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 Claims
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 29, 2023.
Claims 1-14 are amended.
Claims 16-20 are new.
Claim 15 is cancelled.
Claims 1-14 and 16-20 are pending and currently examined.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 09/15/2023 and 01/22/2026 are considered, initialed and are attached hereto.
Priority
Applicant’s claim for the benefit of priority of December 4, 2020, is acknowledged.
Specification
The disclosure is objected to because of the following informalities: a) the number of cells injected to establish the AE17 model is not listed properly (0.5.106, see pg. 12, ln. 21); b) melanoma model is referred to but no examples or descriptions are related to melanoma (pg. 4 ln 30, pg. 13, ln. 34, pg.14, ln. 4).
Appropriate correction is required.
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.
Claim 11 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.
Claim 11 states “wherein said CD40 agonist is selected from the group consisting of: CD40L trivalent and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083”. This is interpreted as CD40L trivalent, hexavalent molecules of CD40L, HERA-CD40L and MEDI5083. However, the specification states CD40 agonist may be selected from: CD40L, trivalent and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083 (pg. 3 ln. 26-27, also see pg. 7 ln 21-22). Therefore, it is unclear if the applicant intend to include CD40L in Claim 11. Claim 11 is interpreted as not including CD40L (i.e. said CD40 agonist is selected from the group consisting of: CD40L trivalent, and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-14 and 16-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method of treating mesothelioma in a subject, comprising administering a combination comprising IL-15 and a CD40 agonist. Either IL-15, the CD40 agonist or both can be administered at subtherapeutic dose that is lower than therapeutic dose, can be administered in a pharmaceutical composition, simultaneously, or administered intravenously, intradermally, or subcutaneously. The CD40 agonist can be a CD40 antibody or antigen binding fragment selected from the group consisting of: Selicrelumab, APXOO5M, ChiLob7/4, ADC-1013, SEA- CD40, CDX-1140, SGN-40, and ABBV-927; or can be selected from the group consisting of: CD40L trivalent, and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083.
The specification explains “combination” refers to any association between IL-15 and CD40, and it can be spatial or use of the two items for a common purpose (pg.10 ln.15 – 18). For instance, the combination can be: a) a composition comprising both components, or b) use of 2 separate compositions, each comprising one of the components, which are used in association with each other in the claimed treatment, and the association may include simultaneous administration of both compositions, or the separate administration that both components are still able to cooperate in the treatment of the intended disorders (pg. 10 ln. 19-25).
The specification states that IL-15 as used in the instant invention may be used as the cytokine itself that regulates the activation and proliferation of T cells and natural killer cells, and recombination forms such as rh IL15, IL-15 agonists and superagonists (pg. 6, ln. 5-9). This is a functional definition and provides no structure for what confers the function.
The specification states that CD40 agonist refers to a molecule which specifically binds to CD40 molecule and increases/enhances/induces one or more CD40 activities (pg. 6, ln. 18-20). Therefore, any molecules, such as nucleic acid and small molecule, can be CD40 agonists. This is a functional definition and provides no structure for what confers the function.
The CD40 agonist could be antibody or antigen binding fragment selected from the group consisting of: Selicrelumab, APXOO5M, ChiLob7/4, ADC-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927 (pg. 3 ln.22-24). The CD40 agonist could be CD40L, CD40L trivalent, and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083 (pg. 3 ln. 26-27). The lists do not provide structural basis for what confers the function.
The specification states a subtherapeutic dose of a therapeutic compound is meant to be a dose which is lower than the usual/typical dose of said compound required to obtain a therapeutic effect, or an amount of a compound/component, which when administered to a patient, is not in itself sufficiently effective in the treatment of the claimed disorders but the combination is sufficiently effective in the treatment of the claimed disorders (pg. 8 ln. 9-10 and ln. 25-30).
Therefore, the claims recite administering a genus of type I IL-15 and a genus of CD40 agonist (or a genus of CD40 antibody or antigen binding fragment, or a genus of CD40L multivalent) through various routes, to treat mesothelioma in any mammal.
The specification has written description of the following example: administering IL-15 at a dose of 2.5 µg (i.p.) and a CD40 agonist (monoclonal antibody FGK-45) at 25 µg (i.p.) increases the animal survival in a mouse AE17 mesothelioma model, compared with control, IL-15 monotherapy and CD40 agonist, and thus, at least one of IL-15 and CD40 agonist, or both can be administered at subtherapeutic dose, and the subtherapeutic dose can be a dose lower than the dose of the compound required to obtain a therapeutic effect in said subject when administered alone (pg. 13 ln. 8-29). Because the AE17 cells are injected subcutaneously at the left abdominal flank, the model is a subcutaneous mesothelioma model. IL-15 is administered daily on Day 0-3, 6-10 and 13-14, while CD40 agonist is administered on Day 0, 3, 7, 10 and 14 (pg. 12 ln. 24-27, Fig. 1). The specification lists IL-15 (NCI) in materials and methods (pg. 12 ln. 24). It is unclear the source and the exact form of IL-15 used. The specification does not state if the IL-15 and CD-40 antibody are combined into a single composition. Therefore, based on the dosing schedule, IL-15 and anti-CD40 antibody are considered to be injected separately in its own formulation, rather than in a single composition.
The specification fails to provide written description to administering any type of IL-15 and any type of CD40 agonist to treat mesothelioma (or pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and testicular mesothelioma) in all mammal, at the claimed routes.
The claimed invention also encompasses the methods of administering any IL-15 and any CD40 agonist to treat all types of mesotheliomas in all mammals. A brief assessment of the state the art is made herein.
The effects of different CD40 agonists are unpredictable. McVey and Beatty (Clin Cancer Res. 2025 Jun 3;31(11):2079–2087) teaches that CD40 agonists are a promising therapeutic strategy for cancer immunotherapy, but many patients fail to respond. The heterogeneity in treatment response underscores the need for strategies to identify patients most likely to benefit from CD40 immunotherapy and to understand the mechanisms for resistance against the therapy (McVey and Beatty). For instance, Sum et al (Clin Cancer Res (2021) 27 (14):4036-4053) teaches a bispecific FAP-CD40 antibody, which induces CD40 activity only in tumor stroma in the presence of fibroblast activation protein α (FAP), mediates complete regression of MC38-FAP tumors in mouse, entailing long-term protection, while nontargeted CD40 agonists fail to inhibit tumor growth even at a higher dose and producing side effects (see abs.). In treating mesothelioma, while Nowak et al (Cancer Res (2003) 63 (15): 4490–4496) teaches that appropriate combination of a CD40 agonist (FGK45) and chemotherapy (gemcitabine) can cure an established mesothelioma in a mouse model of mesothelioma (pg. 4491 section Appropriate Combination of Chemotherapy and Immunotherapy Can Cause Regression and Cure of an Established Tumor), a later study teaches that the objective response rates for patients with malignant pleural mesothelioma are similar between CD40-activating antibody CP-870,893 in combination with chemotherapy (cisplatin and pemetrexed), and chemotherapy alone (Nowak et al, Annals of Oncology 26: 2483–2490, 2015, see abs.)
Different IL-15 have different structures and potency profiles (Knudson et al, Expert Opinion on Biological Therapy, 20(7), 705–709). Tan et al (Expert Opin Drug Deliv. 2020 July ; 17(7): 895–898.) teaches that all forms of IL-15, when administered as monotherapy of solid tumors, were ineffective, and successful clinical translation of IL-15 will hinge upon the optimization of therapeutic regimens and delivery strategies, that allow for safe and sustained IL-15 levels without excessive release of inflammatory cytokines (see section 5. Expert opinion).
IL-15 superagonists are developed to improve the therapeutic potential of IL-15 therapy and are overall described to have greater potency, bioavailability and stability than soluble recombination IL-15 due to their structure (Knudson et al, p. 705-706, section 3. IL-15 superagonists). “IL-15 superagonists appear to have an advantage over rIL-15 in mediating immune effects… it will be important in future clinical trials to optimize the treatment schedule and dose of IL-15 superagonists, especially when combining with other agents that provide costimulatory and activating signals or checkpoint blockade to override immunosuppression” (p. 707 section 6. Expert Opinion). In addition, it will be necessary to examine the differences between the various IL-15 superagonists, since they have different potency and half-life, and this differential may result in preferential stimulation of specific immune subsets or broaden the IL-15 activity to populations usually minimally stimulated by IL-15 (p. 707 right column 2nd para.).
In addition, the safe and efficacious doses of a compound is often depended on the dosing route and properties of the compound. For instance, the maximum tolerated dose (MTD) of intravenous bolus infusion of IL-15 (rhIL-15) is 0.3 µg per kg body weight, subcutaneously administration of IL-15 (rhIL-15) is 2 µg per kg body weight, and continuous IV infusion of IL-15 (rhIL-15) is 2 µg per kg body weight (Tan et al (Expert Opin Drug Deliv. 2020 May 19;17(7):895–898, pg. 2, last para.). As for CD40 agonist, Salomon et al (Front Immunol. 2022 Jul 13;13:940674) teaches that human CD40 agonist antibodies have low efficacy and dose-limiting toxicity, and proposes targeting CD40 to the tumor (by intratumorally administration or bispecific antibodies) to improve the efficacy and safety profile of the existing treatments.
A different compound might achieve therapeutic effect in a different subject at a different dose. For instance, the instant application shows that the neither the IL-15 or CD40 agonist have therapeutic effect in a breast cancer in mouse (inst. specs. pg. 13 ln. 31 – pg. 14 ln.10), while Hirano et al (Blood (1999) 93 (9): 2999–3007) shows agonist anti-CD40 MoAb (M3 hybridoma,10 μg, i.p. injection) is able to increase the survival of the tumor-bearing recipients (pg. 3004 section “srhCD40L exerts antitumor effects in SCID mice bearing human breast carcinoma cells”), and Guo et al (Front. Immunol., 07 February 2021. Sec. Cancer Immunity and Immunotherapy. Volume 11 – 2020) teaches that IL-15cx (IL-15/IL-15Rα complex, 12.5 µg containing 2.5 µg IL-15 and 10 µg IL-15Rα-Fc, i.p. injection) shows tumor growth inhibition or tumor regressions with survival improvement (abs. also see pg.5).
Taken together, the state-of-the-art support the position that the method comprising administering a combination comprising any IL-15 and any CD40 agonist to treat all types of mesotheliomas in all mammals is not predictable.
Therefore, neither the art nor the specification provides a sufficient representative number of species to meet the written description requirement.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed molecules in IL-15 or CD40 agonists. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, there is not identification of any particular portion of the structure that must be conserved or present. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Enablement
Claims 1-14 and 16-20 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for intraperitoneally administrating a specific IL-15 and a specific CD40 agonist to treat mesothelioma in a mouse model in vivo at a very specific dose and a specific dosing schedule, does not reasonably provide enablement for treating all mesotheliomas in all mammals by administrating a combination comprising of any IL-15 and any CD40 agonist, at other administration routes and lower dose ranges. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The nature of the invention and the breadth of the claims
The claims are drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
There are unlimited types of IL-15 and types of CD40 agonists, and they have different properties.
The specification is enabling for the following example: intraperitoneally administrating a specific IL-15 (IL-15, NCI) and a specific CD40 agonist (agonistic CD40 monoclonal antibody FGK-45) to treat mesothelioma in a mouse model in vivo at a very specific dose (2.5 µg of IL-15 and 25 µg of CD40 antibody per mouse per injection) and a specific dosing schedule (Days 0-3, 6-10 and 13-14 daily for IL-15, and Days 0, 3, 7, 10 and 14 daily), does not reasonably provide enablement for treating all mesotheliomas in all mammals by administrating a combination comprising of any IL-15 and any CD40 agonist, optionally at various administration routes and at subtherapeutic doses.
The state of the prior art and the level of predictability of the art
While the state of the art is relatively high with regard to the treatment of specific tumor types with specific reagents, the state of the art with regard to using different regents to treat the same tumor is underdeveloped. The tumor treatment art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to treating mesotheliomas in a mammal with any combination of any IL-15 and any CD40, optionally at various administration routes and at subtherapeutic doses, makes practicing the claimed invention unpredictable.
The effects of different CD40 agonists are unpredictable. McVey and Beatty (Clin Cancer Res. 2025 Jun 3;31(11):2079–2087) teaches that CD40 agonists are a promising therapeutic strategy for cancer immunotherapy, but many patients fail to respond. The heterogeneity in treatment response underscores the need for strategies to identify patients most likely to benefit from CD40 immunotherapy and to understand the mechanisms for resistance against the therapy (McVey and Beatty).
Sum et al (Clin Cancer Res (2021) 27 (14):4036-4053) teaches a bispecific FAP-CD40 antibody, which induces CD40 activity only in tumor stroma in the presence of fibroblast activation protein α (FAP), mediates complete regression of MC38-FAP tumors in mouse, entailing long-term protection, while nontargeted CD40 agonists fail to inhibit tumor growth even at a higher dose and producing side effects (Abs.).
In treating mesothelioma, while Nowak et al (Cancer Res (2003) 63 (15): 4490–4496) teaches that appropriate combination of a CD40 agonist (FGK45) and chemotherapy (gemcitabine) can cure an established mesothelioma in a mouse mesothelioma model (pg. 4491 section Appropriate Combination of Chemotherapy and Immunotherapy Can Cause Regression and Cure of an Established Tumor), a later study teaches that the objective response rates for patients with malignant pleural mesothelioma are similar between CD40-activating antibody CP-870,893 in combination with chemotherapy (cisplatin and pemetrexed), and chemotherapy alone (Nowak et al, Annals of Oncology 26: 2483–2490, 2015, see abs.)
Different IL-15 have different structures and potency profiles (Knudson et al, Expert Opinion on Biological Therapy, 20(7), 705–709). Tan et al (Expert Opin Drug Deliv. 2020 July ; 17(7): 895–898.) teaches that all forms of IL-15, when administered as monotherapy of solid tumors, were ineffective, and successful clinical translation of IL-15 will hinge upon the optimization of therapeutic regimens and delivery strategies, that allow for safe and sustained IL-15 levels without excessive release of inflammatory cytokines (see section 5. Expert opinion).
IL-15 superagonists are developed to improve the therapeutic potential of IL-15 therapy and are overall described to have greater potency, bioavailability and stability than soluble recombination IL-15 due to their structure (Knudson et al, p. 705-706, section 3. IL-15 superagonists). “IL-15 superagonists appear to have an advantage over rIL-15 in mediating immune effects… it will be important in future clinical trials to optimize the treatment schedule and dose of IL-15 superagonists, especially when combining with other agents that provide costimulatory and activating signals or checkpoint blockade to override immunosuppression” (p. 707 section 6. Expert Opinion). In addition, it will be necessary to examine the differences between the various IL-15 superagonists, since they have different potency and half-life, and this differential may result in preferential stimulation of specific immune subsets or broaden the IL-15 activity to populations usually minimally stimulated by IL-15 (p. 707 right column 2nd para.).
The safe and efficacious doses of a compound is often depended on the dosing route and various properties of the compound. For instance, the maximum tolerated dose (MTD) of intravenous bolus infusion of rhIL-15 is 0.3 µg per kg body weight, but the MTD of subcutaneously administration is 2 µg per kg body weight, and MTD of continuous IV infusion is 2 µg per kg body weight (Tan et al (Expert Opin Drug Deliv. 2020 May 19;17(7):895–898, pg. 2, last para.). Similarly, for CD40 agonists, clinically used therapeutic doses for Selicrelumab, amount to about 200 µg whilst for another CD40 agonist, APX005M, the therapeutic dose is 300 µg (inst. specs. pg. 9 ln. 5-7).
A different compound might achieve therapeutic effect in a different subject at a higher or lower dose. For instance, the instant application shows that the neither the IL-15 or CD40 agonist have therapeutic effect in a breast cancer in mouse (inst. specs. pg. 13 ln. 31 – pg. 14 ln.10), while Hirano et al (Blood (1999) 93 (9): 2999–3007) shows agonist anti-CD40 MoAb (M3 hybridoma,10 μg, i.p. injection) is able to increase the survival of the tumor-bearing recipients (pg. 3004 section “srhCD40L exerts antitumor effects in SCID mice bearing human breast carcinoma cells”), and Guo et al (Front. Immunol., 07 February 2021. Sec. Cancer Immunity and Immunotherapy. Volume 11 – 2020) teaches that IL-15cx (IL-15/IL-15Rα complex, 12.5 µg containing 2.5 µg IL-15 and 10 µg IL-15Rα-Fc, i.p. injection) shows tumor growth inhibition or tumor regressions with survival improvement (abs. also see pg.5).
Furthermore, the art indicates the difficulties in going from animal model to clinical studies for drug development for treatment of cancers. Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that the model systems used in cancer drug discovery are not predictive at all (see p. 1, 2nd paragraph).
Taken together, the cited references demonstrate that treatment of mesothelioma using any IL-15 and any CD40 agonist, optionally at various administration routes and at claimed dosing ranges, is unpredictable.
The amount of direction or guidance provided by the inventor and the existence of working examples
The instant specification is only enabling for one example of intraperitoneally administrating a specific IL-15 and a specific CD40 agonist to treat mesothelioma in a mouse model in vivo at a very specific dose and a specific dosing schedule, but does not reasonably provide enablement for treating mesotheliomas in all mammals by administrating any combination comprising of any IL-15 and any CD40 agonist, at various administration routes and dose ranges.
Given the evidence above and the unpredictable responsiveness to different IL-15 and CD40 agonists, one of skill in the art could not reasonably extrapolate the findings from one specific method of treating mesothelioma to unlimited options of administering any IL-15 and CD40 agonists at different routes of administration and different doses to treat mesothelioma in all mammals, without undue experimentation.
In conclusion, the claimed invention does not provide enablement for the treatment of mesotheliomas with the recited method. Therefore, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 9, 10, 12 and 13 are rejected under 35 U.S.C. 102(a1)(a2) as being anticipated by Masteller et al (WO 2016/168149, published on Oct 20, 2016, refer to as Masteller thereafter).
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist. Regarding to claim 1, Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11).
Claim 9 is drawn to the method according to claim 1, wherein the combination is in the form of a pharmaceutical composition. Masteller teaches the limitation of claim1, and further teaches a composition comprising an anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 (para. [012] & [013], also see claims 18, 29 and 31).
Claim 10 is drawn to the method according to claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APXOO5M, ChiLob7/4, ADC-1013, SEA- CD40, CDX-1140, SGN-40, and ABBV-927. Masteller teaches the limitation of claim 1, and further teaches that exemplary CD40 agonists of the compositions and methods of this invention include, for example, anti-CD40 antibodies that enhance CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]).
Claim 12 is drawn to the method according to claim 1, wherein said IL-15 and CD40 agonist are administered simultaneously. Masteller teaches the limitation of claim 1, and further teaches said IL-15 and said CD40 agonist are formulated and administered in one composition and thus simultaneously, as explained for claim 9.
Claim 13 is drawn to the method according to claim 1, wherein said IL-15 and CD40 agonist are administered intravenously, intradermally, or subcutaneously. Masteller teaches the limitation of claim 1, and further teaches wherein said IL-15 and said CD40 agonist are administered subcutaneously (para[0209]).
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, 9 – 10 and 12 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Masteller et al (WO 2016/168149, published on Oct 20, 2016, refer to as Masteller thereafter) in view of Van Audenaerde et al (Clinical & Translational Immunology. Volume 9, Issue 8. e1165. Jan 2020).
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
Claim 2 is drawn to the method according to claim 1, wherein at least one of said IL-15 and CD40 agonist are administered in a subtherapeutic dose.
Claim 3 is drawn to the method according to claim 2, wherein said subtherapeutic dose of said IL-15 and CD40 agonist is a dose which is lower than the dose of said IL-15 and CD40 agonist required to obtain a therapeutic effect in said subject, when administered alone.
Claim 9 is drawn to the method of claim 1, wherein the combination is in the form of a pharmaceutical composition.
Claim 10 is drawn to the method of claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APX005M, ChiLob7/4, ACD-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927.
Claim 12 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered simultaneously.
Claim 13 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered intravenously, intradermally, or subcutaneously.
Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11), and exemplary CD40 agonists includes anti-CD40 antibodies that enhances CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]). Masteller also teaches the anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 could be in the form of a composition (para. [012] & [013], also see claims 18, 29 and 31), and the composition can be administered subcutaneously (para[0209]).
Masteller fails to teach that at least one of said IL-15 and CD40 agonist are administered in a subtherapeutic dose, and the subtherapeutic dose could be a dose that is lower than the dose of the said IL-15 and CD40 agonist required to obtain a therapeutic effect, as cited in claims 2 and 3.
However, Van Audenaerde et al teaches administrating CD40 agonist with interleukin-15 to two mouse models of pancreatic ductal adenocarcinoma exhibits synergistic effects in anti-tumor efficacy, leading to profound reduction in tumor growth and increased survival of mice (abs, also see section Combined IL-15 and CD40 agonist therapy results in increased anti-tumor efficacy in vivo). In addition, IL-15 potentiates CD40 agonist treatment, causing an 8-fold dose reduction in one of the two mouse models compared with the other mouse model without losing any efficacy (pg. 11 left col. 2nd para, also see abs.).
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Masteller et al, with the teaching of Van Audenaerde et al, to administer both IL-15 and a CD40 agonist to treat mesothelioma, with the CD40 agonist used in a subtherapeutic dose, because Van Audenaerde et al teaches IL-15 potentiates the anti-tumor effect of CD40 agonist and causing an 8-fold dose reduction of CD40 agonist. The motivation to do so is that IL-15 and CD40 agonist antibody have synergistic anti-tumor effect, leading to an 8-fold dose reduction of CD40 agonist, and lower doses are desired since they might significantly decrease adverse events in patients (Van Audenaerde et al, abs, pg. 11 left col. 2nd para). One would have a reasonable expectation of success in making the combination because the synergic effect of IL-15 and CD40 is established in the art, and combing the two would lead to better anti-tumor effect and reduced dose of CD40 agonist.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 9 – 10 and 12 – 14 are rejected under 35 U.S.C. 103 as being unpatentable over Masteller et al (WO 2016/168149, published on Oct 20, 2016, refer to as Masteller thereafter) in view of Kim et al (Ann Transl Med. 2017 Jun;5(11):236).
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
Claim 9 is drawn to the method of claim 1, wherein the combination is in the form of a pharmaceutical composition.
Claim 10 is drawn to the method of claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APX005M, ChiLob7/4, ACD-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927.
Claim 12 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered simultaneously.
Claim 13 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered intravenously, intradermally, or subcutaneously.
Claim 14 is drawn to the method according to claim 1, wherein said mesothelioma is selected from the group consisting of: pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and testicular mesothelioma.
Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11), and exemplary CD40 agonists includes anti-CD40 antibodies that enhances CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]). Masteller also teaches the anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 could be in the form of a composition (para. [012] & [013], also see claims 18, 29 and 31), and the composition can be administered subcutaneously (para[0209]).
Masteller fails to teach that the mesothelioma could be pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma or testicular mesothelioma, as cited in claim 14.
However, Kim et al teaches that mesothelioma is a rare malignancy of serosal membranes, including the pleura, peritoneum, pericardium and the tunica vaginalis testes, with pleural mesothelioma more common than malignant peritoneal mesothelioma (section Introduction para.1, abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Masteller et al, with the teaching of Kim et al, to administer both IL-15 and a CD40 agonist to treat different types of mesotheliomas, including pleural, peritoneal, pericardial and testicular mesothelioma, because mesothelioma includes pleural, peritoneal, pericardial and testicular mesothelioma. The rational to do so is there are four types of mesotheliomas, making it obvious to try the claimed method in different types. One would have a reasonable expectation of success in making the combination because these four types of mesotheliomas develop from the same thin layer of tissue (serosal membrane) (Kim et al, section Introduction para.1, abstract).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 4, 8 – 10, 12, 13, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Masteller et al (WO 2016/168149, published on Oct 20, 2016, refer to as Masteller thereafter) in view of Nowak et al (Annals of Oncology 26: 2483-2490, 2015).
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
Claim 4 is drawn to the method according to claim 1, wherein said CD40 agonist is administered at a dose of from about 20 to about 800 µg per kg body weight.
Claim 8 is drawn to the method according to claim 1 wherein said CD40 agonist is administered at a dose of less than 300 µg per kg body weight.
Claim 9 is drawn to the method of claim 1, wherein the combination is in the form of a pharmaceutical composition.
Claim 10 is drawn to the method of claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APX005M, ChiLob7/4, ACD-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927.
Claim 12 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered simultaneously.
Claim 13 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered intravenously, intradermally, or subcutaneously.
Claim 16 is drawn to the method according to claim 4, wherein said CD40 agonist is administered at a dose of from about 30 to about 600 µg per kg body weight.
Claim 17 is drawn to the method according to claim 16, wherein said CD40 agonist is administered at a dose of from about 40 to about 300 µg per kg body weight.
Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11), and exemplary CD40 agonists includes anti-CD40 antibodies that enhances CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]). Masteller also teaches the anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 could be in the form of a composition (para. [012] & [013], also see claims 18, 29 and 31), and the composition can be administered subcutaneously (para[0209]).
Masteller fail to teach the limitations: said CD40 agonist is administered at a dose of from about 20 to about 800 µg per kg body weight; said CD40 agonist is administered at a dose of less than 300 µg per kg body weight; said CD40 agonist is administered at a dose of from about 30 to about 600 µg per kg body weight; said CD40 agonist is administered at a dose of from about 40 to about 300 µg per kg body weight, as cited in claims 4, 8, 16 and 17.
However, Nowak et al teaches a CD40 agonist, Selicrelumab (CP-870,893), is a fully human IgG2 antibody which is agonistic for the CD40 receptor and its single-agent maximum tolerated dose (MTD) is 200 µg per kg body weight (0.2 mg/kg) (pg. 2483 right col. 2nd para.). When administering CP-870,893 intravenously (bolus) with cisplatin and pemetrexed to treat malignant pleural mesothelioma, the MTD of CP-870,893 is at 150 µg per kg bodyweight (0.15 mg/kg) (pg. 2482 section treatment, Abs.).
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Masteller, with the teaching of Nowak et al, to administer a CD40 agonist (CP-870,893 or Selicrelumab) at or below the MTD reported in Nowak et al, which is 150 µg per kg bodyweight, because Nowak et al teaches the MTD of the CD40 agonist CP-870,893 and using a compound above the MTD could cause serious side effects for patients. The rationale to do so is that using the CD40 agonist above the MTD can lead to serious side effect that might affect patient health and safety, such has hepatic vein thrombosis and splenic infarction (Nowak et al pg. 2485 right col. 2nd para.). One would have a reasonable expectation of success in making the combination because using a compound at or below the MTD for patient safety is well established practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 5 - 7, 9, 10, 12, 13 and 18 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Masteller et al (WO 2016/168149, published on Oct 20, 2016, referred to as Masteller thereafter) in view of Tan et al (Expert Opin Drug Deliv. 2020 May 19;17(7):895–898, refer to as Tan thereafter).
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
Claim 5 is drawn to the method according to claim 1 wherein said IL-15 is administered at a dose of from about 0.1 to about 50 µg per kg body weight.
Claim 6 is drawn to the method according to claim 1, wherein said IL-15 is administered intravenously via an IV bolus injection at a dose of less than 0.3 µg per kg body weight; or via a continuous IV drip system at a dose of about or below 2 µg per kg body weight.
Claim 7 is drawn to the method according to claim 1, wherein said IL-15 is administered subcutaneously or intradermally at a dose of less than 2 µg per kg body weight.
Claim 9 is drawn to the method of claim 1, wherein the combination is in the form of a pharmaceutical composition.
Claim 10 is drawn to the method of claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APX005M, ChiLob7/4, ACD-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927.
Claim 12 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered simultaneously.
Claim 13 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered intravenously, intradermally, or subcutaneously.
Claim 18 is drawn to the method according to claim 5, wherein said IL-15 is administered at a dose of from about 0.1 to 20 µg per kg body weight.
Claim 19 is drawn to the method according to claim 18, wherein said IL-15 is administered at a dose of from about 0.1 to 2 µg per kg body weight.
Claim 20 is drawn to the method according to claim 1, wherein:- said IL-15 is administered via a bolus injection intravenously at a dose of less than 0.3 µg per kg body weight; - said IL-15 is administered via a continuous drip system intravenously at a dose of about or below 2µg per kg body weight; or - said IL-15 is administered subcutaneously or intradermally at a dose of less than 2 µg per kg body weight.
Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11), and exemplary CD40 agonists includes anti-CD40 antibodies that enhances CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]). Masteller also teaches the anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 could be in the form of a composition (para. [012] & [013], also see claims 18, 29 and 31), and the composition can be administered subcutaneously (para[0209]).
Masteller fail to teach the following limitations: said IL-15 is administered at a dose of from about 0.1 to about 50 µg per kg body weight (claim 5); said IL-15 is administered intravenously via an IV bolus injection at a dose of less than 0.3 µg per kg body weight; or via a continuous IV drip system at a dose of about or below 2 µg per kg body weight (claim 6); said IL-15 is administered subcutaneously or intradermally at a dose of less than 2 µg per kg body weight (claim 7); said IL-15 is administered at a dose of from about 0.1 to 20 µg per kg body weight (claim 18); said IL-15 is administered at a dose of from about 0.1 to 2 µg per kg body weight (claim 19); -said IL-15 is administered via a bolus injection intravenously at a dose of less than 0.3 µg per kg body weight; - said IL-15 is administered via a continuous drip system intravenously at a dose of about or below 2µg per kg body weight; or - said IL-15 is administered subcutaneously or intradermally at a dose of less than 2 µg per kg body weight (claim 20).
However, Tan teaches the MTD (maximum tolerated dose) of intravenous bolus infusion of IL-15 (rhIL-15) is 0.3 µg per kg body weight (0.3 µg/kg/day), subcutaneously administration of IL-15 (rhIL-15) is 2 µg per kg body weight (2 µg/kg/day), and continuous IV infusion of IL-15 (rhIL-15) is 2 µg per kg body weight (2 µg/kg/day) (pg. 2, last para.).
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Masteller, with the teaching of Tan, to administer IL-15 at or below the MTD reported in Tan, because Tan teaches the MTD of rh IL-15 through different administration routes, and using a compound above the MTD could lead to serious side effects or toxicity in patients. The rationale to do so is that using the IL-15 above the MTD can potentially lead to serious side effect that might affect patient health and safety, and thus doses of IL-15 at or below the MTD is desirable to reduce toxicity and side effects in patients. One would have a reasonable expectation of success in making the combination because using a compound at or below the MTD for patient safety is well established practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 9 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Masteller et al (WO 2016/168149, published on Oct 20, 2016, referred to as Masteller thereafter) in view of Richards et al (Hum Vaccin Immunother. 2019 Sep 5;16(2):377–387.)
Claim 1 is drawn to a method of treating mesothelioma in a subject in need thereof, the method comprising administering to the subject a combination comprising IL-15 and a CD40 agonist.
Claim 9 is drawn to the method of claim 1, wherein the combination is in the form of a pharmaceutical composition.
Claim 10 is drawn to the method of claim 1, wherein said CD40 agonist is a CD40 antibody or antigen binding fragment thereof selected from the group consisting of: Selicrelumab, APX005M, ChiLob7/4, ACD-1013, SEA-CD40, CDX-1140, SGN-40, and ABBV-927.
Claim 11 is drawn to the method according to claim 1, wherein the said CD40 agonist is selected from the group consisting of: CD40L trivalent, and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083.
Claim 12 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered simultaneously.
Claim 13 is drawn to the method of claim 1, wherein said IL-15 and said CD40 agonist are administered intravenously, intradermally, or subcutaneously.
Masteller teaches a method of treating cancer in a subject, the method comprising administering to the subject an anti-CSFIR antibody and at least one immune stimulating agent that can comprises an agonist of CD40 and an agonist of IL-15, and the cancer is can be mesothelioma (para. [007], [008] & [011], also see claims 1 and 11), and exemplary CD40 agonists includes anti-CD40 antibodies that enhances CD40 activity such as CP-870,893, ADC-1013, SEA-CD40, and Chi Lob 7/4 (para[0178]&[0179]). Masteller also teaches the anti-CSFIR antibody and at least one immune stimulatory agent that comprises agonist of IL-15 and agonist of CD40 could be in the form of a composition (para. [012] & [013], also see claims 18, 29 and 31), and the composition can be administered subcutaneously (para[0209]).
Masteller fail to teach the limitation of the said CD40 agonist is selected from the group consisting of: CD40L trivalent, and hexavalent molecules of CD40L, HERA-CD40L and MEDI5083, as cited in claim 11.
However, Richards et al teaches anti-CD40 antibodies, because of their bivalent nature, unless crosslinked, do not provide the required clustering capacity for significant efficacy (pg. 380 right col 3rd para.). Richards further teaches the effect of the hexavalent HERA-CD40L on the expression of activation, differentiation, and antigen-presentation markers is generally stronger than stimulation by trivalent CD40L or bivalent anti-CD40 antibodies (pg. 382 left col. last para.). Therefore, the CD40L-based approaches, especially the soluble hexavalent CD40L molecules are able to provide a true agonistic signal via a defined single mode of action (pg. 382 right col. 1st para.).
It would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Masteller, with the teaching of Richards et al, to use the CD40 hexavalent molecules, such as HERA-CD40L, as CD40 agonist, because CD40 hexavalent molecules have desirable properties over bivalent anti-CD40 antibodies. The motivation to do so is in the teaching of Richards et al: the effect of hexavalent HERA-CD40L is stronger than trivalent CD40 L or bivalent anti-CD40 antibodies and should have stronger safety profiles (Richards et al, pg.382 left col.). One would have a reasonable expectation of success in making the combination because using a compound that has desirable properties and potentially stronger safety profiles is well established practice in the art.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Relevant art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Waldmann et al (Front. Immunol., 18 May 2020. Sec. Cytokines and Soluble Mediators in Immunity. Volume 11 – 2020) teaches a clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15.
Zhang et al (PNAS. 2009 May; vol. 106; no. 18; 7513-7518) teaches that IL-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer.
Zhang et al (J. Immunol., Volume 188, Issue 12, June 2012, Pages 6156–6164) teaches that IL-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for TRAMP-C2 tumors in mice, and augmented IL-15Rα expression by CD40 activation is critical for this synergistic effect.
Conclusion
Claims 1-14 and 16-20 are rejected.
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/TIAN YANG/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674