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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-12, 18-22, 24-26 in the reply filed on 04/21/2026 is acknowledged.
Claims 13-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/21/2026.
Claims Status
The amendments filed 04/21/2026 are entered. Claims 13-17 are withdrawn pursuant to Election
Claims 1-22 and 24-26 are pending. Claims 13-17 are withdrawn pursuant to an election.
Claims 1-12, 18-22, 24-26 are under examination.
Priority
This application, filed 09/21/2023, claims priority benefits from Provisional No. 63408610, filed 09/21/2022. The effective filing date of this application is 09/21/2022, the filing date of Provisional No. 63408610.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/08/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18-22, 25, and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “reducing” and “increasing” in claim 18 and “increasing” in claim 25 are relative terms which render the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
It is unclear what the baseline for comparison should be. Is the claimed effect reducing or increasing in relation to no treatment, monotherapy, or some other combination of therapies?
Claims 19-22 and 26 depend on claim 18, inheriting the indefiniteness of the parent claim, and fail to resolve the indefiniteness.
Claim 18 is further indefinite due to the claim construction of limitation d) making the list grammatically unclear. A possible amendment would be “d) reducing tumor volume, increasing overall survival of the subject, and/or increasing complete response rate in the subject.”
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 10, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (Aarts et al, Cryoablation and immunotherapy: an overview of evidence on its synergy; published 2019) in view of Locy et al (Locy et al, Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend; published 2018), Farias et al (Farias et al, A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment; published 2021), and Takahashi et al (Takahashi et al, Immunostimulatory Effects of Radiotherapy for Local and Systemic Control of Melanoma: A Review; published 2020), as evidenced by Marabelle et al (Marabelle et al, Radiotherapy and Toll-Like Receptor Agonists; published 2015).
Regarding claim 1, Aarts et al teaches a method of treating cancer (i.e. melanoma metastasis) in a subject in need thereof, comprising administering a therapeutically effective amount of a radiotherapy and/or local ablative therapy (i.e. cryoablation) to the primary tumor site, wherein different adjuvants (i.e. immunostimulants) have enhanced the effect of cryoablation for suppressing tumor growth (p. 9, section: Melanoma).
Aarts et al further teaches that combination of cryoablation and immunotherapy may be beneficial to overcome the limitations of immunotherapy (p. 9, section: Melanoma). Aarts et al specifically teaches immune checkpoint inhibitor as an immunotherapy that has increased overall survival in melanoma, but only in some patients. Due to the synergistic mechanisms of actions from the abscopal effect of ablative therapy and immune checkpoint inhibitors, combination of these therapies could enhance overall immune response to cancer (Abstract). Specifically, radiotherapy and other ablative therapies kill individual cancer cells but also release their immunogenic intracellular contents, triggering an immune-specific response that can specifically target tumors outside the primary ablation zone (i.e. the abscopal effect), but this abscopal effect is not always sufficiently potent (p. 2, col 2, para 2).
Aarts et al does not explicitly teach administering the adjuvant specifically to a tumor. Aarts et al hypothesizes but does not explicitly teach an example of the combination of immunotherapy and radiotherapy or ablative therapy, and therefore, also does not explicitly teach the combination with all three components.
However, Locy et al teaches intratumorally (IT) delivered adjuvant, specifically a TLR-4 agonist, in combination with radiotherapy (RT), has successfully elicited anti-tumor immunity in early clinical trials (p. 12, section: TLR4).
Locy et al further teaches the synergistic combination of radiotherapy with immune checkpoint inhibitors seen in preclinical tumor models, and that there are ongoing and numerous clinical trials testing combinations of different checkpoint inhibitors with different radiotherapy with promising results (p. 11, col. 1, para. 3).
Locy et al does not explicitly teach a combination of immune checkpoint inhibitors and an adjuvant, and therefore also does not explicitly teach a combination of all three therapeutics.
However, Farias et al teaches an adjuvant, specifically a TLR4 agonist, improves immune checkpoint blockade treatment of melanoma (Abstract). Farias et al further teaches that immune checkpoint inhibitor monotherapy benefit only a fraction of patients and therefore, combination therapies with TLR agonists and radiotherapy are of particular interests (p. 2, para 2).
As evidenced by Takahashi et al (to show validity of animal models), there are animal models to appropriately evaluate and validate the abscopal effect (p. 9-13), so preclinical models are representative of the mechanism of action of radiotherapy.
Further, Takahashi et al teaches cancers such as melanoma can benefit from a combination of immunotherapy and radiotherapy, since the immunogenicity of melanoma cells is immunostimulated by not only immunotherapy but also by radiotherapy (p. 14, section 3.1.).
Moreover, as evidenced by Marabelle et al, the mechanisms of actions of these components work together to enhance each other (see figure reproduced from Marabelle et al below for reference). Essentially, localized radiotherapy releases tumor immunogens and immunostimulants, such as TLR agonists, that interact with antigen presenting cells (APC), which prime immune cells against tumor antigens, leading to the systemic antitumor abscopal effect of radiotherapy, which is enhanced with checkpoint inhibitor drugs that prevent the inhibition of these immune cells. The adjuvants, such as additional TLR agonists, enhance the activation of the antigen presenting cells, which acts as the intermediary between the tumor antigens and the responding T-cell mediated antitumor immune response.
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(Figure reproduced from Marabelle et al, 2015)
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to combine immunostimulating adjuvants, radiotherapy or ablative therapies, and immune checkpoint inhibitors in a method to treat cancers. Combination therapies comprising radiotherapy or ablative therapy with an adjuvant (Aarts et al), radiotherapy or ablative therapy with immune checkpoint inhibitors (Locy et al), and adjuvant with immune checkpoint inhibitor (Farias et al) have had enhanced effects over monotherapy. Further, each of these references envision including the third component, and differ from the instant application by the lack of actual combination of the elements in a single embodiment.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the three components in light of the successes of each combination of two therapies and the explicit teachings of the potential benefits of these three components in combination.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that these elements will perform their expected, but enhanced, functions in a combination therapy due to the complementary mechanisms of actions of each component, as evidenced by Marabelle et al, and actualized in parts by Aarts et al, Locy et al, and Farias et al.
The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 2, Locy et al teaches the adjuvant comprises a TLR4 agonist (p. 12, section: TLR4).
Regarding claim 3, Locy et al teaches intratumoral administration of TLR4 agonist monophosphoryl lipid A induces an anti-tumor immune response leading to tumor regression (p. 12, section: TLR4). Although, monophosphoryl lipid A is not explicitly taught in the method using another TLR4 agonist in combination with radiotherapy, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, to substitute the TLR4 agonist in the combination therapy with another TLR4 agonist, monophosphoryl lipid A, that has already shown to induce anti-tumor effects. One skilled in the art, before the effective filing date of the instant application, would be motivated to substitute one TLR4 agonist for another and have reasonable expectation of success due to the known, predictable, and shared functions of both molecules.
Regarding claim 10, Aarts et al teaches treatment of melanoma can be performed with cryoablation and radiofrequency ablation (p. 9, col 2, section: Melanoma).
Regarding claim 24, Locy et al teaches the cancer is melanoma or prostate cancer (p. 12, para. 5).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), and Takahashi et al (published 2020), as evidenced by Marabelle et al (published 2015), as applied to claim 1 above, and further in view of Ter Meulen et al (Ter Meulen et al, US20160058852, Immunotherapy of cancer through combination of local and systemic immune stimulation; published 2016), as evidenced by Coler et al (Coler et al, Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant; published 2011).
The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 4, the previous references do not explicitly teach the amount of adjuvant.
However, Ter Meulen et al teaches examples of methods of cancer treatments wherein the therapeutically effective amount of the adjuvant is an intratumoral dose of 5 ug of a TLR4 agonist (Examples 1-4).
Ter Meulen et al further teaches that the adjuvant dose and administration parameters will be determine by a variety of adjuvant-, patient-, and disease-specific factors (para 0274), implying a range of possible therapeutically effective doses. As evidenced by Coler et al, the TLR4 agonist specifically taught by Ter Meulen et al, the synthetic GLA, has similar immunomodulatory activity compared to the naturally-derived monophosphoryl lipid A (MPL) as an adjuvant (Abstract), but 10-100 times more potent (p. 9, section: Discussion, para 1), so it makes sense that the dose is on the lower range of the claimed dosage range. Ter Meulen et al teaches GLA and MLP to belong to the same group of nontoxic lipid A-related adjuvants (para 0144).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to use the dosage provided by one TLR4 agonist, such as GLA, as a starting point to optimize dosage for other TLR4 agonists, in light of the knowledge that optimization will be needed.
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose a known workable dose for a TLR4 agonist adjuvant.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success starting from the known therapeutic dosage for GLP, the teachings regarding its higher potency compared to other lipid A-related adjuvants, and their otherwise similar functions.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), and Takahashi et al (published 2020), as evidenced by Marabelle et al (published 2015), as applied to claim 1 above, and further evidenced by Traini et al (Traini et al, Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen-Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD-L1; published 2019).
The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 25, Locy et al further teaches increasing production of Thl-associated anti-tumor immunity (p. 12, section: TLR4).
Locy et al does not explicitly teach increasing production of Thl-associated IgG2c anti-tumor antibodies.
TLR4 agonists induce a Th1 response, characterized by IgG2c class-switching. As evidenced by Traini et al confirming these effects, TLR agonists generate immune stimulatory effects that favor development of Th1 immune responses (p. 2, col 1, para 1) and Traini et al explicitly teaches the induction of IgG2c isotype using TLR4 agonists (p. 9, col 1, para 2), and this was subsequently used successfully in combination with an immune checkpoint inhibitor to treat melanoma (p. 10, section: 2.6 and p. 11, Figure 7).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that TLR4 agonists used as adjuvants would inherently induce a Th1 immune response, inherently characterized by IgG2c anti-tumor antibodies.
One skilled in the art, before the effective filing date of the instant application, would be motivated to induce an Th1 immune response and would have reasonable expectation of success because it is taught to mediate antitumor immunity (Traini et al, p. 1, col 2). Although TLR agonist inducing these Th1 immune response has experienced limited efficiency as monotherapies, its combination with an immune checkpoint inhibitor provided protection against tumors, as is relevant to the instant claims.
Claims 5-8, 11-12, 18-19, 22, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), and Takahashi et al (published 2020), as evidenced by Marabelle et al (published 2015), as applied to claim 1 above, and further in view of Welsh et al (Welsh et al, WO 2021/127556, Methods of treating cancer comprising low dose radiation; published 2021).
The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 5, the previous references do not explicitly teach the radiotherapy is EBRT or internal radiation therapy.
However, Welsh et al teaches that radiotherapy may be administered in combination with immune checkpoint inhibitors, and the radiotherapy could be external beam radiation therapy (EBRT) and/or internal radiation therapy (para 0051).
Regarding claim 6, Welsh et al further specifically teaches the radiotherapy is local EBRT (referred to as L-XRT) in their example treatment (para 0077).
Regarding claim 7, Welsh et al further teaches alternative suitable radiation therapies includes internal radiation therapy, such as brachytherapy (para 0042 and 0051).
Regarding claim 8, Welsh et al further teaches low dose radiation of 2 Gy total (in 1 Gy fractions) (para 0077) significantly improved anti-tumor outcomes of checkpoint inhibitors (0079 and Fig. 4). Welsh et al further teaches low dosage radiation is about 2-12 Gy total (para 0042).
Regarding claim 11, Welsh et al further teaches the immune checkpoint inhibitor comprises one or more therapeutic agents that inhibit CTLA-4, PD-1, and/or PD-L1, and regarding claim 12, specifically an anti-CTLA-4 antibody (para 0079 and Fig. 4).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to choose from a finite number of identified radiation therapies with predictable results, as these are known radiotherapy options that help have curative and adjuvant activity (para 50). The claims essentially cover the radiation being delivered from the outside of the body (external beam radiation) or from radioactive material placed in the body near the cancer cells (internal radiation) (para 0042).
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose from any one of these alterative options based on availability, preference, or other patient-specific limitations, and one skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success with any of these options as they lead to similar abscopal effects; i.e. the abscopal effects is possible for all radiotherapy, not just specific ones.
Claim 18 incorporates claim 1 and some of its dependent claim limitations towards a narrower scope of the method of claim 1. The teachings of a method to treat cancer wherein the adjuvant is a TLR4 agonist (to induce Th1 anti-tumor response), the radiotherapy or ablative therapy is EBRT, and the immune checkpoint inhibitor is an anti-CTLA-4 antibody (which is FDA approved for treating melanoma and other cancers), and the motivation to combine these therapies and choose these particular ones is provided previously, meeting all the limitations of the claim.
Similarly, regarding claim 26, the teachings that the method inherently induces a systemic anti-tumor immune response is previously presented, regarding the mechanisms of action of this combinatorial drug, in particular the abscopal effects of radiation therapy synergizing with the immune checkpoint inhibitors.
Regarding claim 19, the choice of the TLR4 agonist is taught in the previous explanation for claim 3.
Regarding claim 22, Takahashi et al teaches the therapeutically effective amount of the anti-CTLA-4 antibody is about 10 mg/kg (p. 12, para 2).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), Takahashi et al (published 2020), and Welsh et al (published 2021), as evidenced by Marabelle et al (published 2015), as applied to claim 18 above, and further in view of Ter Meulen et al (Ter Meulen et al, US20160058852, Immunotherapy of cancer through combination of local and systemic immune stimulation; published 2016), as evidenced by Coler et al (Coler et al, Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant; published 2011).
The teachings of the references regarding the parent claims and relevant previous teachings regarding claims 1 and 4 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 20, Ter Meulen et al teaches administration of GLA into BALB/c and C57BL/6 mice (p. 39-41, Examples 1-4), which typically weigh an average of 20-30 grams. Since Ter Meulen et al teaches administration of 5 ug of GLA, that is about 0.17-0.25 mg/kg of the TLR4 agonist. However, since GLA is 10-100 times more potent than monophosphoryl lipid A and potentially other TLR4 agonists, it would be obvious to one skilled in the art, before the effective filing date of the instant application, to start dosing at 10 times higher dose for monophosphoryl lipid A or less potent TLR4 agonists, arriving at 1.7-2.5 mg/kg.
One skilled in the art, before the effective filing date of the instant application, would be motivated to scale dosage from a known dose of a similar TLR4 agonist based on relative potency, and to start with the lower dosage first, especially if administering locally to the tumor instead of systemically.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success due to the known functions and relative potencies of these TLR4 agonists.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), and Takahashi et al (published 2020), as evidenced by Marabelle et al (published 2015), as applied to claim 1 above, and further in view of Raman et al (Raman et al, US9114158B2, Compounds and methods of use in ablative radiotherapy; published 2015) .
The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 9, Raman et al teaches the therapeutically effective amount of radiotherapy is administered in a gradient dose of 2.28 Gy/min or 2.08 Gy/min (para 64) to mimic delivering 15 Gy radiation dose by SABR to treat lung tumors (para 63), which is a form of EBRT since radiation is derived from a source outside the body, which meets the claim limitations of about 2 Gy/min, according to the definition of “about” in the specification (paras 31 and 33) .
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Aarts et al (published 2019) in view of Locy et al (published 2018), Farias et al (published 2021), Takahashi et al (published 2020), and Welsh et al (published 2021) as evidenced by Marabelle et al (published 2015), as applied to claim 18 above, and further in view of Raman et al (US9114158B2, Compounds and methods of use in ablative radiotherapy; published 2015) .
The teachings of the references regarding the parent claim and related claim 9 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Accordingly, regarding claim 21, Raman et al teaches the therapeutically effective amount of EBRT is about 2 to about 20 Gy administered in a gradient dose of about 2 Gy/min.
Conclusion
No claims are allowed.
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/BONIRATH CHHAY/Examiner, Art Unit 1645
May 15, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 May 19, 2026
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