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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/15/2026 has been entered.
Status of Claims
The amended claims filed 01/15/2026 are acknowledged and entered.
Claims 10 has been amended
Claims 1-9, 13-25 are cancelled.
Claims 26-29 have been added.
Claims 10-12 and 26-29 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 112 withdrawn
1. The rejections for claim 18 and 21 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the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends are withdrawn in view of claim 18 and 21 being cancelled.
Claim Rejections - 35 USC § 103 – withdrawn
2. The rejections of claims 10-12 14 and 17 under 35 U.S.C. 103 as being unpatentable over Fuji (US 2013/0189302 A1 publication date July 25, 2013) in view of Weinberg (J Immunother. 2006; 29:575–585), Sun (Cell Reports 25, 3786–3799, December 26, 2018). Metelitsa (US 2018/0264040 Al published Sep. 20 2018) and Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019) are withdrawn in view of Applicant’s amendments to claim 10 and cancellation of claims 14 and 17.
3. The rejection of claims 18, 21, 23 and 24 under 35 U.S.C. 103 as being unpatentable over Fuji in view of Metelitsa, Boyman , and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14) is withdrawn in view of Applicant’s cancellation of claims 18, 21, 23 and 24.
Double Patenting - withdrawn
4. Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 30, 49, 54, and 62-64 of U.S. Patent Application No. 12/280,305 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 10, 12, 14, 26, and 40 of U.S. Patent Application No. 13/834,096 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman. Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1 and 3-4 of U.S. Patent Application No. 17/312,363 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 6-10 of U.S. Patent Application No. 18/179,289 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman. Abandoned.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1-4, 8, 12-14, and 16 of U.S. Patent Application No. 17/618,699 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 15 and 27 of U.S. Patent Application No. 17/781,616 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1-19 of U.S. Patent Application No. 18/317,358 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman. Abandoned.
Claims 10-12, 14, and 17 were provisionally rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1-5 and 23-37 of U.S. Patent Application No. 18/557,879 in view of Fuji, Weinberg, Sun, Metelitsa, and Boyman.
These rejections. are withdrawn in view of Applicant’s amendments to claim 10 and cancellation of claims 14 and 17.
New Rejections based on Amendments
Claim Objections
Claim 10 is objected to because of the following informalities: There is a typo found in the last line of claim 10. In the recitation “….compared to that in a subject administered on the artificial adjuvant vector cell.”. The word “on” should be “only”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
6. Claims 10-12 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming.
Claim 10 recites an “OX40 activator” that is capable of treating tumors by inducing iNKT cells and CTL cells, which encompasses a genus of agents., Claims 11 and 12 are dependent from Claim 10 and do not materially limit the genus of agents, especially regarding the nature of the OX40 activator and are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Therefore, the claims are drawn to a genus of “OX40 activator” for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity (treating tumors by inducing iNKT cells and CTL cells). There is not even any identification of any particular portion of a structure that must be conserved for said activity. Regarding the genus of the claims the specification describes one agonistic antibody capable of binding to OX40 species within the genus claimed (anti-OX40 antibody (product number: BE0031; manufacturer: BioXcell) [0057]). From the specification, it is clear that Applicant is in possession of species of BE0031 (Example 1). The claims, however are not limited to those species but also includes OX40L and variants thereof, any OX40 agonist, any OX40 agonistic antibody, wherein an OX40 agonist could be a peptide, a fusion protein, a conjugate, a small molecule, etc. and the specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
Claim Rejections - 35 USC § 103
Claims 10-12 and 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Fuji (2013 previously cited) in view of Weinberg (2006 previously cited), Metelitsa (2018 previously cited), Boyman (2019 previously cited), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (2015 Previously cited).
Fuji teaches a method of administering an artificial adjuvant vector cell (aAVC) to a subject in need thereof (page 2 [0011]). Examples of the biological samples obtained when following the method include spleen biological samples ([0094] and Example 3) as required by instant claims 10, 26 and 28. Fuji also teaches that the aAVC co-expresses a target antigen and CD1d, is able to activate immunity against the target antigen comprising treating (pulsing) the target antigen and the CD1d co-expressing cell with a CD1d ligand in a culture medium (Fuji claim 1) as required in instant claims 10, 26 and 28. Examples of CD1d ligand include α-galactosylceramide (page 4, [0065]) as required in instant claim 12, Fuji further teaches that the CD1d co-expressing cell is produced by either (a) transfecting a nucleic acid encoding a target antigen or CD1d into a cell, or by (b) transfecting one or two molecular species of a nucleic acid encoding a target antigen and CD1d into a cell (Fuji claim 4) and that the target antigen includes tumor/cancer antigens (page 5 [0074]) as required by instant claim 11. Fuji further teaches that the aAVC can produce cytotoxic T cells (CTLs) to a tumor antigen expressed in the tumor [0169] that is, inducing CTLs specific to the antigen in the subject, (instant claim 10, 26 and 28). Moreover, Fuji teaches a method of inducing immunity comprising administering an effective amount of the aAVC to a subject in need thereof [0011] and the ability of the aAVC to
activate immunity against the target antigen is disclosed as being immunotherapy of cancer (abstract). That is, the effective amount for immune activation makes obvious the effective amount for treating tumors, the intended result (see below for further discussion). Fibroblasts loaded with α-galactosylceramide activate allogeneic NK and iNKT cells in vivo and that CD1dhi-NIH3T3/Gal and CD1hi-B16/Gal (aAVC) act as antigen presenting cells for the innate immune responses of iNKT cells and subsequent NK cell responses. (example 12, [0207]). That is, an aAVC can stimulate the proliferation of iNKT cells (instant claim 10, 26 and 28). The numbers of iNKT and CD8 T (CTL) cells in the recipients were monitored and aAVCs activate iNKT cells in vivo (which makes obvious comparing the number of iNKT cells to the number in an untreated subject), ([0231] [0233] and example 16) and can produce CTL to a tumor antigen expressed in the tumor (which reads on having specificity for the antigen and comparing the number of CTLs to the number in an untreated subject) ([0168] and example 5). That being said, inducing iNKT cells and CTL cells is a mechanism of action (MOA) that is a property of the aAVCs function of treating tumors (the intended result), and does not impact any additional structural feature of the aAVCs. The MOA recitation is considered to flow from the features already present in the aAVCs.
In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Here, it would have been obvious that the method of Fuji can not only be used to induce an immune response but also to treat target tumors. The ability of the aAVC to activate immunity against the target antigen is disclosed as being immunotherapy of cancer (abstract) as discussed above. It would have been equally obvious to a PHOSITA before filing of the instant application that amounts used of the active agents are result effective variables, which Applicant agrees as they acknowledge use of “effective amounts”. Arrive at the effective amounts to treat tumor with the method above would be achieved with no more than routine experimentation, identifying doses. Therefore, a method of treating tumor with the method of Fuji is obvious here and the effective amounts of the claims for treating tumor are equally obvious. Since the method is obvious, the wherein clauses reciting only intended results are necessarily met even if they were given patentable weight, which they are not.
Furthermore, two doses of aAVCs were given with a low dose of 5x106 cells and a high dose of 5x107 cells (effective aAVC amounts of instant claims 10, 26 and 28).
Fuji does not teach the coadministration of aAVCs and an immunostimulant, comprising an anti-agonist OX40 antibody and/or IL-2, and/or an IL-2/anti-IL-2 antibody complex, and/or IL-15, and/or an IL-15/anti-IL15Rα antibody complex as required in instant claims 10-12 and 26-29.
Weinberg teaches the immunostimulatory properties of anti-OX40 (CD134) agonist antibodies (Title and entire article) as required in instant claims 10-12. Specifically, preclinical data in mice showed greatly enhanced immune responses with OX40 agonists that resulted in substantial antitumor activity in multiple murine tumor models (intended results of instant claims 10-12) and that anti-OX40 antibody infusions in nonhuman primates induced a variety of T-cell and B-cell stimulatory effects (page 585, First column, first paragraph). Figure 3 depicts representative tissues in which frequent staining of cells with anti-OX40 was observed (spleen and thymus) as required by instant claim 10. Weinberg further teaches an immunization study to test the adjuvant properties of the anti-OX40 antibody in nonhuman primates and whether in vivo administration of an anti-OX40 agonist antibody or soluble OX40L fusion protein during Ag priming would accentuate T-cell immunity. The anti-OX40 antibody was administered as an intravenous bolus at 10 mL; 2 mg/kg dose (Page 576 and 578 Immunization Study sections), which reads on the effective amount as required by instant claim 10. The results showed dramatic increases in adaptive immunity, including enhanced CD4 and CD8 T cell (CTL) function. However, inducing iNKT cells and CTL cells is a MOA that is a property of an OX40 agonist (including an agonist anti-CD40 antibody) function of treating tumors (the intended result), and does not impart any additional structural feature to the OX40 agonist. The MOA recitation is considered to flow from the features already present in the OX40 agonist.
Since the agents of both Fuji and Weinberg active T cell immunity against tumors, they are taught in the prior art for the same purpose and so it is obvious to combine them in the same therapy regimen to achieve that purpose. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Weinberg does not teach the coadministration of aAVCs and an immunostimulant comprising of IL-2, an IL-2/anti-IL-2 antibody complex, IL-15, and/or an IL-15/anti-IL15Rα antibody complex as required in instant claims 26-29.
Metelitsa teaches that type-I NKT cells (also known as invariant NKT (iNKT) cells) are an evolutionary conserved subset of innate lymphocytes (innate immunity) [0004] and that expansion of CD62L+ NKT cells (which includes a subset of iNKT cells) can be achieved by stimulatory agents such as IL-2 and IL-15 [0012], and that the proliferation of CD62L+NKT cells is useful for immunotherapy of tumors [009]. That is, IL2 and IL15 can stimulate the proliferation of a type of iNKT cells and activate innate immunity (instant claim 26 and 28). That being said, inducing iNKT cells and CTL cells is a mechanism of action that is a property of to the IL2 and/or IL15 function of treating tumors (the intended result), and does not impact any additional structural feature of the IL2 and/or IL15. MOA recitation is considered to flow from the features already present in IL-2 and IL-15. Thus, the required intended results will necessarily occur via addition of these two agents at effective anti-tumor amounts, arrived at by routine experimentation, to the obvious method discussed above since they are also taught as anti-tumor agents and supporters of iNKT cell responses and so are used for the same purpose as the agents supra.
Metelitsa fails to teach an IL-2/anti-IL2 antibody complex as required by instant claim 27 and IL-15/anti- IL-15Rα complex as required by claim 29
Boyman teaches that IL-2 complexes can stimulate potent antitumor CD8+ T cell (cytotoxic T cells or CTLs) responses (page 3, figure 1). Examples of such complexes include IL-2/NARA1 complexes (page 3, figure 1B), wherein NARA1 is an anti-human IL-2 antibody (summary). Boyman also teaches that IL-2/NARA1 complexes preferentially stimulate CD8+T cells and NK cells while sparing Treg cells and endothelial cells, and show strong efficacy in several mouse tumor models (page 3) (instant claim 27).
Stoklasek teaches that a combined IL-15/IL-15Rα immunotherapy maximizes IL-15 activity in vivo (Title) and IL-15/IL-15Rα complex is an effective antitumor immunotherapy agent (Figure 11). Figure 1 depicts that the coadministration of IL-15 and IL-15Rα-Fc enhances CD8 T cell proliferative response to exogenous IL-15 by analyzing splenocyte cell number (spleen) as required by instant claim 29.
Linch teaches the combination of an OX40A agonist (such as OX86, an anti-OX40 antibody) with a IL2 complexes (recombinant IL2 + anti-IL2 antibody). This combination shows significant survival benefit and boosted T cell response in an anergy model (Table 1 Summary of animal studies using OX40 agonists alone or in combination). Several other therapeutic interventions have been reported to complement the anti-tumor activity of OX40 stimulation, including IL-2 (page 8, second column, second paragraph) (instant claim 27).
It would have been obvious to one of ordinary skill in the art to use the teachings of Fuji (administering an aAVC) in combination with Weinberg (in regards to the anti-OX40 agonistic antibody) and/or Metelitsa (in regards to IL2 or IL15) and/or Boyman (in regards to an IL2/anti-IL-2 antibody complex) and/or Stoklasek (in regards to an IL-15/IL-15Rα complex) to develop a method of administering the aAVC in combination with one or more immunostimulants such as anti-OX40 antibodies and/or cytokines such as IL-2 or IL-15 and/or an IL-2/anti-IL-2 antibody complex and/or IL-15/IL-15Rα complex as antitumor immunotherapy in the spleen using the effective amounts of the therapeutics. (Inducing iNKT cells and CTL cells is a mechanism of action that is a property of to the aAVC alone or in combination with anti-OX40 antibodies and/or IL2 and/or IL15 and/or an IL2/anti-IL-2 antibody complex and/or IL-15/IL-15Rα complex function of treating tumors (the intended result) as discussed above). There would be a reasonable expectation of success because separately, the aAVC cells, the anti-OX40 antibody, IL2, IL15, IL2/anti-IL-2 antibody complex and the IL-15/IL-15Rα complex are known to stimulate the immune system individually. It would be expected that a combination of two or more of these therapeutics would have at least an additive effect or even a synergistic effect on the successful stimulation of an immune response to treat tumors, as it is seen in most combination treatments (and shown by Linch with the anti-OX40 agonist antibody with IL-2+anti-IL-2 antibody complex), leading to a more effective cancer cell elimination when compared with a single therapeutic.
It would further be obvious to expect that the combination of the aAVC with the cited immunostimulants would increase the stimulation of the innate and adaptive immune response, leading to an overall increase of treatment efficacy when compared to just administering the aAVC alone. One of ordinary skill would have been motivated to do so because all the references cited above teach the stimulation of the immune response leading to an overall increase of tumor treatment efficacy. There would be a reasonable expectation of success because separately, aAVC cells, OX40 antibody/agonist, IL2 or IL15 or an IL2/anti-IL-2 antibody complex or IL-15/IL-15Rα complex are known to stimulate the immune system individually resulting in a efficacious treatment of a tumor as taught by the prior art references cited above.
It would further be obvious with that the effective amount of a therapeutic is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the effective amount of each therapeutic needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
Claims 10-12 and 26-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 30, 49, 54 and 62-64 of copending application No. 12/280,305 (reference application) in view of Fuji (US 2013/0189302 A1 publication date July 25, 2013), Weinberg (J Immunother. 2006; 29:575–585), Metelitsa (US 2018/0264040 Al published Sep. 20 2018), Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14).
Copending application No. 12/280,305 claims 30, 49 and 54 and 62-64 are drawn to a method of inducing activation and maturation of CD 11c+ dendritic cells and activation of T-cell immune response to a target antigen, antigen-specific immunity, which method comprises administering to a subject in need thereof an effective amount of a composition comprising a aAVC pulsed with a CD1d ligand, wherein the aAVC co-expresses the target antigen and CD1d, thereby both the activation of NKT cells and the T-cell immune response to the target antigen are inducing target antigen-specific immunity in the subject, provided that the aAVC is not a dendritic cell, wherein the composition is administered to the subject with an adjuvant, the target antigen is a tumor antigen and the subject has leukemia, lymphoma, myeloma, or an infection.
Claims 30, 49, 54 and 62-64 of 12/280,305 do not recite the administration of an immunostimulant but they recite the administration of an adjuvant. Adjuvants are defined as substances that enhance the body's immune response to an antigen (Cambridge English Dictionary). Therefore, it has been interpreted that adjuvants are immunostimulants.
Although the claims of the instant application do not explicitly recite that the aAVC is not a dendritic cell, the instant application claims recite an artificial Adjuvant Vector Cells (aAVC) and does not need to be a dendritic cell. A dendritic cell is a species of the genus cell, so the claims of the copending application anticipate the instant application.
Although the claims of the instant application do not recite that the subject has leukemia, lymphoma, myeloma, or an infection, the claims recite a method of treating a subject with the goal of stimulating the immune system, the said method inherently can be used for any indication where an activation of the immune system would be an effective treatment.
Claims 30, 49, 54 and 62-64 of 12/280,305 do not recite the administration of an immunostimulant comprising an anti-0X40 antibody, IL-2, an IL-2/anti-IL-2 antibody complex, IL-15, and an IL-15/anti-IL15Rα antibody complex.
The teachings of Fuji, Metelitsa, Boyman, Stoklasek and Linch regarding the administration of aAVC and an immunostimulant have been discussed above (see Claim Rejections - 35 USC § 103 above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10-12, 26-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 10, 12, 14, 26.and 40 of copending application No. 13/834,096 (reference application and Continuation-In-Part of copending application No. 12/280,305 cited above) in view of Fuji (US 2013/0189302 A1 publication date July 25, 2013), Weinberg (J Immunother. 2006; 29:575–585), Metelitsa (US 2018/0264040 Al published Sep. 20 2018), Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14).
Copending application No. 13/834,096 claims 10, 12, 14, 26 and 40 are drawn to pharmaceutical composition comprising an aAVC co-expressing target antigen(s) and CD1d, and a pharmaceutically acceptable carrier and/or adjuvant, wherein the aAVC are produced by transfecting cells with one or more nucleic acid(s) encoding the target antigen(s) and a CD1d and treating the cells with α-galactosylceramide (CD1d ligand), an effective amount of aAVC is sufficient to a T-cell immune response in a human subject and that the base cell of the aAVC is a cell line
Claims 10, 12, 14, 26 and 40 of 13/834,096 do not recite the administration of an immunostimulant but they recite the administration of an adjuvant. Adjuvants are defined as substances that enhance the body's immune response to an antigen (Cambridge English Dictionary). Therefore, it has been interpreted that adjuvants are immunostimulants.
Although the claims of the instant application do not explicitly recite cell lines, the instant application claims recite artificial Adjuvant Vector Cells (aAVC). A cell line is a species of the genus cell, so the claims of the copending application anticipate this limitation in the instant application.
Claims 10, 12, 14, 26 and 40 of 13/834,096 do not recite the administration of an immunostimulant comprising an anti-0X40 antibody and/or at least one selected from the group consisting of IL-2, an IL-2/anti-IL-2 antibody complex, IL-15, and an IL-15/anti-IL15Rα antibody complex, and wherein the immunostimulant administered to the subject stimulates an innate immunity in the subject, compared to a subject administered only the artificial adjuvant vector cell, thereby inducing cytotoxic T cells having an antigen specificity against the antigen in the subject.
The teachings of Fuji, Metelitsa, Boyman, Stoklasek and Linch regarding the administration of aAVC and an immunostimulant have been discussed above (see Claim Rejections - 35 USC § 103 above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10-12, 14 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of US 11617790 B2 in view of Fuji (US 2013/0189302 A1 publication date July 25, 2013), Weinberg (J Immunother. 2006; 29:575–585), Metelitsa (US 2018/0264040 Al published Sep. 20 2018), Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14).
Claims 1-3 of US 11617790 B2 are drawn to a method for treating a cancer comprising administering a cell to a human, wherein the cell expresses exogenous CD1d (possibly human) and has α-galactosylceramide (CD1d ligand) loaded on the cell surface, including wherein the cell expresses a tumor antigen and the cell is a HEK293-derived cell.
Although the claims of the instant application do not explicitly recite HEK293 cells, the instant application claims recite artificial Adjuvant Vector Cells (aAVC). An HEK293 celli s a species of the genus cell, so the claims of the copending application anticipate this limitation in the instant application.
Although the claims of the instant application do not recite that the treatment is for cancer, the claims recite a method of treating a subject with the goal of stimulating the immune system, the said method inherently can be used for any indication, including cancer where an activation of the immune system would be an effective treatment.
Claims 1-3 of US 11617790 B2 do not recite the administration of an immunostimulant.
The teachings of Fuji, Metelitsa, Boyman, Stoklasek and Linch regarding the administration of aAVC and an immunostimulant have been discussed above (see Claim Rejections - 35 USC § 103 above).
Claims 10-12, 26-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of US 11672851 B2 in view of Fuji (US 2013/0189302 A1 publication date July 25, 2013), Weinberg (J Immunother. 2006; 29:575–585), Metelitsa (US 2018/0264040 Al published Sep. 20 2018), Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14)..
Claims 1 and 4 of US 11672851 B2 are drawn to a method for treating a cancer, comprising administering to a subject a cell derived from a human embryonic kidney (HEK293 cell) comprising a polynucleotide encoding human CD1d and a polynucleotide encoding human NY-ESO-1 wherein the polynucleotide encoding NY-ESO-1 is operably linked to a tetracycline-inducible promoter, wherein the cell is cultured in the presence of tetracycline to express CD1d and NY-ESO-1, wherein a CD1d ligand is loaded on the surface of the cell, and wherein the CD1d ligand is α-galactosylceramide.
Although the claims of the instant application do not explicitly recite that antigen is human NY-ESO-1, the claims do recite an antigen. These recitations speak to the genus of antigen encompassed by the claims of the instant application, so the claims of US 11672851 B2 anticipate this limitation of the instant application.
Although the claims of the instant application do not explicitly recite HEK293 cells, the instant application claims recite artificial Adjuvant Vector Cells (aAVC). An HEK293 celli s a species of the genus cell, so the claims of the US 11672851 B2 anticipate this limitation of the instant application.
Although the claims of the instant application do not explicitly recite an inducible promoter, the instant application claims recite exogenous nucleic acid molecules encoding CD1d and an antigen. These exogenous nucleic acid molecules would necessarily include a promoter. The inducible promoter is a species of the promoter genus so the claims of US 11672851 B2 anticipate this limitation of the instant application.
The teachings of Fuji, Metelitsa, Boyman, Stoklasek and Linch regarding the administration of aAVC and an immunostimulant have been discussed above (see Claim Rejections - 35 USC § 103 above)..
Claims 10-12, 26-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 23-37 of copending Application No. 18/557,879 in view of Fuji (US 2013/0189302 A1 publication date July 25, 2013), Weinberg (J Immunother. 2006; 29:575–585), Metelitsa (US 2018/0264040 Al published Sep. 20 2018), Boyman (Swiss Med Wkly. 2019;149: w14697, published Jan 23, 2019), Stoklasek (J Immunol. 2006 November 1; 177(9): 6072–6080) and Linch (Frontiers in Oncology, February 2015 | Volume 5 | Article 34 1-14).
Copending application No 18/557,879 claims 1-5 and 23-37 are drawn to a cell expressing a CD1d on a cell surface, wherein the CD1d is bound by a CD1d ligand, and the cell further expresses an antigen, wherein the antigen is a spike protein of a coronavirus thereby capable of inducing spike protein-specific immunity; wherein the cell expresses and additional antigen (maybe a cancer antigen); and a method for inducing antigen-specific immunity in a subject by administering to the subject the cell and the subject is infected with a coronavirus or has cancer.
Although the claims of the instant application do not explicitly recite that antigen is Coronavirus spike protein, the claims do recite an antigen. These recitations speak to the genus of antigen encompassed by the claims of the instant application, so the claims of the copending application anticipate this limitation in the instant application.
Although the claims of the instant application do not recite that the treatment is for Coronavirus, the claims recite a method of treating a subject with the goal of stimulating the immune system, the said method inherently can be used for any indication, including an infection disease or cancer where an activation of the immune system would be an effective treatment.
The teachings of Fuji, Metelitsa, Boyman, Stoklasek and Linch regarding the administration of aAVC and an immunostimulant have been discussed above (see Claim Rejections - 35 USC § 103 above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Relevant arguments that apply to new claims
Applicant’s arguments are as follow:
- (a) Lan (TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury, J. Clin. Investigation, (2017)) teaches away from the claims as currently presented. The liver is the "primary site" for iNKT cells, and a small proportion" of iNKT cells reside in the other organs ()). iNKT cells are a "dominant cell type" in the liver accounting for approximately 6% of all retrieved lymphocytes in mice. Moreover, while OX40 is traditionally known as a co-stimulatory molecule that promotes the survival of conventional T cells, Exhibit A provides the unexpected teaching that OX40 serves as a "death receptor" for iNKT cells. Unlike other liver cell types, iNKT cells "constitutively express" OX40. Stimulation of OX40 triggers "massive pyroptotic death" of these iNKT cells and OX40 agonists induce a "marked depletion" of iNKT cells in the liver (e.g., reducing the population from ~6% to ~0.6%)
A person of ordinary skill in the art seeking to activate iNKT cells using aAVC would be strongly discouraged from co-administering an OX40 agonist for the following reasons:
a.1 - Antagonistic Mechanisms of Action. The therapeutic goal of aAVC is to activate iNKT cells via CD1d molecules loaded with a-GalCer. However, an OX40 agonist would be thought to simultaneously "readily deplete" the very cells aAVC aims to activate. Consequently, a person of ordinary skill in the art would conclude that any iNKT cells successfully activated by aAVC would merely become new targets for OX40-mediated cell death. Combining a cell-activator (i.e., aAVC) with a cell-depleting agent (i.e., OX40 agonist) is technically counterintuitive and logically inconsistent.
a.2 – Destruction of the therapeutic platform. Because the combination of an iNKT-activating agent (aAVC) and an 0X40 agonist would result in the destruction of the target cell population and induce severe organ toxicity,. A person of ordinary skill in the art would have had no reasonable expectation of success, and indeed every reason to avoid such a combination
- (b) The experimental results of the present application were unexpected. The combination of aAVC and an OX40 agonist achieves a synergistic therapeutic effect. This combination is nonobvious because the prior art strongly discourages such a combination and fails to suggest the efficacy of OX40 agonists in activating innate immunity.
b.1 - OX40 Agonists Alone Exhibit Minimal Efficacy on Innate Immunity. OX40 agonists, when administered at 200 g per mouse, fail to provide significant therapeutic benefits as a monotherapy in the context of innate immune activation. Fuji Declaration, Appendix A demonstrates that anti-OX40 monotherapy resulted in no increase in the number or ratio of NK cells (3.72 to 3.53) or iNKT cells (1.24 to 1.21). Fuji Declaration, Appendix B, in a tumor-bearing mouse model, the tumor size in the anti-0X40 monotherapy group showed no statistically significant difference compared to the negative control.
b.2 - Unexpected Synergistic Effect of the Combination Including 0X40 Agonist. The combination of aAVC and an 0X40 agonist yields an unexpected and synergistic therapeutic result. Fuji Declaration, Appendix B, the combination therapy (aAVC + anti-0X40) demonstrated a statistically significant reduction in tumor size compared to the aAVC monotherapy group. The OX40 agonist alone showed no therapeutic effect its ability to significantly enhance the performance of aAVC is a surprising result that could not have been predicted.
The combination of aAVC and 0X40 agonists overcomes a known technical barrier, the 0X40-mediated destruction of iNKT cells, to achieve a synergistic effect that neither agent provides alone.
b.3 - Unexpected results and synergy regarding combination of aAVC and IL-15. Redmond (Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression, PLoS One, (2012)) demonstrates that IL-15 fails to upregulate OX40 expression and, the combination of OX40-directed therapy and IL-15 did not affect tumor growth or survival. Given this reported failure, a person of ordinary skill in the art would have had no reasonable expectation that IL-15 would successfully provide any synergistic benefit when combined with another immunotherapy platform, especially one involving the activation of iNKT cells which are concentrated in the liver. In addition, since iNKT cells are uniquely "poised" for death via the OX40/Caspase-1 pathway in the liver, the use of common gamma chain (gamma) cytokines like IL-15 (which are typically used to expand cells) remains highly unpredictable and risky in the context of aAVC. A combination of aAVC with IL-2 (or IL-15) achieves a surprising synergistic effect that exceeds the simple sum of individual components (see FIGS. 6-14 for IL-2 and FIGS. 9-14 for IL-15). This synergy is particularly unexpected because the prior art would lead one to expect antagonism (i.e., IL-2 promoting the death of the cells aAVC is trying to activate).
14. Applicant’s arguments have been considered but are not persuasive. In response to Applicant’s arguments:
- Regarding item (a), Lan teaches NKT cell pyroptosis and injury in the liver, where a high percentage of iNKT cells is found. However. Lan does not teach the % of iNKT cells found in the liver v. the % of iNKT cells found in the spleen, or if pyropoptosis and/or injury happens in the spleen as well (spleen is one of the limitations of claims 10, 26 and 28). Splenocytes are not hepatocytes and there is no evidence to conclude that the administration of an OX40 agonistic antibody would lead to the same outcome in the spleen compared to the outcome in the liver.
While Lan teaches OX40 triggers invariant NKT cell pyroptosis and liver injury, Lan is silent with respect to OX40 agonist in the spleen, as required by instant claim 10. Neither does Lan teach that the combination of Ox40 agonist and aAVC cannot be used for treatment of tumors. Silence does not constitute teaching away. Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005). Even assuming that Lan teaches away from the claimed invention, "[w]here the prior art contains 'apparently conflicting' teachings, each reference must be considered 'for its power to suggest solutions to an artisan of ordinary skill .... considering the degree to which one reference might accurately discredit another."' Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (quoting In re Young, 927 F2d 588, 591 (Fed. Cir. 1991)). Here, we find that a skilled artisan reviewing the prior art (see Claim Rejections - 35 USC § 103 above) as a whole would not have been dissuaded from combining the prior art disclosures of to arrive at the claimed invention. See, e.g., Dome Patent L.P. v. Lee, 799 F.3d 1372, 1381-1382 (Fed. Cir. 2015) (affirming conclusion that a skilled artisan would not have been dissuaded from making the claimed lens material because, even though one prior art reference warns of difficulty in using claimed materials, other references teach that such material could be used effectively).
Moreover, applicant argues that “stimulation of OX40 triggers "massive pyroptotic death" of these iNKT cells and OX40 agonists induce a "marked depletion" of iNKT cells in the liver (e.g., reducing the population from ~6% to ~0.6%)“. Applicant also discloses in Fuji Declaration: “Appendix A demonstrates that anti-OX40 monotherapy resulted in no increase in the number or ratio of NK cells (3.72 to 3.53) or iNKT cells (1.24 to 1.21)” in the spleen and these ratios are not statistically significant, which is not consistent with the "massive pyroptotic death" and "marked depletion" of iNKT cells (e.g., reducing the population from ~6% to ~0.6%)” found in the liver, as disclosed by Lan, where the reduction of the population appears to be statistically significant. Moreover, Fig 5 in the specification indicates the number and percentage of iNKT cells, in the spleen, in untreated mice, in the presence of aAVC alone and aAVC+OX40 antibody. No data is shown for the number of iNKT cells when the anti OX40 antibody is administered alone. However, the biggest increase of iNKT cells is seen in the combination treatment and not in the presence of aAVC alone which is just a bit higher than the untreated data. The Fig. 5 graph seems to indicate the anti OX40 antibody is not depleting the iNKT cells in the spleen and the aAVC monotherapy is not drastically increasing the number of iNKT cells. Therefore, the arguments that (1) an OX40 agonist would destroy iNKT cells in the spleen, that (2) OX40 and aAVC have an antagonistic MOA (a.1) and that (3) there is a destruction of the therapeutic platform (a.2) are not persuasive and Lan does not teach away from the claim invention.
- Regarding item (b), Applicant argues that the combination of aAVC and an OX40 agonist are unexpected due to a synergistic therapeutic effect. This combination is nonobvious because the prior art strongly discourages such a combination and fails to suggest the efficacy of 0X40 agonists in activating innate immunity.
However, and as discussed above, Lan does not teach away from the claim invention. One of ordinary skill in the art would have been motivated to combine aAVC with another immunostimulant as taught by all the prior art discussed above (see Claim Rejections - 35 USC § 103 above) which do not discourage the combination of these therapeutics.
b.1 - Applicant has not offered an explanation regarding the potential discrepancies between Fuji declaration, appendix A and the teachings of Weinberg and others that supports preclinical data in mice showing greatly enhanced immune responses with OX40 agonists that resulted in substantial antitumor activity in multiple murine tumor models and nonhuman primates data (see Claim Rejections - 35 USC § 103 above). The monotherapy treatment renders the combination therapy of aAVC with an OX40 agonist and/or IL2 and/or IL15 obvious. See MPEP § 2144.06. Art Recognized Equivalence for the Same Purpose [R-01.2024]; I. Combining Equivalents Known For The Same Purpose. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
b.2 – Fuji declaration, Appendix B shows a potential synergistic effect in the reduction of tumor size for the combination of aAVC with the BE0031anti-OX40 antibody in B16-HPV tumor cells. However, the BE0031anti-OX40 antibody does not mediate destruction of iNKT cells as discussed above (item (a) discussion) so there is no reason not to expect a synergistic effect. Moreover, the unexpected results described by Applicants are not commensurate in scope with the breadth of the claims as currently presented as the instant application claims any OX40 agonist (see 112a rejection above) and a size reduction in any tumor. MPEP 716.02(d) states: whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
b.3 - The combination of anti-OX40/IL-15c data provided by Redmond did not affect tumor growth. However, Redmond does not teach the outcome with the anti-OX40 alone or with aAVC, IL-15c alone or with aAVC or the combination of anti-OX40/IL-15c with aAVC which is a requirement of the instant claims and necessary to prove synergy. Applicant has not offered an explanation regarding the potential discrepancies between Redmond and Metelitsa’s teachings (see Claim Rejections - 35 USC § 103 above). That is, the expansion of CD62L+ NKT cells (which includes a subset of iNKT cells) can be achieved by stimulatory agents such as IL-2 and IL-15 [0012], and that the proliferation of CD62L+NKT cells is useful for immunotherapy of tumors. Applicant has not provided further information for the argument regarding to which prior art would lead one to expect antagonism (i.e., IL-2 promoting the death of the cells aAVC is trying to activate). Metelitsa does not discuss combination of anti-OX40/IL-15c which is not required by the instant application. Since IL-2 and IL-15 as monotherapy affect tumor growth, the monotherapy treatment renders the combination therapy obvious. See MPEP § 2144.06 discussion above.
FIGS. 6-14 for IL-2 and FIGS. 9-14 for IL-15 do not prove a surprising synergistic effect or unexpected results as the control data when administering IL-12 alone or IL-15 alone is not shown. Furthermore, a showing of unexpected results (synergy) must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). MPEP § 2145. A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). MPEP 716.02 (a). The evidence relied * > upon < should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). MPEP 716.02 (b). Applicant must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). MPEP 716.02 (b). Applicant has failed to provide evidence of unexpected additive or synergistic results when administering the combination of the aAVC cells with the IL-2 or IL-15 in comparison with the administration of the single components.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
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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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/ Supervisory Patent Examiner, Art Unit 1671