DETAILED ACTION
In application filed on 03/29/2023, Claims 36-55 are pending. The claim set submitted on 12/10/2025 is considered because this is the most recent claim set with some preliminary amendments. Claims 42-48 are considered in the current office 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/04/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 12/10/2025 is acknowledged. Claims 36-41 and 49-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/10/2025.
Group II, Claims 42-48 are considered on the merits below.
Drawings
The drawings are objected to because figures, not limited to Figures 1A-D do not have a high resolution. Certain reference characters in the figures are not clear. Applicant should provide Figures with improved legibility and resolution.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over by Hrusovsky et al. (WO2019199871A1, submitted in IDS on 04/04/2024) in view of Jensen et al. (US20190112379A1, submitted in IDS on 04/04/2024) and further in view of Gisslén et al. ("Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study." EBioMedicine 3 (2016): 135-140”).
Regarding Claim 42, Hrusovsky teaches a method comprising:
providing a biological sample from the subject (See Para 0012…the sample of physiological fluid may be obtained from a subject within 24 hours after a medical procedure is performed on a subject);
measuring a neurofilament light chain (NfL) level in the biological sample (See Para 0022…the single-assay test may comprise obtaining, via an immunoassay, a concentration of NF-L in the at least one liquid sample); and
Hrusovsky does not explicitly teach a method of treating immunotherapy-associated neurotoxicity in a subject in need thereof;
wherein the subject has an immunotherapy-associated neurotoxicity; and
administering a treatment for the immunotherapy-associated neurotoxicity before, after, and/or during an immunotherapy when the subject has an elevated NfL level compared to a control or when the subject has an NfL level of more than about 44 pg/mL.
In the analogous art of methods for preventing or ameliorating toxicity caused by or due to a therapy, such as an immunotherapy or a cell therapy, by pre-emptive or early administration of a toxicity-targeting agent(s), Jensen teaches:
a method of treating immunotherapy-associated neurotoxicity (See Abstract… methods for preventing or ameliorating toxicity caused by or due to a therapy, such as an immunotherapy or a cell therapy, by pre-emptive or early administration toxicity-targeting agent(s).) in a subject in need thereof (See Claim 1… the subject has been previously administered a therapy, which therapy comprises an immunotherapy and/or a cell therapy);
wherein the subject has an immunotherapy-associated neurotoxicity (See Para 0020…the steroid is administered at a time in which the subject exhibits grade 2 neurotoxicity or within 24 hours after the subject exhibits a first sign or symptom of grade 2 neurotoxicity following administration of the therapy); and
administering a treatment for the immunotherapy-associated neurotoxicity before, after, and/or during an immunotherapy (See Para 0020…the steroid is administered at a time in which the subject exhibits grade 2 neurotoxicity or within 24 hours after the subject exhibits a first sign or symptom of grade 2 neurotoxicity following administration of the therapy; See Para 0019…the agent or other treatment is or comprises tocilizumab. In some such embodiments, the tocilizumab is administered, thereby teaching “an immunotherapy”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky to incorporate “a method of treating immunotherapy-associated neurotoxicity in a subject in need thereof; wherein the subject has an immunotherapy-associated neurotoxicity; and administering a treatment for the immunotherapy-associated neurotoxicity before, after, and/or during an immunotherapy” as taught by Jensen for the benefit of treating, preventing, delaying, or attenuating the development of a toxicity when the subject has been previously administered a therapy, such as a therapy including an immunotherapy and/or a cell therapy (Jensen, Para 0005-0006), which allows for the provision of a method including the timing of the administration of the agents or treatments for toxicity, that provide various advantages, such as lower toxicity while maintaining persistence and efficacy of the administered cells (Jensen, Para 0003).
The combination of Hrusovsky and Jensen does not teach “when the subject has an elevated NfL level compared to a control or when the subject has an NfL level of more than about 44 pg/mL”.
In the analogous art disclosing that Cerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection, Gisslén teaches that “when the subject has an elevated NfL level compared to a control or when the subject has an NfL level of more than about 44 pg/mL” (See Section 2.5, Page 137…CSF NFL concentrations were measured using a sensitive sandwich method (NF-light® ELISA kit, UmanDiagnostics AB, Umeå, Sweden) as previously described (Jessen Krut et al., 2014; Norgren et al., 2003). The coefficient of variations (CVs) for the repeatability and intermediate precision for this assay is CV < 6% and CV < 7%, respectively, and the lower limit of quantification (LLOQ) is 50 pg/mL determined by repeated measurements (n = 15) of a CSF sample with low (52 pg/mL) concentration and still acceptable variability (CV = 12%). See Page 136…To date, measurement of neurofilament light chain NFL) concentrations in the cerebrospinal fluid (CSF) appears the most sensitive and useful biomarker of active CNS injury in HIV infection—showing elevations in not only overt HAD but also in patients with less severe, inapparent or clinically confounded impairment).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky and Jensen to incorporate the step of ““when the subject has an elevated NfL level compared to a control or when the subject has an NfL level of more than about 44 pg/mL” as taught by Gisslén for the benefit of providing NFL as a reliable noninvasive biomarker for neuronal injury in a variety of neurodegenerative conditions (Gisslén , Abstract), allowing for the demonstration that that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings (Gisslén, Abstract).
Regarding Claim 43, the method of claim 42 is obvious over Hrusovsky, Jensen and Gisslén.
Hrusovsky teaches that the biological sample comprises serum, plasma, or cerebrospinal fluid (CSF) (See Para 0060…the sample of physiological fluid (for example a serum sample, plasma sample, or CSF sample)).
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Hrusovsky et al. (WO2019199871A1, submitted in IDS on 04/04/2024) in view of Jensen et al. (US20190112379A1, submitted in IDS on 04/04/2024) and further in view of Gisslén et al. ("Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study." EBioMedicine 3 (2016): 135-140”) as applied to claim 42 above, and further in view of Farwell et al. (WO2019147960A1) and further in view of Liles et al. (US20190361026A1).
Regarding Claim 44, the method of claim 42 is obvious over Hrusovsky, Jensen and Gisslén.
The combination of Hrusovsky, Jensen and Gisslén does not teach that measuring the NfL level in the biological sample is performed up to 30 days before the subject is expected to receive the immunotherapy.
In the analogous art of the diagnosis and prognosis of spinal muscular atrophy (SMA) as well as identification of responders to treatment of SMA. Also provided are methods of treating subjects with SMA, Farwell teaches that the measuring the NfL level (See Claims 45…wherein the neurofilament is a neurofilament light chain) in the biological sample (See Claim 2…measuring a neurofilament level in a biological sample) is performed before the subject is expected to receive the immunotherapy (See Claims 2, 4, 22 and 26…measuring a neurofilament level in a biological sample obtained from the human subject before initiation of an SMA therapy; and administering a therapeutically effective amount of the SMA therapy to the human subject.).
While combination of Hrusovsky, Jensen, Gisslén and Farwell does not explicitly teach the measuring the NfL level in the biological sample being performed up to 30 days before, Farwell teaches that the measuring the NfL level in the biological sample being performed up to 30 days before by using an overlapping range disclosure ((See Claims 2, 4, 22 and 26…measuring a neurofilament level in a biological sample obtained from the human subject before initiation of an SMA therapy).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen and Gisslén to incorporate that measuring the NfL level in the biological sample is performed up to 30 days before the subject is expected to receive the immunotherapy for the benefit of finding the neurofilament levels that serve as effective biomarkers for spinal muscular atrophy (SMA) wherein the human subject has been previously determined to have, in a biological sample obtained from the human subject, a neurofilament level prior to initiation of the SMA therapy that is higher than a control (Farwell, Claim 1, Page 68; Page1, lines 24-32-Page 2, lines 1-4), allowing for the timely and proper treatment of subjects with SMA, thus, requiring a need for biomarkers of SMA (Farwell, Page 1, Lines 13-21).
The combination of Hrusovsky, Jensen, Gisslén and Farwell does not teach that measuring the NfL level (which is a biomarker as disclosed in Hrusovsky [Para 00106]) in the biological sample is performed up to 30 days before the subject is expected to receive the immunotherapy.
In the analogous art of methods for diagnosing or detecting the risk of an adverse event associated with immunotherapy, such as cytokine release syndrome (CRS), neurotoxicity or both, Liles teaches measuring the NfL level (which is a biomarker as disclosed in Hrusovsky [Para 00106]) (See Para 0128…evaluation of biomarker concentrations) in the biological sample is performed up to 30 days (See Para 0129…day 0 before CAR-T cell) before the subject is expected to receive the immunotherapy (See Para 0128-0129…evaluation of Clinical Laboratory Parameters, CAR-T Cell Counts, and Biomarker Concentrations; See Para 0129…Blood was collected before lymphodepletion, on day 0 before CAR-T cell infusion…).
Further, Liles teaches that adverse event biomarkers may be measured in a subject before pre-conditioning chemotherapy, before immunotherapy (e.g., adoptive immunotherapy infusion comprising a chimeric antigen receptor (CAR) modified T cell), or shortly after pre-conditioning chemotherapy and/or immunotherapy (See Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen, Gisslén and Farwell to incorporate that measuring the NfL level (which is a biomarker as disclosed in Hrusovsky [Para 00106]) in the biological sample is performed up to 30 days before the subject is expected to receive the immunotherapy, as taught by Liles for the benefit of measuring adverse event biomarkers in identifying subjects at risk of adverse events after immunotherapy (Liles, Abstract, Para 0070), allowing for the treatment of subjects identified as at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both to minimize such potential adverse events (Liles, Abstract).
Claims 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Hrusovsky et al. (WO2019199871A1, submitted in IDS on 04/04/2024) in view of Jensen et al. (US20190112379A1, submitted in IDS on 04/04/2024) and further in view of Gisslén et al. ("Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study." EBioMedicine 3 (2016): 135-140”) as applied to claim 42 above, and further in view of Mcmahon et al. (WO2019200251).
Regarding Claim 45, the method of claim 42 is obvious over Hrusovsky, Jensen and Gisslén.
The combination of Hrusovsky, Jensen and Gisslén does not teach that the immunotherapy- associated neurotoxicity is immune effector cell-associated neurotoxicity syndrome (ICANS).
In the analogous art of a method of preventing, lessening the effects, or treating cytokine release syndrome (CRS) or related disorders, and/or neurotoxicity associated with immunotherapy comprising administering defibrotide, Mcmahon teaches that the immunotherapy- associated neurotoxicity is immune effector cell-associated neurotoxicity syndrome (ICANS) (See Para 0017… methods of preventing, lessening the effects, or treating CAR-related encephalopathy syndrome (CRES) (i.e. CAR-T associated neurotoxicity/ICANS) in a patient comprising administering a therapeutically effective amount of defibrotide; Also See Para 0019).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen and Gisslén to incorporate that the immunotherapy- associated neurotoxicity is immune effector cell-associated neurotoxicity syndrome (ICANS) as taught by Mcmahon for the benefit of preventing, lessening the effects, or treating CAR-related encephalopathy syndrome (CRES) (i.e. CAR-T associated neurotoxicity/ICANS) in a patient comprising administering a therapeutically effective amount of defibrotide (Mcmahon, Para 0017), allowing for the provision of methods of administering defibrotide to prevent and/or treat cytokine release syndrome (CRS), especially CRS associated with CAR-T therapy (Mcmahon, Para 0005).
Regarding Claim 46, the method of claim 42 is obvious over Hrusovsky, Jensen and Gisslén.
While Jensen teaches that when the plurality of receptors are ligated, such as upon encounter of a cell expressing the first and second antigens, a desired response is achieved, such as full immune activation or stimulation, e.g., as indicated by secretion of one or more cytokine, proliferation, persistence, and/or carrying out an immune effector function such as cytotoxic killing of a target cell (Para 0167),
The combination of Hrusovsky, Jensen and Gisslén does not explicitly teach that the immunotherapy comprises an immune effector cell therapy.
In the analogous art of a method of preventing, lessening the effects, or treating cytokine release syndrome (CRS) or related disorders, and/or neurotoxicity associated with immunotherapy (See Page 0016…immunotherapy; See Para 0023…(i.e. CAR-T associated neurotoxicity/ICANS) after administration of immunotherapy) comprising administering defibrotide, Mcmahon teaches that the immunotherapy comprises an immune effector cell therapy (See Claim 2… treating CAR-related encephalopathy syndrome (CRES) or chimeric antigen receptor (CAR)-T associated neurotoxicity or immune effector cell (IEC) therapy associated neurotoxicity syndromes (ICANS)…; See Para 0023…ICANS).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen and Gisslén to incorporate that the immunotherapy comprises an immune effector cell therapy as taught by Mcmahon for the benefit of preventing and/or lessening the effects of and/or treating CAR-related encephalopathy syndrome (CRES) or chimeric antigen receptor (CAR)-T associated neurotoxicity or immune effector cell (IEC) therapy associated neurotoxicity syndromes (ICANS) in a patient comprising administering a therapeutically effective amount of defibrotide (Mcmahon, Claim 2; Para 0023), allowing for the provision of methods of administering defibrotide to prevent and/or treat cytokine release syndrome (CRS), especially CRS associated with CAR-T therapy (Mcmahon, Para 0005).
Regarding Claim 47, the method of claim 46 is obvious over Hrusovsky, Jensen and Gisslén.
The combination of Hrusovsky, Gisslén and Mcmahon does not teach that the immune effector cell therapy is a CAR T cell therapy selected from engineered CAR T, universal allogeneic CAR T, CD19-specific CAR T, anti-CD19 CAR T, anti-BCMA CAR T, anti-CD22, anti- CAIX, anti-PSMA, anti-MUC1, anti-FRa, anti-meso-RNA, anti-CEA, anti-IL13Ra2, or anti- HER2.-T.
In the analogous art of a method of preventing, lessening the effects, or treating cytokine release syndrome (CRS) or related disorders, and/or neurotoxicity associated with immunotherapy comprising administering defibrotide, Mcmahon teaches that the immune effector cell therapy (See Para 0066… CAR-T cell therapy; See Para 0067…immunotherapy ( e.g.CAR-T cell therapy or monoclonal antibody) administration…; See Para 00126-00127…patients undergoing CAR-T therapy may have undergone or be undergoing allogenic or autologous CAR-T therapy) is a CAR T cell therapy (See Para 0066… CAR-T cell therapy; See Para 0067…immunotherapy ( e.g.CAR-T cell therapy or monoclonal antibody) administration…; See Para 00126-00127…patients undergoing CAR-T therapy may have undergone or be undergoing allogenic or autologous CAR-T therapy) selected from engineered CAR T, universal allogeneic CAR T, CD19-specific CAR T, anti-CD19 CAR T, anti-BCMA CAR T, anti-CD22, anti- CAIX, anti-PSMA, anti-MUC1, anti-FRa, anti-meso-RNA, anti-CEA, anti-IL13Ra2, or anti- HER2.-T (See Para 00126-00127…patients undergoing CAR-T therapy may have undergone or be undergoing allogenic or autologous CAR-T therapy…the present disclosure has undergone allogenic CAR-T therapy, wherein Universal CAR-T Therapy is also known as Allogeneic CAR-T Therapy).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen and Gisslén to incorporate that the immune effector cell therapy is a CAR T cell therapy selected from engineered CAR T, universal allogeneic CAR T, CD19-specific CAR T, anti-CD19 CAR T, anti-BCMA CAR T, anti-CD22, anti- CAIX, anti-PSMA, anti-MUC1, anti-FRa, anti-meso-RNA, anti-CEA, anti-IL13Ra2, or anti- HER2.-T, as taught by Mcmahon for the benefit of having a patient undergo a type of CAR-T therapy (Mcmahon, Para 00126-00127) in treating a variety of underlying primary diseases ((Mcmahon, Para 00125), allowing for the provision of methods of administering defibrotide to prevent and/or treat cytokine release syndrome (CRS), especially CRS associated with CAR-T therapy (Mcmahon, Para 0005).
Regarding Claim 48, the method of claim 42 is obvious over Hrusovsky, Jensen and Gisslén.
While Hrusovsky teaches detection assays involving the use of multispecific Hrusovsky, Gisslén and Mcmahon does not teach that the immunotherapy comprises a bispecific antibody therapy.
In the analogous art of a method of preventing, lessening the effects, or treating cytokine release syndrome (CRS) or related disorders, and/or neurotoxicity associated with immunotherapy comprising administering defibrotide, Mcmahon teaches that the immunotherapy (See Page 0016…immunotherapy; See Para 0023…(i.e. CAR-T associated neurotoxicity/ICANS) after administration of immunotherapy) comprises a bispecific antibody therapy (See Para 0016…the immunotherapy is a bispecific antibody).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Hrusovsky, Jensen and Gisslén to incorporate that the immunotherapy comprises a bispecific antibody therapy, for the benefit demonstrating that bispecific antibody is a form of immunotherapy used in preventing, lessening the effects, or treating Cytokine Release Syndrome (CRS) in a patient (Mcmahon, Para 0016) allowing for the provision of methods of administering defibrotide to prevent and/or treat cytokine release syndrome (CRS), especially CRS associated with CAR-T therapy (Mcmahon, Para 0005).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
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/OYELEYE ALEXANDER ALABI/ Examiner, Art Unit 1797