 has been canceled. Claims 15 – 20 have been added.
Claims 5 – 7, 9 – 11, and 13 – 20 are under examination on the merits.
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.
(Previous rejection, maintained and modified as necessitated by amendments) Claim(s) 5-7, 10, 11, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20190046640A1, hereinafter, “Deng”), in view of Mieczkowska et al (Cell Death & Disease, 2021, 10.1038/s41419-021-04407-y, hereinafter, “Mieczkowska”).
Deng teaches the use of poxviruses for oncolytic immunotherapy against solid tumors (Title, Abstract). Deng teaches the viruses can include MVA, MVAΔE3L, and inactivated MVA (Abstract, ¶0017). Deng teaches MVA can be used in conjunction with immune checkpoint inhibitor therapy (Abstract, Figure 17). Furthermore, Deng teaches the use of MVA and immune checkpoint inhibitors against cancers such as, but not limited to, melanoma and breast cancer (Figure 17, ¶0260).
Regarding claim 5, Deng teaches the use of heat inactivated MVA and teaches that heat inactivated MVA induces higher levels of IFN and inflammatory cytokines and chemokines gene expression (¶0101). Deng also teaches the use of heat inactivated MVA in conjunction with anti-PD-1 and anti-CTLA-4 antibodies (¶0104). Deng also teaches the use of MVA with anti-PD-1 and anti-CTLA-4 antibodies to treat tumors in a triple negative breast cancer model (¶0260).
Deng does not teach the measuring of either protein levels or RNA levels of PRC2.
However, Mieczkowska teaches breast cancer (BC) such as basal-like BC subtype (BLBC) and triple negative breast cancer subtype (TNBC), which largely overlap, lack early diagnosis and development of targeted therapies (Abstract). As a result, treatment is limited to conventional cytotoxic chemotherapies that can lead to the development of resistance to the treatment (Abstract). Mieczkowska teaches that these tumor cells that survive after chemotherapy have pronounced reduction of PRC2 activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2 (Abstract). Mieczkowska teaches loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions (Abstract). Mieczkowska teaches that context-dependent PRC2/EZH2 function in BC in TNBC/BLBC patients could represent an attractive opportunity for therapeutic treatments (Discussion).
Regarding claim 6, Mieczkowska teaches the measurement of PRC2 mRNA levels from BC cells (Figure 2).
Regarding claim 7, Mieczkowska teaches the measurement of western blot levels of PRC2 (Figure 2, Section: Western blotting).
Regarding claim 10, Deng teaches a heat inactivated MVA (¶0132).
Regarding claim 11, Deng teaches inactivated MVA and anti-PD-1 and anti-CTLA-4 antibodies treatment for BC (Figure 17, ¶0260).
Regarding claims 19, Deng teaches intratumorally administration of inactivated MVA (Figure 17, ¶0260).
Regarding claim 20, Deng teaches intraperitoneal delivery of anti-PD-1 and anti-CTLA-4 antibodies (¶0223).
It would have been prima facie obvious before the effective filing date of the claimed invention to measure PRC2 levels of breast cancer tumors, as taught by Mieczkowska, and treat patients with low PRC2 levels/activity with inactivated MVA and anti-PD-1 and anti-CTLA-4 antibodies, as taught by Deng, because doing so would advantageously circumvent any potential cytotoxic chemotherapies resistance that may arise. One of ordinary skill in the art would have had a reasonable expectation of success of measuring PRC2 while administering MVA and an immune checkpoint inhibitor given that PRC2 is a well-known biomarker and the method of treating breast cancer was well known, has been successfully demonstrated, and commonly used as evidence by the prior art.
(Previous rejection, maintained and modified as necessitated by amendments) Claims 9, 13, 14, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Deng and Mieczkowska as applied to claims 5-7, 10, 11, 19, and 20 above, and further in view of Dai et al (Sci Immunol, 2017, 10.1126/sciimmunol.aal1713, hereinafter, “Dai”), as evidenced by Nagarsheth et al (Cancer Res, 2016, :10.1158/0008-5472.CAN-15-1938., hereinafter, “Nagarsheth”).
As discussed above, claims 5-7, 10, 11, 19, and 20 were rendered prima facie obvious by Deng and Mieczkowska. While the references teach a for treating cancer using inactivated MVA and immune checkpoint inhibitor in tumors with decreased PRC2 activity, the references fail to explicitly teach a method of sensitizing a PRC2 mutant tumor.
However, Dai teaches the use of heat inactivated, as well as UV inactivated, modified vaccinia virus Ankara (MVA) to alter the tumor immune-suppressive microenvironment that leads to antitumor activity (Abstract). Dai administered MVA along with immune checkpoint inhibitors, such as anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies, intratumorally to in murine melanoma models finding the MVA was effective of changing the tumoral from resistant to permissive of checkpoint blockade therapy (Figure 8). Along with turning ‘cold’ tumors to ‘hot’ tumors, Dai found the combination MVA and immune checkpoint inhibitor therapy to stop tumor growth (Figure 8). Dai also teaches the measurement of protein levels within tumor cells such as IRF3 (Supplementary figure 2E) and the measurement of RNA levels within tumor cells such as that of Ifna4 (Supplementary figure 1G). Furthermore, Nagarsheth evidences that PRC2 is known to suppress T-Cell trafficking in cancers, a hallmark of cold tumors (Abstract).
Regarding claim 9, Dai teaches the use of MVA to sensitize or in other words alter the tumor microenvironment to be more permissive to the activity of immune checkpoint inhibitors. Dai uses MVA in combination with immune check point inhibitors such as anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies to effectively treat melanoma tumors within subjects.
Regarding claims 13 and 14, Dai used a combination of inactivated MVA in combination of anti-PD-L1 antibody, delivered intratumorally, to eliminate tumors in 80% of subjects (Section: Intratumoral Heat-iMVA is superior to TLR agonist poly (I:C) in treating large established tumors alone and in combination with immune checkpoint blockade; ¶2).
Regarding claim 17, Dai teaches both a heat inactivated and a UV inactivated MVA to sensitize and treat melanoma tumor models (Abstract).
Regarding claim 18, Dai teaches an inactivated MVA and anti-PD-1 and anti-CTLA-4 antibodies treatment for cold tumors (Figure 8).
Deng, Mieczkowska, and Dai are considered to be analogous to the claim invention because they are in the same field of treating cancer. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the method taught by Deng to sensitize cancers as taught by Dai because, as Nagarsheth evidenced, PRC2 can cause ‘cold’ tumors. Deng and Dai teach a method that would allow the effective treatment of cold tumors. While Dai does not teach the measurement of PRC2, it would have been obvious to measure PRC2 as it is a biomarker because it is well known that PRC2 mutations and activity can lead to cold tumors and that when MVA is administered with an immune checkpoint inhibitor cold tumors are sensitized and treated, such of those found in the murine BC models of Deng. One of ordinary skill in the art would have had a reasonable expectation of success of measuring PRC2 while administering MVA and an immune checkpoint inhibitor given that PRC2 is a well-known biomarker and the method of treating BC was well known, has been successfully demonstrated, and commonly used as evidence by the prior art.
(New rejection, as necessitated by amendments) Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Deng, Mieczkowska, and Dai as applied to claims 5-7, 9, 10, 11, 13, 14, and 17 – 20 above, and further in view of Ueda et al (Leukemia, 2012, 10.1038/leu.2012.146, hereinafter, “Ueda”).
As discussed above, claims 5-7, 9, 10, 11, 13, 14, and 17 – 20 were rendered prima facie obvious by Deng, Mieczkowska, and Dai. The references teach a method for sensitizing and treating cancer using inactivated MVA and immune checkpoint inhibitor in tumors with decreased PRC2 activity. While Mieczkowska teaches decreased PCR2 activity through siRNA mediated knockdown of EZH2, the references fail to explicitly teach a PRC2 mutant tumor comprising a mutation in SUZ12, EED and/or EZH1/2.
However, Ueda teaches that inactivating mutations of EZH2 have been identified in subsets of myeloid disorders including myelodysplastic (MDS) and are predicted to inactivate PRC2 function (Abstract). Ueda also teaches that although EZH2 possesses the methyltransferase activity of PRC2, EZH2 is inactive on its own, and direct interaction of EED to EZH2 is required for EZH2 to fully exert its enzymatic activity (Abstract). Regarding claim 15, Ueda that deletions of different portions of EED cause a decrease in PCR2 in MDS (Figure 1, Figure 2).
Deng, Mieczkowska, Dai, and Ueda are considered to be analogous to the claim invention because they are in the same field of treating cancer. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the method taught by Deng to sensitize cancers that have decreased activity of PRC2 through a mutation of one of its subunits, as taught by Ueda, because, as taught by Mieczkowska, PRC2 activity is decreased by a lack of subunit function. One of ordinary skill in the art would have had a reasonable expectation of success in treating tumors with decreased PRC2 activity caused by a mutation of SUZ12, EED and/or EZH1/2 by administering MVA and an immune checkpoint inhibitor given that mutations of SUZ12, EED and/or EZH1/2 decreasing PRC2 activity was well known, has been successfully demonstrated, and commonly used as evidence by the prior art.
(New rejection, as necessitated by amendments) Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Deng and Mieczkowska as applied to claims 5-7, 10, 11, 19, and 20 above, and further in view of Ueda.
As discussed above, claims 5-7, 10, 11, 19, and 20 were rendered prima facie obvious by Deng and Mieczkowska. The references teach a method for treating cancer using inactivated MVA and immune checkpoint inhibitor in tumors with decreased PRC2 activity. While Mieczkowska teaches decreased PCR2 activity through siRNA mediated knockdown of EZH2, the references fail to explicitly teach a PRC2 mutant tumor comprising a mutation in SUZ12, EED and/or EZH1/2.
However, as discussed above, Ueda teaches that inactivating mutations of EZH2 have been identified in subsets of myeloid disorders including myelodysplastic syndrome (MDS) and are predicted to inactivate PRC2 function (Abstract). Ueda also teaches that although EZH2 possesses the methyltransferase activity of PRC2, EZH2 is inactive on its own, and direct interaction of EED to EZH2 is required for EZH2 to fully exert its enzymatic activity (Abstract). Regarding claim 16, Ueda teaches that deletions of different portions of EED cause a decrease in PCR2 in MDS (Figure 1, Figure 2).
Deng, Mieczkowska, and Ueda are considered to be analogous to the claim invention because they are in the same field of treating cancer. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the method taught by Deng to sensitize cancers that have decreased activity of PRC2 through a mutation of one of it’s subunits, as taught by Ueda, because, as taught by Mieczkowska, PRC2 activity is decreased by a lack of subunit function. One of ordinary skill in the art would have had a reasonable expectation of success in treating tumors with decreased PRC2 activity caused by a mutation of SUZ12, EED and/or EZH1/2 by administering MVA and an immune checkpoint inhibitor given that mutations of SUZ12, EED and/or EZH1/2 decreasing PRC2 activity was well known, has been successfully demonstrated, and commonly used as evidence by the prior art.
Response to Arguments
1) Applicant has amended claims 5 and 9 to now include the limitation of using MVA and ICI in patients suffering from MPNST, myeloid cancer, T-cell or early T-cell precursor ALL, or breast cancer. Applicant states Dai does not teach a method for treating or sensitizing MPNST, myeloid cancer, T-cell or early T-cell precursor ALL, or breast cancer using inactivated MVA and ICI. Nor does Dai teach or suggest that the combination therapy can be used in cancers besides melanoma or colon cancer.
Applicant’s arguments have been fully considered but are not persuasive. Applicant has amended claims 5 and 9 to now include the limitation of wherein the patient suffers from or is diagnosed with malignant peripheral nerve sheath tumor (MPNST), a myeloid disorder, T-cell acute lymphocytic leukemia (ALL), early T- cell precursor ALL, or breast cancer. While the previously cited art does not disclose or teach a treatment comprising an inactivated MVA and an immune checkpoint inhibitor in patients suffering from or is diagnosed with malignant peripheral nerve sheath tumor (MPNST), a myeloid disorder, T-cell acute lymphocytic leukemia (ALL), early T- cell precursor ALL, or breast cancer, the amended claims do not overcome the teachings of the prior art. The current rejection of record, which was necessitated by applicant’s amendment to the claims, is now rejected under, inter alia, Deng and Mieczkowska.
As discussed above, Deng teaches the treatment of triple negative breast cancer tumors using a combination of MVA, including inactivated MVA, and anti-PD-1 and anti-CTLA-4 antibodies. Mieczkowska teaches that triple negative breast cancer has decreased PRC2 activity. Furthermore, Dai also teaches that cancer treatments comprising inactivated MVA and anti-PD-1 and anti-CTLA-4 antibodies are a known and effective treatment for melanoma and colon cancer. Together, the prior art establishes that inactivated MVA and anti-PD-1 and anti-CTLA-4 antibodies can be used in concert to treat a variety of cancers with aberrant PCR2 activity. One of ordinary skill in the art would have a reasonable expectation of success in using inactivated MVA along with anti-PD-1 and anti-CTLA-4 antibodies to treat cancers with decreased PRC2 activity because the prior art establishes that this combination therapy has been used to effectively treat a multitude of cancers with decreased PRC2 activity.
Conclusion
NO CLAIMS ARE ALLOWED
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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