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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C.119 (a)-(d). The certified copy has been filed in parent Application No. PCT/IB2017/001595, filed on 12/21/2017.
Claim Status
The amendment, filed on 08/28/2025, in which claims 1, 11, and 15 are amended and claims 12-13, 16-17, and 27-28 are canceled, is acknowledged. Claims 1-11, 14-15, 18-26, and 29-30 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 08/28/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Listed NPL reference “Tao et al.” has been placed in the application file, but the information referred to therein has not been considered. All other references where not lined through have been considered.
Withdrawn Objections and Rejections
In the office action dated 04/30/2025,
Claims 1-10, 19-21, and 23-26, and 29 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/423,370 in view of Beug and Messenheimer. Applicant’s abandonment of the copending application has rendered the rejections moot and the rejections are withdrawn.
Claims 1, 7, 19-22, 24 29 were provisionally rejected on the ground of non-statutory double patenting rejection as allegedly being unpatentable over claim 17, 19, 21, and 26-27 of U.S. Patent Application No. 18/328,707 (herein US707) in view of Beug and Messenheimer. Applicant’s abandonment of the copending application has rendered the rejections moot and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding instant claim 14, which recites “…induction period is continued until the cancer is assessed to be of high immunogenicity,” fails to further limit the base claim 1 which recites “…induction period is continued until the frequency of PD-L1 expressing cells/and or CD8+ cells in the tumor microenvironment exceeds a predetermined threshold for high immunogenicity…” Determining “high immunogenicity” as disclosed in the specification involves analysis of a marker in a patient’s biological sample (pg 12, ¶ 1). While PD-L1 is disclosed as a preferred marker, other markers include those that identify tumor infiltrating lymphocytes (TILs) and/or mutation burden, which does not exclude additional markers that would otherwise broaden the scope of the base claim.
Regarding instant claim 15, dependent on claim 14, the instant claim does not further limit the subject matter of the base claim 1, as the base claim already recites that the induction period is continued until the frequency of PD-L1 expressing cells and/or CD8+ cells in the TME exceeds a predetermined threshold for high immunogenicity.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5, 7, 9, 14-15, 19-25, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Korneluk (US 2021/0322545 A1) in view of Beug (cited in previous action) and Messenheimer (cited in previous action).
Regarding claims 1, 7, 9, 14-15, 21, 23-24, and 29, Korneluk teaches a method of promoting tumor immunity (i.e. cancer treatment) comprising administering to a subject a second mitochondria-derived activator of caspases (Smac) mimetic compound (SMC) (¶ [0009], Table 1), in combination with an immune checkpoint inhibitor (ICI) (¶ [0012], Table 4) (¶ [0006], claim 51). Korneluk teaches SMCs are known IAP antagonists that degrade and downregulate cIAP1/2 and XIAP proteins that prolong cancer cell survival, thereby inducing apoptosis (¶ [0002], [0191]-[0192], [0219], [0254], [0273]-[0274]). Korneluk teaches that the SMC may be administered in single or multiple doses depending on the patient and that administration may vary widely and may depend on subject and cancer type (¶ [0142]-[0143]). Korneluk teaches the SMC and an additional agent are administered sequentially (within 1 min or up to 28 days apart), or concurrently, and that the frequency of administration of both are not identical (¶ [0162]-[0164], claims 55-56). Korneluk teaches that combination doses and frequency depend on administration method, disease, severity and patient specific factors (¶ [0170]).
Korneluk discloses practical examples using sequential administration of anti-PD-1 antibody and LCL161 (monomeric SMC) or Birinapant (dimeric SMC) (multiple rounds, 1 day apart) in CT-2A and GL261 brain tumor models (¶ [0237]-[0239]), MPC-11 multiple myeloma model (¶ [0242]), EMT6 mammary tumors (¶ [0241]) (Example 4, Example 7, ¶ [0258]-[0260]). Korneluk further teaches monitoring CD8+ in a patient’s biological sample as a means of both determining a cancer’s receptivity/response to treatment (¶ [0258]). Korneluk observed that SMC only treatment increases proportion of CD8+ PD1+ infiltrating immune cells and T cell activation (FIG 54B; FIG 61D; FIG 67), and that CD8+ T cells are the primary cell type responsible for in vivo treatment efficacy as depletion assays abrogate cure rate in mouse models (¶ [0264] FIG 59D-E). As such Korneluk predicts SMCs can potentiate the activity of ICIs in anti-tumor immunity in a CD8+ T cell dependent manner (¶ [0276]), and teaches a complimentary mechanism for synergy between SMC and ICI therapies (FIG. 67).
Korneluk does not explicitly disclose administering the IAP antagonist until a predetermined threshold for high immunogenicity (frequency of PD-L1 expressing and/or CD8+ cells in the TME) is exceeded, followed by administration of an anti-PD-1 molecule.
Beug teaches the combined use of a SMC and ICI as a method to treat cancer in which administering one therapy agent was ineffective (Abstract). Beug discloses that there is synergy between SMC and ICI, wherein the anti-cancer effects are amplified by the ICI: “…SMCs exert their anti-cancer effects, specifically through the potentiation of cytotoxic T-cell (CTL) activity against tumours, which is amplified with an ICI.” (page 2, left column, ¶ 3). Beug teaches that SMCs play a key role in stimulating dendritic cell maturation and T-cell proliferation as well as potentiate cytotoxic T-cell activation (pg 12, left column, lines 2-6). Beug hypothesizes the synergy between SMC and ICI enhanced immune response is due to SMC-mediated T-cell co-stimulatory signal that develop against the tumor and the adaptive immune system responds fully once the ICIs are administered and the co-inhibitory signals from PD-1 or PD-L1 are blocked (pg 12, right column, ¶ 2). This would suggest SMCs work mechanistically upstream of PD-1 co-inhibitory signals as the effectiveness of anti-PD-1 is dependent on functional adaptive immune response (i.e. presence of T cell expressing PD-1) (pg 8, left column, ¶ 1). Furthermore, Beug teaches that the SMC mechanism of T-cell activation is “likely by providing a tumor necrosis factor receptor superfamily (TNFRSF) co-stimulatory response (similar to 4-1BB or OX40 activation)” (Figure 9 and legend - portion shown below).
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Messenheimer teaches the timing of PD-1 blockade is critical for effective combination immunotherapy in some tumors (abstract). Specifically, sequential administration of OX40 (TNFRSF4) agonist antibody (i.e. induction period observed to increase proportion of PD-1+ T cells in tumor bearing spleens - Figure 4A) followed by delayed administration of anti-PD-1 or anti-PD-L1 antibody (i.e. PD-1 blockade) greatly enhanced the anti-tumor effects when compared to concurrent administration or reversed order of administration (abstract; pg 6166, column spanning ¶; pg 6170, right column, ¶ 2; Figure 4). Messenheimer suggests that delaying inhibitory receptor-targeted therapies (e.g. PD-1 or PD-L1) until after OX40 agonist boosts tumor-specific T cells to a state where checkpoints are inhibiting the antitumor response and optimizes the antitumor immune response by minimizing toxicity from acute cytokine release (pg 6176, left column, ¶ 2).
One of ordinary skill in the art at the time of filing would recognize the mechanistic benefit of priming the immunogenicity of the TME with SMCs alone, thereby increasing tumor infiltration of CD8+ PD-1+ T cells as taught by Korneluk, and increasing the therapeutic potential of subsequent treatment with anti-PD-1 ICI therapeutics. Furthermore, a skilled artisan would recognize that SMCs, which work upstream of TNFRSF signaling as taught by Korneluk and Beug, may work similar OX40 agonist therapies. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify a combination ICI + SMC treatment as taught by Korneluk, switching the order of administration to allow for an SMC induction period to potentiate CD8+ T cell infiltration and activation within the TME (i.e. increase tumor immunogenicity) as taught by Korneluk and Beug, and would be motivated to do so as Messenheimer further teaches that delaying anti-PD-1 therapy post TNFRSF activation (OX40 agonist) can improve tumor immunotherapies, especially for those cancers with low initial immunogenicity. Moreover, as Korneluk teaches the synergistic effect between SMC and anti-PD-1 is dependent on a CD8+ T-cells, it would be obvious to one of ordinary skill to include assessment of this cell type beyond a certain threshold to ensure the TME is primed for effective secondary ICI therapy.
Regarding Claims 2-4, Korneluk, Beug, and Messenheimer teach the methods claim 1 as discussed above. Korneluk further discloses an administration schedule where the SMAC mimetic and ICI are administered simultaneously or within 6 hours of each other, 24 hours of each other, 5 days of each other, 10 days of each other, 5 days of each other or 28 days of each other (claims 55 and 56). Moreover, Messenheimer teaches a sequential combination treatment wherein tumor bearing mice were treated with OX40 agonist (3 doses total, 2 days apart), followed by anti-PD-1 or anti-PD-L1 (3 doses total 2 days apart) six days after initial dose of OX40 (“delay” i.e. induction period), which showed enhanced effectiveness compared to concurrent administration (Figure 4).
Regarding Claim 5, Korneluk, Beug, and Messenheimer teach the method of claim 1 discussed above. Beug further teaches an administration schedule wherein SMC treatment is continued after the administration with the anti-PD-1 molecule has started (Figure 4E). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the method as taught by combined teachings of Korneluk, Beug, and Messenheimer could be modified to incorporate additional IAP treatment time points after anti-PD-1 administration with a reasonable expectation of success for reducing tumor burden.
Regarding Claims 19 and 20, Korneluk, Beug, and Messenheimer teach the method of claim 1 discussed above. Korneluk also teaches anti-PD-1 molecules within scope of the claimed species (Table 4; Claim 54).
Regarding Claims 22 and 30, Korneluk, Beug, and Messenheimer teach the method of claim 1 discussed above. Korneluk also teaches administering anti-PD-1 molecule in combination with administering an oncolytic virus (¶ [0073]).
Regarding Claim 25, Korneluk, Beug, and Messenheimer teach the method of claim 24 discussed above. Korneluk teaches the monovalent SMCs including Debio1143 (¶ [0009]; Table 1; claim 54), suggesting to an artisan of ordinary skill that this species would be reasonably interchangeable with LCL161 as used in practical examples.
Claims 6, 8, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Korneluk, Beug, and Messenheimer as applied to claim 1 above, and further in view of Zou (cited in previous action).
Regarding Claims 6, 8 and 26, Korneluk, Beug, and Messenheimer teach the method of claim 1 discussed above. Korneluk discloses that a combination IAP Antagonist/anti-PD-1 molecule therapy can be used to treat colorectal, pancreatic, head and neck cancer, and melanoma (claim 64).
Korneluk does not explicitly disclose cancer response rate percentages as recited in the instant claims (e.g. known to be responsive to treatment with an anti-PD-1 molecule in 10% or more, 10% or less, or 5% or less of treated patients).
Zou teaches the clinical response rate in different cancer types treated with an anti-PD-1 molecule (e.g. anti-PD-L1 antibody). Zou teaches a 17% clinical response rate in melanoma, a 10.2% clinical response rate in NSCLC, and a 5.9% clinical response rate in ovarian cancer treated with an anti-PD-1 molecule (table 1).
An artisan would recognize that the teachings disclosed by Zou would provide the information of treating a certain type of cancer that demonstrated clinical response rates to treatment with an anti-PD-1 molecule (e.g. anti-PD-L1 antibody). An artisan would have recognized that treating the types of cancers disclosed by Zou would have yielded the predictable result of improved clinical response rates of patients with the types of cancer due to receiving combination immunotherapy (SMC/anti-PD-1 molecule). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat cancer patients using the combined teachings of Korneluk, Beug, and Messenheimer for sequential administration of SMC, followed by an induction period, and administering anti-PD-1 molecule (e.g. PD-L1 antibody) to patients with melanoma, NSCLC, or ovarian cancer. One would have been motivated to treat these types of cancers because Korneluk teaches that the SMC and anti-PD-1 molecules can be combined to treat the cancers, wherein said cancer species have variable response rates to anti-PD-1 molecule monotherapies as taught by Zou. An artisan would be motivated to administer an SMC and PD1/PDL1 checkpoint inhibitor to the types of cancers disclosed by Korneluk and Zou (e.g. response rate of 10% or more, 10% or less, 5% or less) to broadly improve anti-tumoral response rates.
Claims 10-11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Korneluk, Beug, and Messenheimer as applied to claim 1 above, and further in view of Rosenberg (cited in previous action).
Korneluk, Beug, and Messenheimer teach claim 1 discussed above. In the instant specification, Applicant discloses that a poorly immunogenic cancer is one where a pretreatment patient biological sample is tested for specific markers of immunogenicity, and graded accordingly. In a preferred embodiment, Applicant discloses the marker is either PD-L1 expressed on cancer cells and/or immune cells or tumor-infiltrating lymphocytes and/or tumor mutation burden (Specification, Page 11, lines 29-31). Korneluk discloses a method whereby a subject is evaluated after receiving treatment to determine if the level of immunogenicity of the cancer changes after treatment with a combination SMC/anti-PD-1 molecule therapy, and teaches that SMC monotherapy increases the proportion of CD8+PD-1+ TILs (¶ [0257]).
Korneluk, Beug, and Messenheimer do not disclose taking a biological sample prior to the induction period, specifically a tumor or liquid biopsy.
Rosenberg teaches a method of treatment patients with metastatic urothelial carcinoma with an anti-PD-L1 antibody in a clinical trial. Rosenberg teaches that tumor samples (i.e. biopsies) from patients were taken prior to enrollment in the trial (methods).
An artisan would have recognized that adding the known technique of a pre-treatment assessment of the tumor to the base product would have yielded the predictable result of determining the baseline of patients prior to receiving cancer treatment. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to include a known method of pretreatment assessment as taught by Rosenberg to the method as taught by the combined teachings of Korneluk, Beug, and Messenheimer as discussed above because this would allow clinicians to evaluate the efficacy of the treatment and ensure patient safety. Furthermore as Korneluk teaches that SMC treatment would increase CD8+ cell infiltration a skilled artisan would be motivated to set a immunogenicity threshold value that would stratify initial biopsies to be below the targeted value (i.e. fail the predetermined threshold) to facilitate a measure for establishing how long to delay the secondary anti-PD-1 molecule following SMC treatment (i.e. duration of induction period).
Response to Arguments - 35 USC § 103
Applicant's arguments filed 08/28/2025 regarding rejections under 35 USC § 103 have been fully considered but they are not persuasive.
Applicant states:
“… claim 1 has been amended… to recite, in pertinent part, that the induction period is continued until the frequency of PD-L1 expressing cells and/or CD8+ cells in the tumor microenvironment exceeds a predetermined threshold for high immunogenicity.
None of Korneluk, Beug, or Messenheimer teach or suggest an induction period [recited above] as currently required by amended claim 1. The Office Action also has not explained why a person of ordinary skill in the art would have been motivated to modify the disclosures of Korneluk, Beug, or Messenheimer in order to arrive at a method of amended claim 1 with a reasonable expectation of success” (Remarks, pg 8, ¶ 2-3)
In response to applicant’s argument regarding amended claim 1, the current rejection has been modified to address the amended claim limitations as discussed above. Briefly, Korneluk and Beug teach the synergistic effects of SMC and anti-PD-1 molecule therapies; both teach that this effect is in CD8+ T cell dependent, that SMC is responsible for increasing CD8+ TILs, and mechanistically this infiltration/activation likely relies on TNFRSF signaling, which Beug teaches is similar to OX40 activation. Messenheimer teaches OX40 activation prior to anti-PD1 molecules greatly improves anti-tumoral immune response compared to concurrent or reverse order of administration. Therefore one of ordinary skill would be motivated to modify combination treatments as taught by Korneluk and Beug to employ anti-PD-1 as a secondary treatment as taught by Messenheimer after OX40 agonist treatment because Beug implies SMC works mechanistically upstream to activate pathways similar to OX40. Furthermore, as combination therapy is dependent on CD8+ cells and it is known that SMC monotherapy increases CD8+PD-1+ TILs, it would further be obvious to one of ordinary skill to incorporate an assessment of CD8+ T cells within the tumor stroma after SMC treatment to confirm patients would respond to subsequent anti-PD-1 molecules.
Applicant states:
“…differential mechanisms and therapeutic rationales for SMAC mimetics (as taught by Korneluk and Beug) and OX40 modulators (as taught by Messenheimer)… unlike OX40 modulators, SMAC mimetics do not solely target immune cells to enhance their function, but they also directly target the tumor cells to cause tumor cell death…OX40 modulators do not have any direct action on tumor cells and do not induce direct tumor cell death, nor tumor antigen release.” (Remarks, pg 8, ¶ 4)
In response to applicant’s argument regarding mechanistic differences in SMCs and OX40 agonists, it is noted that the features upon which applicant relies (i.e., tumor cell death/tumor antigen release) are not recited in the rejected claims. Furthermore, the test of for obviousness is not necessarily whether the features of the of the secondary reference may be equivalent to the primary reference or expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this instance both Korneluk and Beug recite mechanistic similarities between SMC and OX40 activation of immune cells (i.e. CD8+ cells), and therefore a skilled artisan would recognize that priming CD8+ cells using either method (SMC or OX40) could with a reasonable expectation of success sensitizing the TME (via increased CD8+ TILs) for subsequent ICI therapies.
Applicant states:
“…Zou does not cure the deficiencies of Korneluk, Beug, and Messenheimer.” (Remarks, pg 9, ¶ 3)
“Rosenberg does not cure the deficiencies of Korneluk, Beug, and Messenheimer noted above…” (Remarks, pg 10, ¶ 3)
In response to applicant’s argument regarding the deficiencies of Korneluk, Beug, and Messenheimer, this argument is addressed above and examiner deems subsequent arguments based on this rationale to be unpersuasive.
Conclusion
No claims are 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.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647