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 Claims
The amended claims filed 06/24/2026 are acknowledged and entered.
Claims 10, 26 and 28 have been amended
Claims 1-9 and 13-25 are cancelled
Claims 30-31 are new.
Claims 10-12 and 24-31 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Claim Objections - Withdrawn
The rejections for claim 10 are withdrawn in view of applicant’s amendment of the claim.
Rejections Maintained
Claim Rejections - 35 USC § 112 - Maintained
1. Claims 10-12 remain 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.
Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments:
- (a) The Applicant argues that:
1. The Specification describes a plurality of anti-0X40 agonist antibodies.
The Examiner stated that "the specification describes one agonistic antibody capable of binding to 0X40 species within the genus claimed (anti-0X40 antibody (product number: BE0031; manufacturer: BioXcell) [0057])." However, the specification is not limited to BE0031. The specification expressly discloses, in paragraph [0018] of the specification, the following anti-0X40 agonist antibodies by name: GSK3174998, MOXR0916, PF-04518600, and MEDI0562. In addition, the specification states, in the same paragraph, that anti-0X40 agonist antibodies described in the following international publications may be used: WO 2012/027328 A, WO 2013/028231 A, WO 2015/153514 A, and WO 2015/095423 A.
These antibodies were independently developed by different pharmaceutical companies with different CDR sequences and epitope specificities. These antibodies were developed by multiple independent research groups and pharmaceutical companies, demonstrating that the genus was well-characterized and that the specification discloses species that adequately represent the structural diversity of the genus
2. Identifying characteristics with known function-structure correlation.
The functional characteristic defining the genus is clear: an antibody that binds to 0X40 and exhibits agonist activity. The correlation between this function and the structural characteristics of such antibodies was well established in the art before the filing date of the present application. By the filing date, multiple anti-0X40 agonist antibodies had been developed to clinical stage by different pharmaceutical companies, with their structures (including CDR sequences) published in issued U.S. patents and patent applications, including but not limited to U.S. Patent No. 7,550,140 B2 (Janssen Vaccines and Prevention BV) and U.S. Patent Publication No. 2015/0307617 Al (F. Hoffmann-La Roche AG).
A person of ordinary skill in the art would have been able to identify and produce anti- OX40 agonist antibodies using well-known techniques
Further, the Federal Circuit's recent decision in Teva Pharmaceuticals International GmbHv. Eli Lilly & Company, No. 24-1094 (Fed. Cir. Apr. 16, 2026), further supports the adequacy of the written description here. In Teva, the court reversed a judgment of invalidity for claims directed to methods of treating headache using a genus of humanized anti-CGRP antagonist antibodies, even though the specification disclosed only one humanized species. The court held that, where a claim "pertains to a well-known genus that is not, itself, the invention," adequate written description may be found in the specification read together with the background knowledge in the art. Id., slip op. at 9; see also Ajinomoto Co. v. ITC, 932 F.3d 1342, 1359 (Fed. Cir. 2019); In re Herschler, 591 F.2d 693, 700-01 (CCPA 1979). Critically, the court rejected the argument that amino acid sequences had to be disclosed, reasoning that if a skilled artisan "possessed an anti-CGRP antagonist antibody, he or she could determine its amino acid sequence through known sequencing techniques." Id. at 15-16.
The same reasoning applies here: the claimed subject matter is not the anti-0X40 agonist antibody itself, but the therapeutic use of such an antibody, as described above. Anti-0X40 agonist antibodies were commercially available and their sequences publicly known as of the filing date of the present application. Accordingly, under Teva, the specification's disclosure of various anti-0X40 agonist antibodies satisfies the written description requirement for the amended claims.
Examiner’s Response to Arguments Applicant’s arguments have been carefully considered but are not found persuasive.
Applicant arguments are based on a group of anti-OX40 antibody agonists found in the art prior to the filing date of the claimed invention. This group is characterized as being OX40 agonist but there is no indication or further characterization offered by the applicant that any of these antibody agonist will bind to the same epitope, will show identical CDRs sequences and therefore showing identical activities or functions. As applicant has argued above: “These antibodies were independently developed by different pharmaceutical companies with different CDR sequences and epitope specificities”. The requisite function/activity as recited in claim 1 is: “treating tumors by inducing iNKT cells and CTL cells (when administered in conjunction with an artificial adjuvant vector cell (aAVC))”, the function is not being a OX40 antibody agonist. There is not any identification of any particular portion of a structure that must be conserved among these agonists for said tumor treatment activity.
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). This is not the case here. There are no identifying characteristics, being an OX40 agonist (binding OX40L exhibiting agonist activity), is not an identifying structure, physical or chemical characteristic that correlated to the “treating tumors by inducing iNKT cells and CTL cells (in conjunction with aAVC)” activity.
In Teva v. Eli Lilly, Teva’s claims were directed to a therapeutic method (“using anti-CGRP antagonist antibodies to treat headaches”). The genus was well known at the priority date (background knowledge in the art), and humanization was routine. Every member performs the same function within the method, so the scope is coextensive with the discovery. As discussed above, the instant claims are directed to “treating tumors by inducing iNKT cells and CTL cells (in conjunction with aAVC)”. However, applicant has not disclosed how every member of the OX40 antibody agonist genus (background knowledge of the art), is shown to function within the method as claimed so the scope is not coextensive with the discovery.
In addition, applicant’s arguments to traverse the written description rejection are based on the supposition that all these antibody agonist are representative of the same genus and consequently, must be capable of “treating tumors by inducing iNKT cells and CTL cells (in conjunction with aAVC)”. However, applicant’s arguments to traverse the 103 rejection (see below) are based on the supposition that the OX40 antibody agonist of Weinberg is not capable of “treating tumors by inducing iNKT cells and CTL cells (in conjunction with aAVC)”. Applicant has not provided any explanation as to why Weinberg’s antibody agonist is not a member of the OX40 antibody agonists genus listed above, when all of the antibodies listed above (as being representative species of the genus) and Weinberg’s are all OX40 antibody agonists.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Claim Rejections - 35 USC § 103 – Maintained
2. Claims 10-12 and 26-29 remain rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of 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).
Claims 10, 26 and 28 have been amended to add the limitation: “comprising intravenously administering to the subject an effective amount of an artificial adjuvant vector cell and an effective amount of an anti-0X40agonist antibody (claim 10); Interleukon-2 (IL-2) (claim 26) and IL-15 (claim 28)”. In claim 10, the limitation “OX40 activator” has been narrowed to “an anti-0X40agonist antibody”.
Fuji teaches that an aAVC is a cell that co-expresses a target antigen and CD1d, loaded with CD1d ligand [0008]. In Example 15, a mouse was immunized by intravenous administration of 5x105 cell of CD1dhi-NIH3T3/Gal-ova to evaluate the antitumor immunity [0224] or CD1dhi-NIH3T3/Gal-trp2 (tyrosinase-related protein 2 (trp2)) to evaluate adaptive antitumor response [0228], (NIH3T3 loaded with a-GalCer is referred as NIH3T3/Gal) [0208]), Since these cells are aAVC (they express CD1d and a target antigen and are loaded with a-GalCer) and are intravenously injected, the requirement is met for the aAVC.
Weinberg teaches the intravenous administration of anti-OX40 agonist antibody (page 580 second paragraph, In Vivo Stimulatory Effects of Anti-OX40: B-cell and T-cell Responses) as required by the amendment for the anti-OX40 agonist antibody.
Metetsila teaches that the pharmaceutical composition comprises a composition for parenteral, transdermal, intraluminal, intra-arterial, intrathecal or intravenous administration or for direct injection into a cancer [0075]. The composition can comprise CD62L-positive NKT cells are activated by stimulation of T-cell receptor and co-stimulation by co stimulatory receptors and/or cytokines [0010]. The cytokine is selected from the group consisting of IL-21, IL-2, IL-7, IL-15, IL-12, TNFalpha, and a combination thereof [0012]. In another embodiment, mice received intravenous injection of 2xl05 luciferase-transduced Daudi lymphoma cells (day 0) followed by (day 4) intravenous injection of 107 CAR.CD19-transduced NKTs with IL-2 (1000 U/mouse) [0019] as required by the amendment for IL-2 and IL-15.
Applicant’s arguments have been fully considered and are not persuasive. Therefore,
the rejections are maintained.
Applicant’s Arguments:
- (A) The wherein clauses are substantive limitations that must be given patentable
weight
1. The Federal Circuit recognizes a clear exception: "wherein" clauses that are
material to patentability must be given limiting effect.
The wherein clauses in the present claims fall squarely within the Hoffer/Allergan
exception. They are not generic statements of intended purpose. Rather, they recite the specific quantitative differential - an increase in splenic iNKT cells and antigen-specific CTLs compared to administration of aAVC alone that distinguishes the claimed combination method from the prior art aAVC-only methods of Fujii and others. This differential is a critical aspect of the claimed methods; it is a technical contribution that the specification describes and that Applicant relies upon in this response. Under Allergan, that is precisely the circumstance in which "wherein" clauses must be given patentable weight.
2. The wherein clauses define the claimed method, not merely its intended result.
The wherein clauses are not mere descriptions of an outcome; they define the scope of the term "effective amount" recited in the positive method steps. The claim recites administration of "an effective amount" of aAVC and "an effective amount" of an anti-0X40 agonist antibody. The wherein clauses give specific meaning to the term "effective amount" in this context: the amounts of each component must be sufficient to produce an increase in splenic iNKT cells and CTLs compared to administration of aAVC alone. This use of wherein clauses to define the operative scope of positively recited steps is precisely the kind of "wherein" language that the Federal Circuit has held must be given patentable weight. See Griffin v. Bertina, 285 F.3d 1029, 1033 (Fed. Cir. 2002) (wherein clauses that "relate back to and clarify what is required" and give "meaning and purpose to the manipulative steps" are limiting); Allergan Sales, LLC v. Sandoz, Inc., 935 F.3d 1370 (Fed. Cir. 2019).
3. When the wherein clauses are given their proper patentable weight, no prior art
reference teaches or suggests them.
None of Fujii, Weinberg, Metelitsa, Boyman, Stoklasek, or Linch teaches or suggests that the combination of aAVC and an anti-0X40 agonist antibody results in an increase in splenic iNKT cell numbers compared to aAVC alone, or an increase in antigen-specific CTL numbers compared to aAVC alone. The combination of these references therefore does not render the claimed invention obvious when the wherein clauses are given their proper limiting effect.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
- (A) As explained in more detail in the previous office action dated 02/09/2026; Fuji teaches two doses of aAVCs were given with a low dose of 5x106 cells and a high dose of 5x107 cells [0045 and 0233] (effective aAVC amounts of instant claims 10, 26 and 28). Weinberg that 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. Metetsila teaches an intravenous injection of 107 CAR.CD19-transduced NKTs with IL-2 (1000 U/mouse as effective dose) [0019] as required by claim 26 and Stoklasek teaches the results from Mice when given 1 ×105 B16-F1 cells intravenously. (day 0), followed by two doses of either PBS or IL-15 (2.5 μg), (figure 11) as required by claim 18.
Regarding the argument about the amounts of each component must be sufficient to produce an increase in splenic iNKT cells and CTLs compared to administration of aAVC alone, please refer to the discussion about Kerkhoven below.
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”. Arriving at the effective amounts to treat tumor with the method above would be achieved with no more than routine experimentation, identifying doses. In addition, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Therefore, a method of treating tumor with the method of Fuji and Weinberg is obvious here and the effective amounts of the claims for treating tumor are equally obvious. Since the method is obvious, and the combined prior art meets all the method steps (including the induction of splenic iNKT cells and antigen-specific CTLs in a subject), the wherein clauses reciting only intended results are necessarily met even if they were given patentable weight, which they are not.
Applicant’s Arguments:
(B) No motivation to combine: 0X40 agonist antibodies are not useful alone for inducing iNKT cells in the spleen, and may actively undermine aAVC's mechanism
The Examiner relies on In re Kerkhoven for the proposition that combining compositions taught to be useful for the same purpose is primafacie obvious. However, this principle requires that the prior art teach the components to be useful for the specific purpose of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007). Here, the prior art does not support such a motivation.
1. OX40 agonist antibodies are not useful for the purpose of increasing splenic iNKT cells when used alone.
The claims are specifically directed to a method that induces iNKT cells in the spleen.
The prior art does not teach that 0X40 agonist antibodies are useful for this specific purpose. To the contrary, and as acknowledged by the Examiner on page 23 of the Office Action, the evidence shows that 0X40 agonist antibody monotherapy had no effect on splenic iNKT cells (see Appendix A of the previously submitted Declaration). If the 0X40 agonist antibody is not useful for the specific purpose of inducing splenic iNKT cells, then Kerkhoven provides no motivation to combine it with aAVC for that purpose.
2. OX40 agonist antibodies expand immunosuppressive Tregs in the spleen, which
is counterproductive to aAVC's mechanism. Ruby et al., "Cutting Edge: OX40 Agonists Can Drive Regulatory T Cell Expansion if the Cytokine Milieu Is Right," J. Immunol. 2009;183(8):4853-4857 demonstrated that systemic administration of an OX40 agonist antibody to naive mice resulted in approximately four-fold expansion of CD4+FoxP3+ regulatory T cells (Tregs) in the spleen in a dose-dependent manner (Fig. 2A, 2B). Critically, these expanded Tregs retained their suppressive function, as confirmed by suppression assays (Fig. 2E).
Tregs are immunosuppressive cells that dampen immune responses. The therapeutic
efficacy of aAVC depends on the activation of immune responses-specifically, through iNKT cell activation that leads to dendritic cell maturation and subsequent induction of antigen-specific CTLs. A person of ordinary skill in the art would have recognized that OX40 agonist antibody administration would expand functional Tregs in the spleen, potentially suppressing the very immune response that aAVC is designed to activate. In the spleen, OX40 agonist antibodies (i) do not enhance iNKT cell numbers and (ii) expand immunosuppressive Tregs that retain their suppressive function. Neither teaching provides any motivation to combine an OX40 agonist antibody with aAVC for the purpose of inducing iNKT cells and CTLs.
Examiner’s Response: Applicant’s arguments have been carefully considered but are not found persuasive as discussed supra.
(B) Kerkhoven cites that “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…” Both aAVC and the OX40 agonist antibody stimulate CTLs and thus it would be obvious to combined them even if the aAVC additionally induces iNKT cells. The purpose is the same for the mono- and combination therapies: treating cancer tumors as explained in more detail in the previous office action.
In addition, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Rubi teaches that OX40 stimulation drives all lineages of CD4 T cell development including Treg and the plasticity of the response is dependent on local cytokines. That is, OX40
signaling can augment the accumulation of all CD4 T cell lineages; however its accentuation of
immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu (abstract). Ligation of OX40, a costimulatory molecule transiently expressed on recently activated T cells, is known to augment effector T cell expansion, function, and survival (introduction first line) and OX40 stimulation at priming has also been shown to boost cancer vaccine responses (page 6, 1st paragraph). Therefore Rubi does not contradict the teachings of Weinberg as the expansion of functional Tregs is clearly dependent on the local cytokines, and the OX40 pathway induces also the expansion of effector T cells. Rubi teaches that OX40 stimulation boost anticancer vaccine responses. OX40 agonist antibody, by definition, stimulates the OX40 pathway. Weinberg teaches us that the stimulation also includes CTLs so there is no reason to assume that a person of ordinary skill in the art would not combine an OX40 agonist antibody with aAVC to induce an iNKT cell and CTL responses. In addition, applicant is referred to the discussion above regarding the 112a written description rejection.
The reason or motivation to combine the references may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Applicant’s Arguments:
(C) No Reasonable Expectation of Success
1. The prior art teaches conflicting effects of OX40 agonist antibodies on iNKT cells.
The prior art available before the filing date provided no consistent guidance on the effect of OX40 agonist antibodies on iNKT cells. Lan et al. (Exhibit A, submitted with the prior response) teaches that OX40 stimulation triggers pyroptotic death of iNKT cells (in the liver). Applicant's Appendix A of the previously-filed Fujii Declaration shows that OX40 agonist antibody monotherapy had no effect on splenic iNKT cells. No prior art teaches that OX40 agonist antibodies enhance iNKT cell numbers. Faced with these conflicting and negative teachings, a person of ordinary skill could not have had a reasonable expectation that the addition of an OX40 agonist antibody to aAVC would increase splenic iNKT cell numbers compared to aAVC alone.
2. The prior art affirmatively teaches a mechanism by which the combination could fail. Exhibit C, submitted herewith, teaches that OX40 agonist antibodies expand functional immunosuppressive Tregs in the spleen. This teaching provides an affirmative reason to expect that the combination of aAVC and an OX40 agonist antibody could fail to enhance-or could even suppress-the immune response that aAVC is designed to activate.
3. The immunotherapy field is unpredictable, and combinations of immunostimulants do not inevitably produce additive or synergistic effects. Applicant's previously-filed Exhibit B (Redmond et al., PLoS One, 2012) demonstrates that the combination of OX40-directed therapy and IL-15 did not affect tumor growth or survival-direct evidence that combinations of immunostimulatory agents do not inevitably produce additive or synergistic effects. The Examiner's general assertion that combining immunostimulants produces "at least additive" effects is therefore not supported as a generalized expectation in this art.
The complex, context-dependent biology of OX40-illustrated by Weinberg's own contradictory findings between 2006 and 2009-further underscores the unpredictability of the field. Under these circumstances, a reasonable expectation of success in achieving the specific results recited in the claims is lacking.
Examiner’s Response to Arguments Applicant’s arguments have been carefully considered but are not found persuasive.
(C) The prior art available before the filing date provided no consistent guidance on the effect of OX40 agonist antibodies on iNKT cells.
(1) Regarding Exhibit A please refer to the arguments in the previous office action when exhibit A was submitted.
(2) Regarding Rubi, please refer to the arguments above.
(3) Regarding Redmond, the immunotherapy field is unpredictable, and combinations of immunostimulants do not inevitably produce additive or synergistic effects, please refer to the arguments when exhibit B was submitted and the arguments about Kerkhoven and MPEP § 2144.06 discussions in the previous office action.
In view of the successes of the prior art, an absolute guarantee of success is not required to establish a prima facie case of obviousness under MPEP § 2143; instead, a reasonable expectation of success is all that is required
Applicant’s Arguments:
(D). The Examiner's analysis reflects impermissible hindsight
The Examiner's rejection requires combining six prior art references (Fujii, Weinberg, Metelitsa, Boyman, Stoklasek, and Linch) to arrive at the claimed invention. No single reference, and no subset of these references, teaches or suggests combining aAVC with an OX40 agonist antibody. The selection of these specific references from the vast immunotherapy literature, and their assembly into the claimed combination, appears to have been guided by knowledge of Applicant's invention-a hallmark of impermissible hindsight reconstruction. See In re McLaughlin, 443 F.2d 1392 (CCPA 1971); MPEP § 2142.
This concern is reinforced by the fact that in the approximately seven years between the publication of Fujii (2013) and Applicant's filing date (2020), no prior art reference appears to have attempted or suggested combining aAVC with any immunostimulant, much less an OX40 agonist antibody. If the claimed combination were truly obvious-much less "painfully obvious"-one would expect to find evidence of such a combination, or at least a suggestion of it, in the literature predating the filing.
Examiner’s Response to Arguments Applicant’s arguments have been carefully considered but are not found persuasive.
(D) In response to Appellants’ argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed below, there is ample motivation to combine the references independent of the inherent feature. Lack of research between 2013 and Applicant's filing date of 2020 is irrelevant for an obviousness finding. In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Double Patenting - Maintained
3. Claims 1, 3-4, 9 and 11 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 6 of U.S. Patent US 10,980,874 B2 ((reference patent) which is a CON of US 10,751,411B2 which is a CON of US 10,391,165, which is a CON of US. 9,999,665) in view of Ligas (J Virol, May 1988, p. 1486-1494) and Xu (Rev Med Virol. 2019; 29: e2054).
Applicant’s Arguments:
Each of the above double patenting rejections is based on the combination of the claims of the copending applications or issued patents with the same six prior art references (Fujii, Weinberg, Metelitsa, Boyman, Stoklasek, and Linch) relied upon in the § 103 rejection. Since, as set forth in detail above, the combination of these references does not render the present claims obvious-for lack of motivation to combine, lack of a reasonable expectation of success, and impermissible hindsight reconstruction-the double patenting rejections based on those references are likewise improper and should be withdrawn for the same reasons.
Examiner’s Response to Arguments Applicant’s arguments have been carefully considered but are not found persuasive.
The §103 rejection combining the references listed above has been maintained and thus the double patenting rejections based on those references is proper and is maintained for the same reasons.
New Rejections Based on New Claims
Claim Rejections - 35 USC § 103
4. The claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over under 35 U.S.C. 103 as being unpatentable over the combined teachings of 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) Pillai (US2017/0029777A1) Publication date Feb. 2 2017) and Conlon (J Clin Oncol 33, 74-82(2015)).
The teachings Fuji, Weinberg, Metelitsa, Stoklasek, and Linch have been discussed in previous Office Actions and incorporated herein in their totally.
In addition, Metelitsa teaches the step where NKTs are stimulated with aGalCer-loaded Ramos cells in IL-2 containing media for 10 days and the step where NKTs are stimulated with aGalCer loaded PBMCs and IL-2 (100 U/ml) for 12 days [0124]. Another embodiment teaches mice received intravenous injection of 2xl05 luciferase-transduced Daudi lymphoma cells (day 0) followed by (day 4) intravenous injection of 107 CAR.CD19-transduced NKTs with IL-2 (1000 U/mouse) [0019]. These teaching reads on a period of time of 10 days or 12 days for cells to be exposed to IL-2 or after 4 days of injecting the cells.
Pillai teaches methods of producing ex vivo natural killer T (NKT) cells, and therapeutic uses thereof for treatment of certain conditions including cancer, autoimmunity, inflammatory disorders, allergic disorders, tissue transplant-related disorders, and infections. One step of these methods includes stimulating harvested cells with (i) a glycolipid or a CD1 reagent, (ii) IL-2, and (iii) IL-7 [0042] ; conducted for 2 to 14 days. In one specific embodiment, this step is conducted for 7 days [0060], [0085], [0158], claims 1 and 13). These teachings read on a period of time of 2 -14 days, including 7 days for cells to be exposed to IL-2.
In addition to the teaching incorporated herein, Stoklasek teaches an adoptive transfer model to gauge the effect of IL-15 on the proliferation of CD8 T cells. CD45.1 CFSE-labeled CD8-enriched splenocytes were transferred to normal CD45.2 mice that were then treated with PBS, IL-15 alone (2.5 μg), IL-15Rα (15 μg), or a mixture of IL-15 (2.5 μg) and IL-15Rα (15 μg). Results were measured four days after treatment with IL-15 alone (Page 4 Coadministration of IL-15 and IL-15Rα drives CD8 memory T cell and NK cell proliferation in vivo).
Conlon teaches that IL-15 has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. A trial was conducted to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy (purpose). This reads on a period of time of 12 days for cells to be exposed to IL-15.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Fuji, Weinberg, Metelitsa, Stoklasek, and Linch with Pillai and Conlon to determine an starting administration regimen for IL-2 and IL-15 and from the starting regimen to arrive to an optimized regimen with the optimal schedule for the administration of either IL-2 and/or IL-15. That is, it would be obvious that the compound dosages in a composition, days needed before administration, days and frequency of administration and related regimen parameters are 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 optimal regimen 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.
One of ordinary skill would have been motivated to do so because Metelitsa, Stoklasek, and Linch with Pillai and Conlon cited above teach the stimulation of the immune responses leading to an overall increase of cancer treatment efficacy. There would be a reasonable expectation of success because separately, aAVC cells, OX40 agonist, IL2 or IL15 or are known to stimulate the immune system individually. It would be expected that a combination of both the aAVC with these immunostimulant would have at least an additive effect on the successful stimulation of an immune response as it is seen in most combination treatments.
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.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IMMA BARRERA whose telephone number is (571) 272-0674. The examiner can normally be reached Monday - Friday 9 to 5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached on (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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