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 .
Priority
The instant application is a domestic application filed May 30, 2023 claiming benefit to U.S. Provisional Application Nos. 63/482,448 filed January 31, 2023 and 63/347,221 filed May 31, 2022.
Status of Claims
Acknowledgement is made of previously presented (1-3, 5, 7-18), amended (4, 6), and cancelled (19-20) claims filed on January 21, 2026. Claims 1-18 are pending in instant application.
Response to Arguments
Applicant’s amendments filed January 21, 2026 have overcome the rejection of claims 4, 6 under 35 U.S.C. 112(b). The replacement drawing sheets have overcome the objection to the Drawings.
Applicant's arguments filed January 21, 2026 have been fully considered but they are not persuasive.
Regarding the title (see 1/21/26 Remarks at p. 6), per MPEP § 606.01, where the title is not descriptive of the invention claimed, the examiner should require the substitution of a new title that is clearly indicative of the invention to which the claims are directed. This may result in slightly longer titles, but the loss in brevity of title will be more than offset by the gain in its informative value in indexing, classifying, searching, etc. The Examiner again urges Applicant to amend to a more descriptive title that reflects the substance being administered (beraprost) and the conditions being treated (CRS, ICANS) in addition to the associated condition (CAR T-cell therapy) in order to reflect the invention claimed.
Regarding no reasonable expectation of success (see 1/21/26 Remarks at pp. 9-11) and unexpected results (see 1/21/26 Remarks at pp. 12-14), As an initial issue, Applicant argues the specification was relied upon to reach a conclusion of a POSITA (see 1/21/26 Remark at p. 11 ¶3). The Examiner would like to clarify; the limitation,
“…the first pharmaceutical composition does not reduce a cell killing mediated by the population of CAR T-cells by more than 5%.”
is a result-effective variable. One would expect that administering a composition that meets the structural limitations set forth in the claim,
“…administering to the subject a population of CAR T-cells, and a first pharmaceutical composition; wherein: the first pharmaceutical composition comprises at least an effective amount of beraprost, a beraprost isomer, or a pharmaceutically acceptable salt thereof…”,
would have the same resulting property of not reducing a cell killing mediated by the population of CAR T-cells by more than 5%. Prior art that teaches the same structural limitations of the claim would thus expect to have the same property, absent the contrary, whether or not it was detailed by the prior art (see MPEP § 2112(I), "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).). The specification supports this claim construction that the limitation is a property of a composition that meets the structural limitations by showing treatment with CTO1681 did not affect CD19 CAR T-cell activity at any dose tested in vitro (see instant spec. at p. 117 Example 64 [00672]) or in vivo (see instant spec. at p. 118 Example 65 [00677]).
A reasonable expectation of success for the prior art thus amounts to the claimed utility at hand, “[a] method of treating cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or both associated with CAR T-cell administration in a subject”. As discussed in the prior 10/16/25 Office Action, there is an expectation of success to treat such conditions with beraprost because the prior art teaches beraprost alleviates a viral-associated cytokine storm by reducing IFN, IL-6, and IL-10 cytokine levels (see Faulds at p. 13 Table 9), the same which are elevated in CAR T-cell associated cytokine storms (see SV at p. 7 left col. ¶4). Accordingly, a POSITA would have a reasonably expectation of success to treat a CAR T-cell cytokine storm with elevated cytokines with a known treatment for reducing cytokine levels (beraprost).
Applicant argues that Faulds teaches away from the result-effective variable, and goes on to cite the instant spec stating: “[t]ocilizumab, while FDA approved for the treatment of CRS, may have some drawbacks, as IL-6 has been clearly proven to promote the proliferation of T-cells, and it is unclear if IL-6 blockade may impair the in vivo proliferation of CAR T-cells” (see 1/21/26 Remarks at p. 11 ¶2). The statement is a conjecture, and not of concrete fact. Moreover, the prior art Si et. al.1 teaches tocilizumab is a “cornerstone in the treatment of CAR T-cell therapy associated CRS as evidenced by its ability to dampen CRS without compromising CAR T-cell efficacy” (see Si at p. 711 right col. ¶3). This also contradicts Applicant’s unexpected property argument; a similar cytokine suppressor (tocilizumab) does not reduce a cell killing mediated by a population of CAR T-cells, the limitation is thus not a “surprising property” in the art of CAR T-cell adjuvant therapies (see 1/21/26 Remarks at p. 12 ¶3). Again, Examiner reiterates the “does not reduce” clause to be a result of a composition that meets the structural limitations of the claim.
Regarding combining prior art teachings (see 1/21/26 Remarks at p. 12), the Examiner reiterates that the preservation of CAR T-cell function is a result of administering a composition that meets the structural limitations of the claim. The prior art teaches a motivation for administering a known viral-associated cytokine storm treatment (beraprost) to a CAR T-cell associated cytokine storm, because beraprost is known to reduce the cytokine levels elevated in both storm scenarios (as taught by Faulds and SV).
Regarding the teachings of Holtzmann (see 1/21/26 Remarks at pp. 14-15), Holtzmann is merely closing the gap of beraprost to treat ICANS associated with CAR T-cell therapy, since Faulds and SV establish beraprost to treat CRS associated with CAR T-cell therapy. As stated above, the preservation of CAR T-cell function is a result of administering a composition that meets the structural limitations of the claim.
Regarding the double patenting rejection (see 1/21/26 Remarks at p. 16), As stated above, the preservation of CAR T-cell function is a result of administering a composition that meets the structural limitations of the claim.
Claim Interpretation
Claim 1's limitation of "the first pharmaceutical composition does not reduce a cell killing mediated by the population of CAR T-cells by more than 5%" is understood to be a property of the composition that meets the structural limitations of the claim. The instant specification supports this understanding by showing treatment with CTO1681 did not affect CD19 CAR T-cell activity at any dose tested in vitro (see instant spec. at p. 117 Example64 [00672]) or in vivo (see instant spec. at p. 118 Example 65 [00677]).
The instant specification states "Beraprost sodium contains 4 stereoisomers, one of which (314d) contains nearly all of the biological activity and is chemically identical to CTO1681" (see instant spec. at p. 109 [00628]). Accordingly, art detailing administering beraprost sodium is art detailing administering at least BPS-314d also known as CTO1681.
Modified/Maintained Objection(s)
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The Examiner suggests the title should reflect the compound being administered and the purpose. For example: BERAPROST COMPOSITIONS FOR TREATING CYTOKINE RELEASE SYNDROME FROM CAR T-CELL ADMINISTRATION.
Modified/Maintained Rejection(s)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-20 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0275237 A1 to Faulds et. al.2 in view of Shimabukuro-Vornhagen et. al.3
Regarding claim 1, 19-20 and administering a composition comprising beraprost to treat a cytokine storm and a kit, Faulds teaches administering beraprost isomer(s), including beraprost 314d, to treat a viral disease associated with a cyctokine storm (see Faulds at claims 1, 10-14). Faulds teaches administering beraprost lowers lung cytokine concentration in viral infected mice (see Faulds at p. 13 Table 9).
Regarding claim 2 and reducing cytokine levels, Faulds teaches administering beraprost reduced IFN, IL-6, and IL-10 (see Faulds at p. 13 Table 9).
Regarding claim 6, Faulds teaches administering beraprost and its isomers reduced cytokine levels compared to a control placebo (see Faulds at p. 13 Table 9, compare PSS with Cmpd A-D and Beraprost).
Regarding claims 8-9 and beraprost isomers, Faulds teaches administering beraprost isomer A (also known as BPS-314d, see Faulds at p. 5 Table 1 and Figure 1) resulted in superior cytokine reduction in viral infected mice (see Faulds at p. 13 Example 8).
Regarding claims 11, 14-17 and administration and dosing, Faulds teaches embodiments of administering beraprost or its isomers at 0.05 mg/day to 1 mg/day (see Faulds claim 16), or 0.1 to 300 ug/kg/day and may be administered to humans at once or divided into two or more daily doses (see Faulds at p. 9 [0155]).
The prior art differs from the instant claims as follows: While Faulds teaches beraprost compositions for treating cytokine storms associated with viral infections, Faulds does not specify treating cytokine storms associated with CAR T-cell therapy.
However,
Regarding claim 1, 19-20 and cytokine release syndrome associated with CAR T-cell administration and a kit, SV teaches CRS is a systemic inflammation response, and the most important adverse event of CAR T-cell therapy (see SV at p.1 left col. par. 1 and p.2 left col. par. 1). SV teaches hypertension is a symptom of grade 2 CRS (see SV at p. 9 Fig 3). Faulds teaches the compositions can be administered in a variety of unit dosage forms depending on administration method (see Faulds at p.7 ¶[0131]) and may be administered with additional therapies such as anti-inflammatories at the same time or sequentially as separate formulations or together in a single formulation (see Faulds at p. 9 ¶[0156]).
Regarding claim 3, 19 and a second pharmaceutical composition and a kit, SV teaches low grade CRS is treated symptomatically with antihistamines, antipyretics and fluids (see SV at p. 10 left col. par. 4). SV teaches pre-medication with corticosteroids and dose adjustments is known to help severe CRS (see SV at p. 10 left col. ¶5). SV teaches administration of monoclonal antibodies against IL-6 (siltuximab) and its receptor (tocilizumab) led to rapid resolution of CRS symptoms (see SV at p. 10 right col. ¶2).
Regarding claim 7 and increased levels of cytokines, SV teaches IL-6, IL-10, and IFN-y are core cytokines found to be elevated in CRS (see SV at p. 7 left col. ¶4).
Regarding claim 10 and CAR T cell therapy for cancer, SV teaches CAR T-cell therapy is in development for hematological malignancies such as diffuse large B cell lymphoma, acute lymphoblastic B cell leukemia, chronic lymphocytic leukemia (see SV at p. 1 right col. ¶2).
Regarding claims 12-13 and administering prior to CRS, SV teaches a prophylactic protocol consisting of cytoreduction, dose adjustment, and premedication with corticosteroids has been devised, that resulted in a reduced incidence of severe CRS (see SV at p. 10 left col. ¶5).
Regarding claim 18 and CAR T cells, SV teaches CD-19 targeted CAR T cells as a T cell therapy (see SV at p. 2 left col. ¶2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding claim 1 and cytokine release syndrome associated with CAR T-cell administration, per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one skilled in the art to apply a known substance (e.g. beraprost) known for treating CRS associated with a virus (as taught by Faulds) to a patient with CRS associated with CAR T-cell therapy (as taught by SV) because the substance is known to reduce cytokine levels (as taught by Faulds) which would reasonably be expected to alleviate CRS which is associated with high cytokine levels (as taught by Faulds and SV) (see also MPEP § 2144.07), this reads on administering to a subject a population of CAR-T cell and then a first pharmaceutical composition. The prior art composition would not be expected to reduce a cell killing mediated by the population of CAR T-cells by more than 5% given the instant spec. states treatment with B314d did not affect CD19 CAR T-cell activity at any dose tested in vitro (see instant spec. at p. 117 Example 64 [00672]) or in vivo (see instant spec. at p. 118 Example 65 [00677]).
Regarding claim 3-4, 19-20 and a second pharmaceutical composition and a kit, per MPEP § 2144.06(I), "[i]t 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” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to one skilled in the art to administer a composition comprising beraprost and a composition comprising a corticosteroid or tocilizumab either separately or together because the prior art teaches both are known to treat cytokine release syndrome (as taught by Faulds and SV), so each composition would be performing its art-recognized function together or separately. An artisan would readily appreciate that such compositions could be manufactured and separated in a unit dosage form for individual administrations (e.g., kits), as Faulds teaches the therapies can be administered as separate formulations(see, e.g., MPEP § 2143(I)(A),(G)). Furthermore, one would expect that a CRS patient receiving a treatment to reduce cytokine levels would require less of a second treatment for reducing cytokine levels compared to a CRS patient who has not received a reducing cytokine treatment.
Regarding claims 7, 12-17 and dosage regimens, per MPEP § 2144.05(II), a prima facie case of obviousness exists for optimization within prior art conditions or through routine experimentation. It would have been obvious to one skilled in the art to optimize a dosage routine including amount administered (as taught by Faulds), timing of administration (as taught by SV), daily dosages (as taught by Faulds), because the prior art teaches these variables have been considered. In addition, per MPEP § 2144.04(IV)(C), selection of any order of performing process steps (such as the instantly claimed orders of administrating compositions) is prima facie obvious in the absence of new or unexpected results, see In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946)
Accordingly, claims 1-4, 6-20 are obvious over Faulds in view of SV.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Faulds and SV as applied to claims 1-4, 6-20 above, and in further view of Holtzmann et. al.4
Claim interpretation: The phrase “Parkinsonism effects” is understood to comprise of including tremors, muscle stiffness, neurologic issues, psychomotor retardation, handwriting changes, and gait changes (see instant spec. at p. 18 ¶[0081])
The prior art differs from the instant claims as follows: While Faulds and SV teach administering beraprost compositions for treating CRS associated with CAR T-cell therapy, they do not specify administering to treat ICANS (i.e. parkinsons effects).
However,
Holtzman teaches that while exact mechanism of CAR T-cell therapy induced ICANS is unclear, current predisposing factors include prior cytokine release syndrome, or elevated inflammatory marker such as CRP, IL-1, IL-6, IL-10, and interferon-gamma (see Holtzman at p. 113 left col. ¶2). In the study conducted by Holtzmann, all ICANS patients had preceding cytokine release syndrome (see Holtzmann at p. 115 right col. ¶5).
Regarding claim 5 and Parkinsonism effects, Holtzmann teaches ICANS symptoms can include minor headaches, confusion, and handwriting changes to aphasia, seizures, cerebral edema, and even coma requiring mechanical ventilation (see Holtzmann at p. 113 ¶3).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one skilled in the art to administer a known beraprost composition for treating CRS by reducing cytokine levels (as taught by Faulds) to a patient with ICANS because the prior art teaches predisposing factors for ICANS include CRS and elevated cytokine levels (as taught by Holtzmann). Accordingly, reducing cytokine levels would be expected to treat ICANS including reducing ICANS symptoms such as Parksonism effects (as taught by Holtzmann). One skilled in the art would expect a patient receiving a treatment to reduce cytokines would experience less symptoms associated with elevated cytokine levels compared to a patient who receives no treatment.
Accordingly, claim 5 is obvious Faulds and SV in further view of Holtzmann.
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 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, 31, 34 of copending Application No. 18/679,9995 (reference application) in view of Faulds, SV, Holtzmann, and Sommer et. al.6 Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant claims 1, App’999 claims a method of treating CRS in a patient undergoing CAR T-cell therapy comprising administering a composition comprising beraprost (see App’999 claim 1).
Regarding instant claim 6, App’999 claims wherein the subject experiences reduced CRS relative to a subject who does not receive the composition (see App’999 claim 21) or no CRS at all (see App’999 claim 22).
Regarding instant claims 8-9, App’909 teaches wherein the beraprost is beraprost sodium salt (see App’999 claim 2) or BPS-314d (see App’999 claim 4).
Regarding instant claim 10, App’999 claims wherein the CAR T-cell therapy is for treating cancer such as B-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, multiple myeloma, etc (see App’999 claim 5).
Regarding instant claim 11, App’999 claims wherein the subject is human (see App’99 claim 10).
Regarding instant claims 12-16, App’999 claims administering the CAR T-cell therapy with the beraprost composition (see App’999 claim 11), administering the beraprost composition after the CAR T-cell therapy (see App’999 claim 12) including 1-7 days after (see App’999 claim 13), administering the beraprost composition after the CAR T-cell therapy and before CRS detection (see App’999 claim 15), administering the beraprost composition after the CAR T-cell therapy and when CRS is detected by elevated cytokine levels (see App’999 claims 16-17), administering the beraprost composition for 1-30 days (see App’999 claim 18), administering the beraprost composition before the CAR T-cell therapy (see App’99 claim 20).
Regarding instant claim 17, App’999 claims wherein the beraprost dose is 0.1 – 5000 μg (see App’999 claims 29, 31).
Regarding instant claim 18, App’999 claims wherein the CAR T-cell therapy comprises autologous or allogenic CAR T-cells (see App’999 claims 23-24). Sommer teaches that CD-19 CAR T-cells can be autologous or allogeneic (see Sommer at Abstract and at p. 1126 Introduction). Sommer also teaches BCMA CAR T-cells are a treatment for multiple myeloma (see Sommer at p. 1128 left col. ¶1). Sommer also teaches only two autologous CD-19 CAR T-cells are approved by the FDA (see Sommer at p. 1126 left col. ¶1).
Regarding claim 19-20, App’999 claims a kit comprising a beraprost composition and a CAR T-cell therapy (see App’999 claim 34).
The copending claims differ from the instant claims as follows: While App’999 claims a beraprost composition for treating CRS associated with CAR T-cell therapy, App’999 does not specify a second composition or treating ICANS.
However,
Regarding instant claims 1, 5 and ICANS, Holtzman teaches while exact mechanism of CAR T-cell therapy induced ICANS is unclear, current predisposing factors include prior cytokine release syndrome, or elevated inflammatory marker such as CRP, IL-1, IL-6, IL-10, and interferon-gamma (see Holtzman at p. 113 left col. ¶2). In the study conducted by Holtzmann, all ICANS patients had preceding cytokine release syndrome (see Holtzmann at p. 115 right col. ¶5). Holtzmann teaches ICANS symptoms can include minor headaches, confusion, and handwriting changes to aphasia, seizures, cerebral edema, and even coma requiring mechanical ventilation (see Holtzmann at p. 113 ¶3).
Regarding instant claims 1, 3-4, 19, and a second therapeutic composition, SV teaches low grade CRS is treated symptomatically with antihistamines, antipyretics and fluids (see SV at p. 10 left col. par. 4). SV teaches pre-medication with corticosteroids and dose adjustments is known to help severe CRS (see SV at p. 10 left col. ¶5). SV teaches administration of monoclonal antibodies against IL-6 (siltuximab) and its receptor (tocilizumab) led to rapid resolution of CRS symptoms (see SV at p. 10 right col. ¶2).
Regarding instant claim 2, Faulds teaches administering beraprost reduces IFN, IL-6, and IL-10 (see Faulds at p. 13 Table 9).
Regarding instant claim 18 and specific CAR T-cells, per MPEP § 2143(I)(E), a prima facie case of obviousness exists for choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. It would have been obvious to one skilled in the art to try different CAR T-cells including BCMA or CD-19 CAR T-cells to treat a B-cell malignancy because Sommer teaches there are limited types of CAR T-cell therapies available, and specifies BCMA CAR T-cells and CD-19 CAR T-cells.
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending claims for at least the following reason(s):
Regarding claim 1 and a second composition, per MPEP § 2143(I)(A), a prima facie case of obviousness exists for combining prior art elements according to known methods to yield predictable results. It would have been obvious to one skilled in the art to administer the beraprost adjuvant composition for reducing CRS (as claimed by App’999) and another known composition (e.g. tocilizumab) for treating CRS or reducing cytokine levels (as taught by SV) in order to treat CRS or ICANS which are associated with elevated cytokine levels (as taught by SV and Holtzmann).
Accordingly, one would arrive at the instantly claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8-19, 22-29 of copending Application No. 18/162,3447 (reference application) in view of SV and Faulds. Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding instant claims 1, 5, 8-9, App’344 claims a method for treating cancer comprising administering a CRS-inducing amount of a bispecific antibody and a composition comprising BPS-314d (see App’344 claim 1), wherein the composition does not reduce a T cell-meidated killing of a cancer cell by more than about 5% (see App’344 claim 4). App’344 also claims a method of treating CRS or ICANS associated with a bispecific antibody comprising administering a CRS-inducing amount of a bispecific antibody and a composition comprising BPS-314d (see App’344 claim 12).
Regarding instant claim 2, App’344 claims wherein the composition reduces levels of cytokines (see App’344 claims 3, 19).
Regarding instant claim 3, App’344 claims further administering to the subject a composition comprising a corticosteroid, tocilizumab, IL-6 receptor blocker or a combination (see App’344 claims 2, 18).
Regarding instant claim 6, App’344 claims wherein the subject experiences reduced CRS relative to a subject who does not receive the beraprost composition (see App’344 claim 26).
Regarding instant claim 7, App’344 claims wherein the beraprost composition is administered after CRS is detected (see App’344 claim 10).
Regarding instant claims 12, 16, App’344 claims administering the beraprost composition before the bispecific antibody (see App’344 at claim 25).
Regarding instant claim 13, App’344 claims administering the beraprost compostion after the bispecific antibody (see App’344 at claim 23).
Regarding instant claims 14-15, App’344 claims administering the beraprost composition from 1 to 30 days (see App’344 claim 11).
Regarding instant claims 19-20, App’344 claims kits for treating cancer or CRS or ICANS comprising a beraprost composition and a bispecific antibody composition (see App’344 claims 28-29).
The copending claims differ from the instant claims as follows: While App’344 claims methods of treating CRS with a beraprost composition, the primary difference is App’344 claims an additional composition comprising a bispecific antibody and does not specify a CAR T-cell therapy.
However,
Regarding instant claims 1, 10, 18 and bispecific antibodies vs CAR T-cell therapy, SV teaches CAR T-cell therapy and bispecific T-cell engaging single-chain antibodies are both cancer treatments for B-cell leukemia and lymphomas associated with CRS (see SV at Abstract and at p. 1 right col. ¶2). Faulds teaches administering beraprost isomer(s), including beraprost 314d, to treat a viral disease associated with a cyctokine storm (see Faulds at claims 1, 10-14). Faulds teaches administering beraprost lowers lung cytokine concentration in viral infected mice (see Faulds at p. 13 Table 9).
Regarding claim 7, 11 and elevated cytokines, SV teaches IL-6, IL-10, and IFN-γ are core cytokines elevated in patients during CRS. An artisan would readily appreciate a patient could be a mammal such as a human.
Regarding instant claim 17, Faulds teaches embodiments of administering beraprost or its isomers at 0.05 mg/day to 1 mg/day (see Faulds claim 16), or 0.1 to 300 ug/kg/day and may be administered to humans at once or divided into two or more daily doses (see Faulds at p. 9 [0155]).
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending claims for at least the following reason(s):
Regarding bispecific antibodies vs CAR T-cell therapy, per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to one skilled in the art to substitute a bispecific antibody therapy for a CAR T-cell therapy in order to treat a cancer such as leukemia or lymphoma because they are known treatment options for leukemia or lymphoma (as taught by SV). Furthermore, the additional beraprost composition would still be expected to reduce the effects of an associated cytokine storm because it is known to reduce cytokine levels (as taught by Faulds).
Regarding instant claims 4-5, it would have been obvious to one skilled in the art that a patient receiving treatment for reducing cytokine levels would result in lowered cytokine levels compared to a patient that does not.
Accordingly, one would arrive at the instantly claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The specification is objected to.
Claims 1-18 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.R./ Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Si et. al. "Spotlight on Tocilizumab in the Treatment of CAR-T-Cell-Induced Cytokine Release Syndrome: Clinical Evidence to Date" Ther Clin Risk Manag 2020, 16, 705-714. DOI: 10.2147/TCRM.S223468.
2 Cite No. 13 in the IDS filed 1/4/24. Hereinafter Faulds.
3 Shimabukuro-Vornhagen et. al. "Cytokine release syndrome" Journal for ImmunoTherapy of Cancer 2018, 6, 56, 1-14. DOI: 10.1186/s40425-018-0343-9. Hereinafter SV.
4 Holtzman et. al. "Immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes" Neuro-Oncology 2021, 23, 1, 112-121. DOI: 10.1093/neuonc/noaa183 Hereinafter Holtzmann.
5 Hereinafter App’999.
6 Sommer et. al. "Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma" Molecular Therapy 2019, 27, 6, 1126-1138. DOI: 10.1016/j.ymthe.2019.04.001. Hereinafter Sommer.
7 Hereinafter App’344.