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 .
Applicant’s remarks, filed 1/21/2026, are acknowledged and entered into the record. Applicants amended claims 1 and 17, and canceled claim 4, in the remarks of 1/21/2026.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/21/2026 has been entered.
Priority
The instant application is a request for continued examination (RCE), filed 3/17/2025.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/304,955, filed 1/31/2022.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-27) in the reply filed 3/25/2024 is acknowledged. Claims 28-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/25/2024.
Status of Claims
Claims 1-3, 8-19 and 22-29 are pending. Claims 28-29 are withdrawn. Claims 1-3, 8-19 and 22-27 are being examined on the merits.
Claim Objections
Claims 1 and 17 are objected to because of the following informalities: Claim 1 recites “CRS” without defining the abbreviation in its first use. Claim 17 recites “cytokine release syndrome (CRS)”. CRS should be defined in its first use, in claim 1, and not re-defined upon its subsequent use, in claim 17. 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.
Claim 13 is 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 13 recites “wherein the administering comprises oral delivery or intravenous injection delivery.” Claim 13 depends from claim 1 which recites administering a bispecific antibody and administering a first pharmaceutical composition. It is unclear whether “the administering” of claim 13 is referring to that of the bispecific antibody or the first pharmaceutical composition, or both. Thus, the metes and bounds of the claim are unclear.
Claim Rejections – Maintained
The following rejection has been amended in view of applicant’s amendments to the claims, whereby claims 1 and 17 were amended to include the limitations of now canceled claim 4.
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 8-19 and 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over Topp et al., (Journal of Clinical Oncology, 2014, 32(36)) and Faulds et al., (from IDS; US 20140275237; published 9/18/2014).
Topp et al. teaches a phase II trial of Blinatumomab, which is an anti-CD19/CD3 bispecific T cell-engager (BiTE) antibody, for treating patients with B-precursor acute lymphoblastic leukemia (ALL; abstract). Topp teaches that multiple cohorts received treatments with Blinatumomab. Specifically, “the dose of 15 ug/m2 per day was evaluated in the first cohort (cohort 1);” and that “because of grade 4 cytokine release syndrome (CRS) in one patient, a treatment prephase with dexamethasone up to 24 mg for up to 5 days and/or 200 mg/m2 of cyclophosphamide for up to 4 days was permitted,” (pg. 3, para. 2). Further, “in addition, in the second cohort (cohort 2a), the initial dose in the first week of treatment was lowered to 5 ug/m2 per day and then increased to 15 ug/m2 per day,” (pg. 3, para. 2). Topp teaches that within cohort 1, patients showed the highest rates of AEs overall and of SAEs; and one patient developed grade 4 CRS, and was replaced (pg. 5, para. 1). Topp teaches two patients (across cohorts) had grade 4 CRS; a treatment prephase consisting of dexamethasone and cyclophosphamide was recommended thereafter, and no incidence of grade > 3 CRS was reported during the remainder of the study (pg. 12, para. 1). Topp concludes, “Clinically important AEs of specific interest included CRS; recently, administration of an anti-interleukin-6 antibody was described as a feasible approach for the management of CRS in patients treated with CD19 CAR-modified T cells. In our study, stepwise dosing, along with prephase treatment seemed to be successful in the prevention of severe CRS,” (pg. 13, para. 2).
Thus, Topp teaches that a single administration of 15 ug/m2 per day dose of the bispecific antibody Blinatumomab can induce CRS, and that, subsequently, efforts were made to alter the dosing regime in order to mitigate CRS in response to Blinatumomab. Topp also teaches the art of administering an anti-IL-6 antibody as a means of managing CRS in patients treated with CD19-binding T cell constructs analogous to the CD19 BiTE of the invention. Thus, Topp provides motivation to the skilled artisan to devise strategies to mitigate CRS in response to Blinatumomab, including subsequent treatment with an additional agent to ameliorate CRS once it has been induced. However, Topp does not teach administration of beraprost.
Faulds et al. teaches the use of beraprost as a therapeutic for the treatment of viral disease and other pathologies associated with the induction of a cytokine storm (abstract). Faulds teaches a cytokine storm as an activated immune system response in which large amounts of pro-inflammatory cytokines, such as INF-γ and IL-6, are released (pg. 1, para. 0004); and is also termed hypercytokinemia (para. 0005). Faulds teaches “in various embodiments a therapeutic agent is provided that inhibits the release of overstimulated cytokines and chemokines, especially INF-γ,” (pg. 1, para. 0011); and that “it was discovered that specific GPCR agonists, such as beraprost sodium are a potent inhibitor of the hypercytokinemia,” (pg. 1, para. 0012). Faulds teaches that cytokine storms can occur in a number of infectious and non-infectious diseases, including graft versus host disease, sepsis, systemic inflammatory response syndrome, and others; and that the (beraprost) therapeutic compositions may be used in the treatment and/or prophylaxis of any of these pathologies (pg. 5, para. 0221). Thus, Faulds teaches that beraprost may be used to treat CRS, generally, and regardless of the pathology that initiates CRS. Faulds teaches beraprost in pharmaceutical formulations (pg. 6, para. 0115), and administration of beraprost formulations in a method for treating a cytokine storm (pgs. 13-14, claims 1 and 10-14).
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Topp to include administration of a pharmaceutical composition of beraprost for mitigating CRS. One would have been motivated to do so given the suggestion by Topp that mitigating CRS is an important consideration when administering the bispecific antibody Blinatumomab, especially when administered at high initial doses. There would have been a high expectation of success given the knowledge that administration of a pharmaceutical composition of beraprost is effective in inhibiting a cytokine storm (i.e. treating CRS) in response to a viral infection, as taught by Faulds et al. Thus, 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 the combination of Topp and Faulds makes obvious a method of administering beraprost in order to inhibit CRS resulting from administration of a bispecific antibody directed toward cancer immunotherapy (i.e. as a cancer treatment; claims 1-16), it stands to reason that the same obviousness would apply to methods to administer beraprost for treatment of CRS itself (i.e. as a non-cancer CRS treatment), wherein the CRS is induced by administration of any bispecific antibody to a subject (re. claims 17-27).
Regarding claims 1 and 17, the combination of Topp and Faulds teaches a method of treating cancer (or CRS) in a subject, comprising administering a single CRS-inducing dose of a bispecific antibody and an additional pharmaceutical composition comprising beraprost (including BPS-314d), as described above. Faulds teaches administration of beraprost specifically for suppression of a cytokine storm, regardless of the insult that initiates the cytokine storm, as beraprost is a GPCR agonist that suppresses production of cytokines. Faulds teaches “for a treatment of a patient having a pathology characterized by a cytokine cascade, the dosage of the composition comprising a beraprost isomer (e.g., beraprost isomer A (BPS-314d)) will be that amount that is effective to treat the pathology such as a viral disease (the “effective amount”) and/or to partially or fully inhibit the cytokine cascade, e.g., as indicated by the production of a pro-inflammatory cytokine such as INF-γ, and/or CCL2, and/or IL-6,” (pg. 9, para. 0155). It is obvious to optimize the dose of beraprost to treat the excessive cytokine cascade of CRS by partially, but not fully, inhibiting the cytokine cascade in a manner that allows for T cells to maintain killing of the cancer cells. MPEP section 2144.05 (II)(A) discusses the obviousness of routine optimization. “Where 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.” T cells kill cancer cells via multiple mechanisms; for example Topp teaches the bispecific antibody, Blinatumomab, transiently induces a cytolytic synapse between a cytotoxic T cell and the cancer cell target; consequently, granzyme-containing granules and the pore-forming perforin fuse with the T-cell membrane and discharge their toxic content (pg. 2, Introduction). Thus, the release of cytokines is not an exclusive mechanism for inducing cancer cell death. This is evidenced by the instant specifications (Experiment 12, pg. 50, para. 00245), which teaches that BPS-314d (i.e. CTO1681; esuberaprost; specs. pg. 22, para. 0092) reduces cytokine levels, but does not impact or interfere with the tumor/ target cell killing effect of CD19-directed CAR-T cells (pg. 51, para. 00248). Thus the prior art composition of Faulds would not be expected to reduce T cell-mediated cell killing by more than 5% given the instant spec teaches that it is an inherent property of BPS-314d, at doses up to 225 nM (see Figures 1A-1G), to reduce cytokine release but not reduce T cell-mediated target cell killing by more than 5%. Further, as Faulds teaches that administering beraprost reduces IL-6 and IFN-γ (pg. 13, claim 1), as well as TNF-α (Pg. 10, example 3, para. 0167), it is an inherent property that BPS-314d would dose-dependently reduce levels of IL-6, TNF-α and IFN-γ (see instant Figures 1A-1G). Thus the combination of Topp and Faulds makes obvious the methods of instant claims 1 and 17.
Regarding claims 2 and 18, Topp further teaches administering an anti-IL-6 antibody is a feasible approach for management of CRS (pg. 13, para. 2) and thus makes obvious administering a second pharmaceutical composition of claims 2 and 18.
Regarding claims 3 and 19, Faulds teaches wherein the therapeutic agent (beraprost) is effective at partially or fully suppressing the cytokine storm characterized by release of large amounts of IFN-γ, IL-10 or IL-6 (‘237; pg. 13, claims 1 and 10; see also pg. 13, Table 9, for examples of beraprost effectively reducing cytokines).
Regarding claims 8-10, 12, 22-25 and 27; the combination of Topp and Faulds makes obvious the method of treating cancer (or CRS) in a subject comprising administration of a bispecific antibody and an additional therapeutic composition comprising beraprost, as described above. Topp teaches alternative prephase treatments (dexamethasone and/or cyclophosphamide) to prevent CRS; and suggests administering an anti-IL-6 antibody after administration of the bispecific antibody to treat CRS once it has been detected. Faulds teaches the administration of beraprost may be used in the treatment or prophylaxis of CRS; with treatment being directed to administering beraprost after onset of virally-mediated CRS. Thus, each of Topp and Faulds contemplate strategies whereby the beraprost may be provided before, concurrently or after the administration of the CRS-inducing dose of a bispecific antibody. As described above, the MPEP teaches routine experimentation for optimizing protocols are obvious where the general conditions of the claim are disclosed in the prior art (MPEP Section 2144.05(II)(A)). Faulds teaches beraprost binds GPCRs to inhibit cytokine release, which is downstream of, and regardless of, the insult that initiates CRS. Thus, it would be obvious to a skilled artisan to administer beraprost concurrently with administration of a CRS-inducing dose of a bispecific antibody, as a prophylaxis, in order to prevent the occurrence of CRS; likewise it is obvious to administer beraprost for treatment, after CRS has been induced and/or detected. Thus, claims 8-10, 12 and 22-25, whereby the order of administrating the CRS-inducing dose of a bispecific antibody relative to the beraprost CRS treatment are varied, are obvious modifications that would result from routine optimization of the general protocol of the combination of Topp and Faulds. Further, as administration of beraprost as a prophylactic, whereby it is administered concurrently with the administration of the CRS-inducing dose of a bispecific antibody, and prevents the excessive release of cytokines, it naturally flows from concurrent administration that the subject does not experience CRS; and thus claim 27 is also made obvious.
Regarding claim 11, the combination of Topp and Faulds makes obvious the method of treating cancer (or CRS) in a subject comprising administration of a therapeutic composition comprising beraprost, as described above. Faulds further teaches the administration of the composition comprising beraprost for the treatment of CRS in a mouse model of lethal influenza, wherein the beraprost composition is administered for 6 days (pg. 13, example 8, paras. 0187-0189).
Regarding claim 13, Faulds teaches the administration of the beraprost composition via a route selected from inhalation, transdermal, intravenous, subcutaneous, or oral administration (pg. 14, claim 23).
Regarding claims 14-16, the combination of Topp and Faulds makes obvious the method of treating cancer (or CRS) in a subject comprising administration of a bispecific antibody and an additional therapeutic composition comprising beraprost, as described above. Topp teaches the bispecific antibody of the cancer immunotherapy is Blinatumomab (re. instant claim 15), which is a CD19-CD3 bispecific antibody, or BiTE (re. instant claim 16); and functions through the recruitment of T cells (pg. 2, Introduction). Thus, the antibody of the invention has a mechanism of action of recruitment and activation of immune cells (re. instant claim 14).
Regarding claim 26, the combination of Topp and Faulds makes obvious the method of treating CRS in a subject comprising administration of a bispecific antibody and an additional therapeutic composition comprising beraprost, as described above. Faulds further teaches the treatment of CRS resulting from a lethal dose of influenza virus, termed the mouse lethal challenge influenza model (pg. 11, example 4, para. 0168). In example 8 (pg. 13, para. 0187), said mice were separated into treatment groups to determine the efficacy of a beraprost composition in inhibiting cytokine release resulting from influenza virus challenge. Table 9 (pg. 13, Example 8, beraprost vs PSS groups vs uninfected groups) shows that treatment with a beraprost composition reduced the concentration of cytokines CCL2, IFN-γ, IL-6 and IL-10 (associated with CRS) compared to the placebo group (re. claim 26) or the uninfected group, which did not show CRS. It would have been obvious to one of skill in the art to utilize influenza virus injections rather than bispecific antibody administration as a means to induce CRS for the purposes of treating the symptoms of CRS with a beraprost composition. There would have been a reasonable expectation of success as CRS (i.e., cytokine storm or hypercytokinemia) is a systemic inflammatory response that can be triggered by a variety of factors including T cell activating immunotherapies, or by viral infection, as taught by Faulds (pg. 1, para. 0004).
Response to Arguments
Applicant's arguments filed 1/21/2026 have been fully considered but they are not persuasive. Applicants contend that Topp does not teach a CRS-inducing amount of a bispecific antibody in a single administration, rather that Topp teaches away from a single high dose administration by implementing a stepwise dosing, specifically to prevent CRS (remarks, pg. 10, paras. 1-2). Applicants contend that the single administration, cohort 1, of Topp relies on a continuous 4-week infusion of blinatumomab, and that this infusion regime is fundamentally different from a single administration as recited in the claims, is different from a single bolus administration, and is opposite of a single administration (remarks, pg. 10, para. 3-4). Applicants contend that the office fails to consider Topp as a whole, such that the methods of Topp are designed to prevent CRS through stepwise dosing strategy, and that stepwise dosing is Topp’s solution to the CRS problem (pg. 11, paras. 2-3).
In response the examiner contends that Topp teaches various strategies for administering blinatumomab and addressing CRS, and presenting various alternative solutions to a problem is not equivalent to teaching away. MPEP section 2144 discusses supporting a rejection under 35 U.S.C. 103, including Implicit Disclosure (section 2144.01). The MPEP states “in considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” The disclosure of Topp teaches administering blinatumomab, a CD19/CD3 bispecific antibody, for the treatment of acute lymphoblastic leukemia (ALL), can induce CRS in some patients. Topp teaches “different blinatumomab administration regimes were explored,” (pg. 2, Introduction, last line). As described above, Topp discloses “the dose of 15 ug/m2 per day was evaluated in the first cohort (cohort 1);” and that “because of grade 4 cytokine release syndrome (CRS) in one patient, a treatment prephase with dexamethasone up to 24 mg for up to 5 days and/or 200 mg/m2 of cyclophosphamide for up to 4 days was permitted,” (pg. 3, para. 2). Further, “in addition, in the second cohort (cohort 2a), the initial dose in the first week of treatment was lowered to 5 ug/m2 per day and then increased to 15 ug/m2 per day,” (pg. 3, para. 2). Thus, different cohorts of Topp received different methods of administering blinatumomab, whereby each cohort ultimately receives 15 ug/m2 per day, which is the goal of the cancer treatment method. Topp teaches that within cohort 1, patients showed the highest rates of AEs overall and of SAEs; and one patient developed grade 4 CRS, and was replaced (pg. 5, para. 1). Topp teaches two patients (across cohorts) had grade 4 CRS; a treatment prephase consisting of dexamethasone and cyclophosphamide was recommended thereafter, and no incidence of grade > 3 CRS was reported during the remainder of the study (pg. 12, para. 1). Thus, the disclosure of Topp infers a solution to CRS includes a prephase treatment with dexamethasone. Topp concludes, “Clinically important AEs of specific interest included CRS; recently, administration of an anti-interleukin-6 antibody was described as a feasible approach for the management of CRS in patients treated with CD19 CAR-modified T cells. In our study, stepwise dosing, along with prephase treatment seemed to be successful in the prevention of severe CRS,” (pg. 13, para. 2). Thus, Topp also teaches anti-IL-6 antibodies, and/or stepwise dosing as alternative solutions for management of CRS. It is implicit in the disclosure of Topp that administration of higher doses of blinatumomab is likely to induce CRS (as it did in cohort 1) and that strategies to mitigate the CRS need to be considered when administering the bispecific antibody therapy. Topp implemented or inferred several different strategies consistent with this implicit teaching including (a) pre-treating patients with either dexamethasone or cyclophosphamide (cohort 1), (b) utilizing one of 2 different step-wise dosing strategies (cohorts 2a and 2b), where the goal was to eventually get to high dose blinatumomab administration without inducing CRS; or (c) administering anti-IL-6 antibodies as an alternative strategy for the management of CRS once induced, which Topp teaches as an art-recognized solution to CRS. MPEP section 2143 provides examples of rationales that may support a conclusion of obviousness, including section 2143(I)(C)- use of known techniques to improve similar methods in the same way; and 2143(I)(D)- applying a known technique to a known method ready for improvement to yield predictable results. In this case, the known technique, strategies for mitigating CRS upon administration of a bispecific antibody therapy, is applied to similar methods, whereby the method of Topp administers either a single dose (cohort 1) or a stepwise dose (cohorts 2 and 3) of bispecific antibody therapy which induces CRS. In either case, the necessary CRS is induced, for which Topp suggests various strategies for mitigating. The limitation of a single CRS-inducing administration of a bispecific antibody is reduced to practice in cohort 1 of Topp. Implicit in the disclosure of Topp is that administration of high doses of bispecific antibody therapy is feasible, but may cause CRS; and Topp infers that strategies to mitigate CRS should be considered. Topp teaches that dexamethasone and/or anti-IL-6 antibody administration are two such approaches, and/or using a stepwise dosing regimen to prevent CRS from occurring. Topp does not teach that a single administration of high dose blinatumomab cannot be administered, thus Topp does not teach away from administering a single high dose. Thus, the disclosure of Topp, considered as a whole, discloses alternative solutions to the CRS problem, including a single administration of high dose blinatumomab combined with an agent for preventing CRS, and/or a stepwise dosing strategy as a solution to the CRS problem. MPEP section 2141.02(VI) teaches “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.” Here Topp ultimately promotes the benefits of a step wise dosing strategy to reduce overall AEs that may arise with a high dose administration, but also discloses dexamethasone and/or IL-6 antibody administration for managing CRS that may arise from a single dose blinatumomab administration. Thus, applicant’s contention that Topp is not considered as a whole, or that Topp teaches away from a single CRS inducing administration is unpersuasive.
Regarding applicant’s contention that a continuous 4-week infusion is fundamentally different from a single administration, as recited in the claims. The claims do not recite a “single bolus” administration; further, the specifications do not describe or define a single bolus administration. Thus it is unclear what dose/route/duration parameters qualify as a single bolus administration. Rather, the specifications describe “bispecific antibodies are typically delivered by infusion in one administration, although multiple administrations are also possible,” (specs., pg. 16, para. 0068). Topp teaches a single continuous infusion administration over 4 weeks. Thus the “single administration” limitation of the claims is broadly defined as “infusion in one single administration,” and encompasses varying durations of the single administration. Therefore the single continuous administration of Topp, which is consistent with the art of administering bispecific antibody therapy for treating cancer, is encompassed by the claim limitations; and applicant’s contention that it is the opposite of a single administration is unpersuasive.
Applicants contend that Faulds does not cure the deficiencies of Topp because Topp does not teach a single administration of a CRS-inducing amount of a bispecific antibody, and Faulds does not teach bispecific antibodies at all (remarks, pg. 11, para. 4). Further, applicants contend that Faulds does not teach T cell mediated killing of cancer cells, and thus does not teach dose-dependent reduction of cytokines in the context of bispecific antibody therapy (remarks, pg. 11, last paragraph – pg. 12, top paragraph).
In response to applicant's arguments against the references individually, 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). The rejection of the current method is based on the combination of Topp and Faulds, whereby Topp teaches administering dexamethasone to prevent CRS in response to a single high-dose administration of blinatumomab, and whereby beraprost (of Faulds) is substituted for dexamethasone in the method Topp, for the same purpose. Faulds teaches the cytokine storm is associated with highly elevated levels of various cytokines including IFN-γ and IL-6 (Faulds, pg. 5, para. 0105); and that the effective dose of beraprost would partially or fully inhibit said cytokines (pg. 9, para. 0155). Thus, Faulds teaches the expectation is that BPS-314d would lower the pro-inflammatory cytokines. The instant specifications (Example 12, pg. 50; Figures 1A-1G) provide evidence that it is an inherent property of BPS-314d, to dose-dependently reduce levels of IL-6, and it is an inherent property of BPS-314d, at doses ≤ 225 nM, that T cell-mediated killing of tumor cells is not decreased by more than 5%. The BPS-314d compound of Faulds is identical to the CTO1681 compound of instant experiment 12 (see specs. pg. 22, para. 0092). MPEP 2112.01 teaches that “products of identical compositions cannot have mutually exclusive properties. If the prior art teaches the identical chemical structure, the properties applicant discloses are necessarily present.” The examiner has held that Topp teaches a CRS-inducing dose of a bispecific antibody in a single administration (discussed above). Further, the dose dependent reduction of cytokines and the preservation of T-cell mediated killing of tumor cells are inherent properties of the compound of Faulds, regardless if Faulds explicitly describes these properties. Thus, the combination method of Topp and Faulds, utilizing the identical BPS-314d compound of Faulds, makes obvious the method of claims 1 and 17, and applicant’s arguments are unpersuasive.
Applicants contend that beraprost is not a substitutable agent for dexamethasone because (1) Faulds teaches beraprost for treating viral-induced cytokine storms and not for bispecific antibody-induced CRS; (2) Faulds teaches BPS-314d has “immune-modulating activity” which would lead one skilled in the art to expect BPS-314d could interfere with T-cell function; and (3) the present claims require dose-dependent cytokine reduction while preserving T-cell killing, which is not taught or expected from Faulds based on Faulds’ teaching of “immune-modulating activity”.
Regarding the first point, and as discussed previously in the OA of 9/25/2024, Faulds teaches beraprost as a treatment for CRS, regardless of the insult or pathology that triggers the CRS. Faulds teaches that beraprost acts as an agonist at a GPCR to potently inhibit the production of cytokines, and thus by acting at the level of T cells to reduce cytokine release, beraprost will work to treat CRS from any insult that triggers CRS. While Faulds explicitly teaches beraprost for treating virally-induced CRS, Faulds repeats, extensively, throughout the disclosure that the use of beraprost for treating CRS is not limited to only virally-mediated CRS; and therefore encompasses CRS induced by bispecific antibody cancer treatments. For example, Faulds teaches CRS resulting from a “systemic inflammatory response” (Faulds, pg. 5, para. 0112), which is akin to bispecific antibody therapy-induced CRS. Regarding point 2, Faulds teaches beraprost has “immune modulating activity” because beraprost acts at a GPCR on T cells to reduce cytokine release; a property appreciated in instant Example 12 (Figures 1A-1G). Having “immune modulating activity” is the very purpose of administering beraprost to treat CRS, which is an immune response. This broad and vague term does not dissuade one skilled in the art from using beraprost for its intended purpose, and the purpose of beraprost (i.e. treating CRS) is the same as that of dexamethasone, which is also taught by Topp. MPEP 2143-simple substitution- is for function, not for structure or mechanism of action. One only needs a reasonable expectation for success that substituting beraprost for dexamethasone would function to reduce CRS. Faulds does not teach away from using beraprost in T-cell mediated treatment for cancer, Faulds is silent regarding effects on T cell mediated killing of tumor cells; “immune modulating activity” does not inform the artisan one way or another whether beraprost would affect T cell mediated killing of tumor cells. Further, Topp teaches the primary means by which T cells kill cancer cells is through granzyme-containing granules and the pore-forming protein perforin, whereby the T cells discharge their toxic content into the tumor cell (Topp, pg. 2, Introduction). Thus, Topp teaches that cytokine release is not the primary mechanism for T cell mediated killing, and thus a skilled artisan would not be dissuaded from using beraprost in Topp’s method for treating cancer because targeting cytokines for treating CRS is a separate mechanism from T cell cytosis of tumor cells. This is further exemplified in instant Figures 1D-1G, which use dexamethasone as a control against which the actions of beraprost are compared; dexamethasone also decreased cytokines IL-6 and TNF-α (Figs. 1D-1E) while preserving tumor cell killing (Fig. 1G). As the beraprost isoform BPS-314d of Faulds is the same as CTO1681 of the instant examples, the dose-dependent reduction of cytokines and the preservation of tumor killing activity of T cells are inherent properties of the compound. Thus, the artisan substituting beraprost for dexamethasone in the method of Topp, for the same purpose, would have a reasonable expectation for success. Applicant’s arguments that beraprost is not a substitutable agent for dexamethasone are unpersuasive.
Applicants contend that modifying Topp would render it unsatisfactory for its intended purpose because the stepwise dosing regime is the core teaching of Topp for managing CRS risk (remarks, pg. 13, paras. 1-2).
The examiner has already re-iterated that Topp teaches multiple strategies for administering blinatumomab as a treatment for cancer, and also mitigating CRS; and that promoting a stepwise administration regime does not teach away from alternatively administering a single high-dose infusion of blinatumomab with an agent (dexamethasone) for preventing CRS. Further, the combination of Topp and Faulds is not taught in Topp alone. That is, Topp does not reduce to practice a method of administering blinatumomab with beraprost for reducing CRS, and offers no opinion, for or against, such a method. The method of Topp, cohort 1, did not use a step-wise dosing regimen; cohort 1 received dexamethasone or cyclophosphamide treatment, and the initial high dose (15 ug/m2) of blinatumomab. Topp teaches, in doing so, “no incidence of grade > 3 CRS was reported during the remainder of the study.” Thus, the methods of Topp do not require step-wise dosing; step-wise dosing is one suggested strategy for eventually reaching high dose administration, and further supports that high dose administration is the risk factor for inducing CRS. Topp also suggests administering an anti-IL-6 antibody as a feasible strategy for mitigating CRS. Thus, “the method” of Topp has various embodiments and does not require step-wise dosing; modifying the methods of Topp does not require breaking the step-wise dosing regimen, nor does it render Topp unsatisfactory for its intended purpose. Therefore, administering beraprost as a strategy for mitigating CRS does not render Topp unsatisfactory for its intended purpose because a) Topp doesn’t require step-wise dosing as the only method for administering high dose bispecific antibody therapy, b) Topp contemplates various alternative strategies for mitigating CRS including co-administering alternative anti-CRS agents, and c) administering beraprost to mitigate CRS in conjunction with high dose bispecific antibody therapy arrives at Topp’s intended purpose, which is administering bispecific antibody therapy for the treatment of cancer without severe CRS-related AEs. Applicant’s arguments that modifying Topp would make is unsatisfactory for its intended purpose are unpersuasive.
Applicants contend that the claims are now commensurate in scope with the unexpected results; that the claims are amended to require a dose-dependent reduction in cytokines while maintaining, within 5%, the T cell mediated killing of cancer (remarks, pg. 13, paras. 3-4; pg. 14, para. 1). Further, applicants cite the examiner’s previous comment that specific dose limitations are not claimed in the instant invention, and suggest that the amended claims now directly address the concern (pg. 13, para. 4).
The rejection of amended claims 1 and 17 are addressed in the amended rejection above. Specifically, the properties of dose-dependently reducing cytokines and maintaining T cell mediated killing of tumor cells are inherent properties of the BPS-341d compound of Faulds, as demonstrated in instant example 12. Further, example 12 highlights that dexamethasone also had the same properties, and therefore supports substituting beraprost for dexamethasone for the same purposes as both dexamethasone and beraprost were taught in the prior art for reducing CRS. Applicants have not included a specific dose in the claim limitations, for which the “unexpected result” of decreasing cytokines while preserving T cell mediated killing of tumor cells was “discovered”. The evidence on record does not make it unexpected that beraprost would have these same properties; the evidence supports that beraprost would dose-dependently reduce cytokines, and there is no evidence that beraprost would affect T cell mediated killing of tumor cells; Faulds is silent to such a property. Without some previous teaching of an expectation that beraprost would inhibit T cell killing, it is not unexpected that it does not affect T cell mediated killing. Topp cites T cell mediated killing is accomplished through granzymes and perforins, and does not rely on cytokines. As discussed above, Faulds’ disclosure that beraprost has “immune modulating activity” is in the context of its stated function of reducing cytokine release from immune cells to treat CRS, and has no bearing on whether or not beraprost would inhibit T cell granzyme and/or perforin activity in killing targeted tumor cells. That beraprost successfully inhibits cytokine production without reducing T cell mediated killing of tumor cells is an inherent property of beraprost, specifically BPS-314d, that was present at the time of Faulds, whether, or not, Faulds explicitly disclosed it. MPEP 2112(I) teaches the discovery of a previous unappreciated property of a prior art composition does not render the old composition patentable new to the discoverer. Further, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference (MPEP 2112(II)). BPS-314d, of Faulds (and instant claim 1) is the same compound used in instant experiment 12, and therefore possesses the same properties. Faulds is silent as to BPS-314d effect on T cell mediated killing function, but teaches BPS-314d effectively reduces cytokine production as a means of treating CRS. Therefore the skilled artisan would have reasonable expectation for success in using beraprost in the methods of Topp, for treating CRS, whereby the dosing may be optimized for overall treatment efficacy. The art is silent regarding whether beraprost, at any dose, would significantly affect T cell mediated killing; thus there is no expectation for the skilled artisan on this property. The skilled artisan would substitute beraprost for dexamethasone, for the purpose of reducing cytokines and treating CRS, and would naturally optimize dosing so as to maintain the effectiveness of the cancer treatment. Dexamethasone was also known in the art for reducing cytokines for treating CRS, and that does not dissuade Topp from using it in conjunction with a bispecific antibody that recruits T cell mediated killing of cancer cells, because dexamethasone doesn’t affect granzyme and/or perforin function in T cells, as inferred by Topp. Thus, an artisan may presume beraprost, an alternative equivalent for treating CRS, might also work to decrease CRS without decreasing T cell mediated killing in the same manner as dexamethasone. There is no teaching that beraprost would be expected to render T cell killing activity inadequate; there is teaching that it works to reduce cytokines similarly to dexamethasone, which is beneficial for treating CRS in a bispecific antibody therapy, thus providing motivation for its use in the methods of Topp. Therefore, it is not unexpected that it works for the purpose for which it was taught. In order to argue unexpected results, there would need to be an explicit teaching or demonstration that beraprost would render the method ineffective, such that applicants found a property, or dose, which defies the expectation of failure in the art. Instead the art is silent, and applicants rely on the speculation that an artisan might be dissuaded from using beraprost because Faulds broadly stated beraprost has “immune modulating activity”. It is clear that Faulds was describing the property of beraprost to reduce in cytokine release to treat CRS, which is indeed an immune modulating property, and would be the same immune modulating activity of dexamethasone in the methods of Topp. That beraprost does little to effect T cell killing activity of cancer cells is an inherent property, also shared by dexamethasone, which may have been unappreciated, but is not unexpected. There is no evidence from which to set an expectation that beraprost would innately inhibit T cell killing activity due to its intended function of inhibiting cytokine release, when Topp, and the art, teach granzyme and perforin primarily mediate T cell function of killing the tumor cells, more than cytokine release. Blinatumomab is a CD3/CD19 bispecific antibody which functions to bring CD3+ T cells into contact with tumor cells, and thus further supports the granzyme/perforin mediated cell-to-cell contact mechanism of tumor cell killing. Applicant’s contention that an inherent property of beraprost provides an unexpected result, is unpersuasive, because there was no expectation in the art that is being defied to make it unexpected. Beraprost works to treat CRS as expected based on the teachings of Faulds, and works in the methods of Topp as a substitute for dexamethasone, for the same purpose.
Applicants contend that the “routine optimization’ argument is improper because the general conditions are not disclosed. Applicants contend that neither Topp nor Faulds disclose administering BPS-314d with a CRS-inducing single dose of bispecific antibody, and Faulds is silent on T cell-mediated killing of cancer cells. Thus, the prior art simply does not provide a starting point for the claimed combination, and therefore routine optimization cannot apply because there is no result-effective variable of the proposed combination (remarks, pg. 14, para. 3).
Examiner has maintained that the combination of Topp and Faulds, when considered together, make obvious a method of administering BPS-314d with a CRS-inducing single dose of a bispecific antibody, as described above. The limitations of not reducing a T cell-mediated killing of a cancer cell by more than 5% and wherein the pharmaceutical composition dose-dependently reduces levels of IL-6, TNFα and IFN-γ, are each a result effective variable. One would expect that administering a composition that meets the structural limitations set forth in the claim would have the same resulting properties; and which are supported in the specifications (example 12; Figs. 1A-1G). Therefore, it is obvious, under routine optimization of the protocol to determine the doses that would be most efficacious for the cancer treatment method, such that CRS is reduced and the efficacy of the bispecific antibody therapy in killing tumor cells is maintained. Applicant’s arguments against routine optimization of the combination method of Topp and Faulds, are unpersuasive.
Applicants contend that presence of a property not possessed by the prior art is evidence of non-obviousness. Applicants contend that the need for an explicit teaching in the art that BPS-314d would not work is required in order to establish “unexpected results” is contrary to the law and sets an improper bar for establishing unexpected results. Applicants contend that Faulds teaches BPS-314d has “immune modulating activity”, and therefore a skilled artisan would recognize that an agent with immune modulating activity would affect T cell function, because T cell function is essential for bispecific antibody therapy. Thus, that BPS-314d dose dependently reduces CRS-inducing cytokines while simultaneously preserving T cell mediated killing is unexpected result and therefore prima facie non-obvious (remarks, pg. 15, paras. 1-2).
The examiner has addressed the contention of “unexpected results” as being unpersuasive, above. First, the “immune modulating activity” of Faulds is in reference to the notion that BPS-314d acts on GPCRs on T cells to reduce cytokine release, therefore making beraprost a good agent for treating CRS, regardless of the pathology or insult that triggered the CRS. Second, Topp teaches that T-cell mediated killing of tumor cells occurs primarily through granzymes and perforin, in a cell-to-cell contact method, whereby the cytotoxic agents from the T cell are deposited in the tumor cell. Third, Topp teaches administering dexamethasone, which is also known to decrease cytokine release, for treating CRS in a method of administering bispecific antibody treatment for cancer. As demonstrated in example 12, where dexamethasone is used as a control, dexamethasone also does not inhibit T cell mediated killing of tumor cells. Therefore, there is a reasonable expectation for success for substituting beraprost for dexamethasone, for treating CRS induced by a single, high-dose infusion of bispecific antibody therapy. It follows that beraprost, similar to dexamethasone, also does not interfere with granzyme/perforin killing of cancer cells by T cells, which has been demonstrated by the instant experiments. Thus, the feature is inherent to the BPS-314d compound and not the result of, for example, a structural modification of BPS-314d performed by the applicants. The prior art is silent on the particular property of beraprost to not interfere with T cell killing activity. However, it is reasonable to expect that it would work in a manner similar to dexamethasone and not interfere with T cell killing activity. Therefore, in order to establish that its inherent properties were “unexpected results” at the time, the applicants need to demonstrate where the art, or data, teaches away from beraprost for use in treating CRS in a T cell-mediated cancer therapy. Otherwise, there is no expectation on record for which applicants can claim “unexpected results”. For example, a claim to unexpected results may come from a direct comparison to the closest art, whereby the compound shows a significantly superior property than would have been expected by comparison to the art. In this case, beraprost has similar activity to dexamethasone (Figures 1A-1G). Applicant’s contention that the vague phraseology of Faulds that beraprost has “immune modulating activity” sets an expectation, is not persuasive for establishing that the results of BPS-314d are unexpected, as discussed above. Regarding applicant’s contention that the presence of a property not possessed by the prior art is evidence of non-obviousness; the examiner re-iterates that the CTO1681 compound is structurally identical to BPS-314d of Faulds, and the BPS-314d of instant claim 1. Therefore, the property in question was possessed by the prior art of record, it was an inherent property of the identical structure. Applicants have not “invented” a new structure, or dose, or method of using the compound, which has new properties. The BPS-314d of Faulds is being used, as it was intended based on the disclosure of Faulds, in the method of Topp, in an obvious substitution for dexamethasone, for the same purpose. There is no teaching in the art of what is being defied, to categorize the claim limitations or the data of the specifications as “unexpected”. Applicant’s arguments of unexpected results are unpersuasive.
Applicants contend that an inherent property does not necessarily flow from the teachings of the prior art. Applicants cite that the examiner must provide a basis in fact that the allegedly inherent characteristic necessarily flows for the teachings of the prior art in an obviousness analysis (remarks, pg. 15 - pg. 16, section C). Applicants contend that the examiner has improperly derived an inherent limitation on a feature of a prior art modification of Topp rather than what necessarily flows from what it taught by Faulds. Applicants contend that Faulds does not teach administering BPS-314d with antibody therapy, and that the claimed method requires a specific combination of properties, including dose-dependent reduction in cytokines while preserving T cell mediated killing. Therefore, this limitation is distinguished from what is taught or suggested by the prior art and cannot be considered inherent since it does not flow from Faulds in isolation (remarks, pg. 16, para. 2).
As discussed above, the basis of inherency is that the BPS-314d compound of Faulds and that of the instant claims are identical compounds. It is important not to conflate the issue of obviousness with the issue of inherent properties. MPEP 2112.01 teaches that “products of identical compositions cannot have mutually exclusive properties. If the prior art teaches the identical chemical structure, the properties applicant discloses are necessarily present.” That is, identical structures have identical properties, regardless of whether those properties were known or not at the time; those properties are inherent to the identical structure. The dose dependent reduction of cytokines and the lack of inhibition of T cell mediated killing of cancer cells were inherent properties of the BPS-314d compound of Faulds, at the time of Faulds, regardless of whether or not Faulds disclosed them; they are inherent properties of the structure of the compound. They are inherent properties in any compositions or methods that use the compound, in any way, as long as the structure of the compound is identical. The properties inherent to the structure of the compound transfer to any methods or compositions that use the identical compound; the properties of the structure are inherent and naturally flow from the structure of the compound. The issue of obviousness is based on the teachings of Topp and Faulds, whereby both dexamethasone and BPS-314d have the property of reducing CRS, and therefore it is obvious to substitute one for the other, with motivation to reduce CRS. Once BPS-314d is substituted for dexamethasone, in the methods of Topp, all the inherent structural properties of BPS-314d transfer with it, as they are inherent to the structure of the compound. Therefore, the added limitations whereby the BPS-314d dose-dependently reduces the levels of IL-6, TNF-α and IFN-γ while not reducing the T cell mediated killing of cancer cells by more than 5% are inherent properties of BPS-314d when used in a method of bispecific antibody therapy for treating cancer, just as they are inherent properties if BPS-314d is used in any other method or composition. Once it is obvious to use the beraprost of Faulds in a combination method of Topp and Faulds, the structural properties of BPS-314d are inherent in the methods of Topp and Faulds. Applicant’s arguments against the inherent properties of BPS-314d are unpersuasive. In view of the entirety of applicant’s arguments being unpersuasive, the rejections are maintained.
Claim Rejections – New
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-3, 8-19 and 22-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 10-13, 15-18, 20-24, 29 and 31 of copending Application No. 18/679,999 in view of Topp et al., (Journal of Clinical Oncology, 2014, 32(36)) and Faulds et al., (from IDS; US 20140275237; published 9/18/2014) and Brownstein et al., (from IDS; US 20200129617; published 4/30/2020).
Application ‘999 claims a method of treating CRS in a subject undergoing CAR T-cell therapy wherein the method comprises administering a pharmaceutical composition comprising beraprost (claim 1); wherein the beraprost is beraprost sodium salt (claim 2), wherein the beraprost is BPS-314d (claim 4); wherein the CAR T-cell therapy remains effective for treatment of cancer and wherein the cancer is acute lymphoblastic leukemia (ALL; claim 5); wherein the subject is human (claim 10), whereby the CAR-T therapy and the beraprost composition are administered concurrently (claim 11), or whereby the beraprost composition is administered after the CAR T cell therapy (claim 12) , whereby the beraprost composition is administered up to about 7 days after the CAR T cell therapy (claim 13), whereby the beraprost composition is administered after the onset of CRS (claim 15), wherein the CRS is detected by an increased level of cytokines such as IL-6 (claims 16-17), whereby the beraprost composition is administered for 1 to 30 days (claim 18); whereby the beraprost composition is administered before the CAR-T cell therapy (claim 20); whereby the subject experiences reduced CRS (claim 21) or no CRS (claim 22); whereby the CAR T cell therapy comprises autologous CAR T cells (claim 23) or allogenic CAR T cells (claim 24); and whereby the amount of beraprost is 0.1 ug to about 5000 ug (claims 29 and 31).
The combination method of Topp and Faulds is described above, specifically whereby the CRS is induced by a single administration of a high-dose of bispecific antibody (i.e. the anti-CD19/CD3 antibody Blinatumomab), and wherein the beraprost composition does not reduce T cell mediated killing of cancer cells by more than 5%, and wherein the beraprost composition dose-dependently reduces levels of IL-6, TNF-α and IFN-γ in the subject.
Brownstein et al. teaches methods for mitigating cytokine release syndrome (CRS) and infusion related reactions associated with administration of T cell activating bispecific antibodies (abstract). Specifically, Brownstein teaches cytokine release syndrome is a systemic inflammatory response that can be triggered by a variety of factors, including T cell-activating cancer immunotherapies resulting from effects induced by binding of a bispecific antibody or CAR T cell to its antigen; and that CRS is the result of the massive release of cytokines including IFN-γ, IL-6 and TNF-α (pg. 1, para. 0004). Brownstein goes on to teach that “the management of the toxicities of cancer immunotherapy is a challenging clinical problem, and that mitigating CRS is a hallmark of administering certain treatment modalities, for example, bispecific antibodies targeting T cells,” (pg. 1, para. 0005).
It would have been obvious to one of ordinary skill in the art to utilize the methods of treating CRS induced by CAR T cell therapy, of application ‘999, with the modification of treating CRS induced by a single administration of a CRS-inducing amount of a bispecific antibody, as taught by the combination of Topp and Faulds. One would have been motivated to do so given that CRS is induced by either bispecific antibody or CAR-T cell cancer immunotherapy as taught by Brownstein et al. There would have been a reasonable expectation of success given that beraprost compositions inhibit CRS, induced by any pathology or insult, as taught by Faulds et al. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Specifically, application ‘999 claims 1-2, 4-5, 10, 13, 23-24, 29 and 31 over Topp, Faulds and Brownstein, makes obvious instant claims 1-3 and 13-19; ‘999 claims 11-12, 15-17 and 20 make obvious instant claims 8-10, 12 and 22-25; ‘999 claim 18 make obvious instant claim 11; ‘999 claims 21-22 makes obvious instant claims 26-27.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 8-19 and 22-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/325,930 in view of Topp et al., (Journal of Clinical Oncology, 2014, 32(36)) and Faulds et al., (from IDS; US 20140275237; published 9/18/2014) and Brownstein et al., (from IDS; US 20200129617; published 4/30/2020).
Application ‘930 claims a method of treating CRS or ICANS associated with CAR T cell administration in a subject comprising administering a population of CAR T cells and a first pharmaceutical composition comprising beraprost, a beraprost isomer, or an acceptable salt thereof, and wherein the pharmaceutical composition does not reduce the cell killing mediated by the population of CAR T cells by more than 5% (claim 1); wherein the pharmaceutical composition reduces levels of IL-6, IFN-γ and TNF-α (claim 2); and wherein the CAR T cells are a population of CD19-CD3 bispecific CAR T cells (claim 18). Application ‘930 also claims wherein the beraprost is BPS-314d (claims 8-9).
However, application ‘930 does not claim whereby the methods for treating cancer comprises administering a bispecific antibody, or a CRS-inducing amount of a bispecific antibody in a single administration.
The combination methods of Topp and Faulds are described above, whereby it is obvious to administer a CRS inducing amount of blinatumomab (a CD19-CD3 bispecific antibody) in a single administration with beraprost isomer BPS-314d in the first pharmaceutical composition. Topp teaches that CAR T cells targeting CD19 have been investigated in several single-center trials, with response rates as high as 83% (pg. 12, Disscussion, para. 1). Brownstein teaches CRS is a systemic inflammatory response that can be triggered by a variety of factors, including T cell-activating cancer immunotherapies resulting from effects induced by binding of a bispecific antibody or CAR T cell to its antigen; and that CRS is the result of the massive release of cytokines including IFN-γ, IL-6 and TNF-α (pg. 1, para. 0004). Brownstein goes on to teach that “the management of the toxicities of cancer immunotherapy is a challenging clinical problem, and that mitigating CRS is a hallmark of administering certain treatment modalities, for example, bispecific antibodies targeting T cells,” (pg. 1, para. 0005).
It would have been obvious to one of skill in the art to substitute a CD19/CD3 bispecific antibody therapy for a CD19/CD3 CAR T cell therapy in order to treat cancer because they are known treatment options for ALL, as taught by Topp. MPEP 2143(I)(B) supports a prima facie case for obviousness exists for simple substitution of one known element for another to obtain predictable results. There would have been a reasonable expectation for success given that both bispecific antibody treatment and CAR T cell therapy may induce CRS, as taught by Brownstein, and that BPS-314d is effective to reduce symptoms of CRS regardless of the insult that causes CRS, as taught by Faulds. Thus the invention was prima facie obvious to one of skill in the art at the time the invention was made. Further, the limitation that BPS-314d dose-dependently reduces cytokines IL-6, TNF-α and IFN-γ is an inherent property of the BPS-314d compound, as described above.
Thus, application ‘930 claims 1-2, 8-11 and 17-18, over Topp, Faulds and Brownstein, make obvious instant claims 1, 3, 17 and 19.
Application ‘930 also claims wherein the method further comprises administering tocilizumab (claim 3) and thus makes obvious instant claims 2 and 18.
App. ‘930 claims wherein the beraprost composition is administered once CRS is detected (claim 7), before administration of CAR T cells (claim 12), after administration of CAR T cells (claim 13), or starting one day before and continuing for 14 days (i.e. concurrently; claim 16). Thus application ‘930 claims 7, 12-13 and 16, over Topp, Faulds and Brownstein, make obvious instant claims 8-10, 12 and 22-25.
App. ‘930 claims wherein the beraprost composition is administered for 1 day to about 30 days (claims 14-15), and thus makes obvious instant claim 11.
Faulds teaches the administration of the beraprost composition via a route selected from inhalation, transdermal, intravenous, subcutaneous, or oral administration (pg. 14, claim 23) and Topp teaches the bispecific antibody is administered I.V. Thus, application ‘930 over Topp, Faulds and Brownstein make obvious instant claim 13.
Topp teaches the CD19/CD3 bispecific antibody is blinatumomab; thus application ‘930 over Topp, Faulds and Brownstein, make obvious instant claims 14-16.
App. ‘930 claims wherein the subject has reduced treatment with the second composition (i.e. tocilizumab) as a result of treatment with the beraprost composition (claim 4); wherein the subject experiences reduced parkinsonism effects (claim 5) or reduced CRS or ICANS compared to a subject that does not receiving the beraprost composition (claim 6). Faulds teaches the administration of the beraprost composition via a route selected from inhalation, transdermal, intravenous, subcutaneous, or oral administration (pg. 14, claim 23) and Topp teaches the bispecific antibody is administered I.V. Thus, application ‘930 claims 4-6, over Topp, Faulds and Brownstein, make obvious instant claims 26-27.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642