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 .
DETAILED ACTION
Applicant’s response filed on August 14, 2026, has been considered. Rejections and/or objections not reiterated from the previous office action mailed February 18, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-41, 47-54, and 56 were cancelled. Claims 42, 44 55, and 64-65 were amended. Claims 68-69 are new.
Claims 42-46, 55, and 57-69 are pending and examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on August 14, 2026, has been considered.
New Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 42-46, 55, and 57-69 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new rejection made in response to Applicant’s amendments to the claims.
The factors to be weighed to evaluate whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is undue are set forth in MPEP 2164.01(a).
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Although all the factors have been considered, the relevant factors will be addressed below.
Breadth of the claims: Claims 42 and 55 recite the following claim language “A method of reducing the likelihood of developing non-immune effector cell associated neurotoxicity syndrome (non-ICANS) neurotoxicity in a subject who has received ciltacabtagene autoleucel (cilta-cel) for the treatment of multiple myeloma in the subject … administering to the selected subject an anti-inflammatory agent in an amount effective to reduce the likelihood of developing non-ICANS neurotoxicity in the subject, wherein the anti-inflammatory agent is administered before the selected subject has developed non-ICANS neurotoxicity … wherein the non-ICANS neurotoxicity comprises movement adverse events, neurocognitive adverse events, personality change adverse events, or any combination thereof
The broadest reasonable interpretation is that this method reduces the risk of developing Non-ICANS neurotoxicities associated with movement adverse events, neurocognitive adverse events, and/or personality change adverse events after recovering from grade ≥2 CRS or ICANS by administering any anti-inflammatory to treat the CRS or ICANS and before non-ICANS neurotoxicity occurs
Nature of the invention: The subject matter of the invention relates to a method of reducing the likelihood of developing non-immune effector cell associated neurotoxicity syndrome (non-ICANS) neurotoxicity in a subject who has received ciltacabtagene autoleucel (cilta-cel) by administering anti-inflammatories to treat CRS or ICANS and prevent non-ICANS neurotoxicity from occurring
State of the prior art: The prior art teaches that anti-inflammatories can be used to treat CRS and ICANS following BCMA CAR-T cell therapies (including ciltacabtagene autoleucel), as identified by Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021) and Santomasso et al. (Cancer Discovery 8: 958-971. 2018, that neurotoxicity (i.e. Non-ICANS) sometimes occurred after CRS/ICANS had completely resolved, as identified by Santomasso, and that dysgraphia and handwriting assessments have previously been used for identifying neurotoxicities, such as ICANS, in patients, as identified by Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019)
Regarding the term non-ICANS, this is interpreted to refer to neurotoxicities that occur after recovery from cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS) based on Applicant’s specification (paragraphs 0033 and 0085). Time of onset after recovery from cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS) is one of the primary identifiers differentiating ICANS and non-ICANS as the instant specification discloses multiple symptoms that are associated with ICANS and non-ICANS neurotoxicities, including encephalopathy, tremor, dysgraphia, and apraxia (paragraphs 0036 and 0063).
Banerjee teaches a method of treating CRS in patients that received 1 of 4 different BCMA CAR-T cell therapies (including ciltacabtagene autoleucel) to treat multiple myeloma and providing a mitigating therapeutic (tocilizumab) for patients with an initial CRS grade of 2 and peak CRS grade of 2. ~50% of the patients had a peak CRS grade of 2. 40% of patients received corticosteroids to treat CRS. ~25% of the patients in the study exhibited any grade of ICANS (abstract and table 2). Note that table 2, “Early Toci” of Banerjee demonstrates that at least a portion of these patients had both a CRS grade of 2 and corticosteroid administration. Additionally, Banerjee teaches that tocilizumab was employed for the management of grade 2 or higher CRS (page 477.e2, column 1, paragraph 2).
Although Bannerjee teaches administering tocilizumab to patients with grade 2 CRS, Bannerjee does not teach determining non-ICANS neurotoxicity in the subject after recovery from CRS or ICANS.
Santomasso teaches that they treated patients experiencing CRS and/or neurotoxicities associated with CAR T-cell therapy by administering tocilizumab and/or corticosteroid with 43.7% of patients that received tocilizumab having their peak neurotoxicity prior to or on the day of tocilizumab administration. Santomasso teaches that severe neurotoxicity often began as disorientation and impaired attention before progressing to myoclonus, depressed level of consciousness, and encephalopathy. The instant specification discloses that these neurotoxicity symptoms are considered to be associated with non-ICANS neurotoxicities and correspond to movement adverse events or cognitive adverse events (paragraphs 0035-0036). Santomasso teaches that neurotoxicity sometimes occurred after CRS and/or ICANS had completely resolve. Santomasso specifically states that neurotoxicity sometimes occurred after CRS had completely resolved. Furthermore, as can be seen in Figure 1, multiple patients with varying levels of neurotoxicites fully recovered (i.e. grade 0) before experiencing neurotoxicities again at least once. See for example rows 2-3, 6-7 and 9-11 for patients with a peak neurotoxicity grade of 1-2 and rows 5, 9-10, 12-13, and 16 for patients with a peak neurotoxicity grade of 3-4 (page 960, column 1, paragraph 1-page 965, column 2, paragraph 3, Table 1, and Figure 1). Thus, non-ICANS neurotoxicity as defined above was known to occur after recovery from neurotoxicites and/or CRS.
Furthermore, although Banerjee is directed to treating CRS and is silent to treating non-ICANS neurotoxicity after CRS, Santomasso teaches that the anti-IL6R monoclonal antibody tocilizumab, with or without corticosteroid, is often used to mitigate CRS and neurotoxicity (page 961, paragraph 1). As such, although Banerjee focuses on treating CRS, their methods would also have an effect on reducing neurotoxicity in their patients.
Lee teaches a system for assessing neurologic toxicity in a subject associated with a medical treatment (abstract and page 632, column 1, paragraph 3 - column 2, paragraph 1). Lee teaches that one of the early symptoms of ICANS is dysgraphia (page 631, column 2, paragraph 4). Lee teaches that one aspect of the grading of ICANS is based on handwriting abilities (table 5 and page 634, column 1, paragraph 1).
Level of predictability in the art: The prior art has successfully reduced to practice that anti-inflammatories are consistently used as a mitigating therapeutic to treat CRS and ICANS and that neurotoxicities can occur after recovery from CRS and ICANS. However, the prior art does not identify that any of these mitigating therapeutics reduces the likelihood that one will develop non-ICANS neurotoxicities.
Amount of direction provided by the inventor and existence of working examples: The specification identifies that they examined patients from multiple clinical studies and found a correlation between patients developing grade ≥2 CRS and/or any grade ICANS and the development of non-ICANS neurotoxicities (Examples 1-5). They identified that in the 68284528MMY2001 Clinical Study 16 patients exhibited CRS and/or ICANS and that 12 of those developed other neurotoxicities after recovering from CRS and/or ICANS and that 5 of those experienced movement and neurocognitive toxicities. All 16 of the patients who developed CRS and/or ICANS were treated with anti-inflammatories before developing non-ICANS at a later date (Example 1). Example 2 identifies that in the 68284528MMY2003 Clinical Study, an additional 3 patients experienced non-ICANS and Example 3 identifies that in the 68284528MMY3002 Clinical Study, an additional 3 patients experienced Non-ICANS neurotoxicities. In Example 2, only one of the patients is identified as receiving anti-inflammatories as mitigating therapeutics to treat CRS and none were identified in Example 3. Example 4 is focused on evaluating factors contributing to the non-ICANS neurotoxicities based on the data from the 68284528MMY2001 Clinical Study with 97 total patients and 12 with identified non-ICANS neurotoxicities (of which 5 were categorized as movement and neurocognitive Treatmenet Emergent Adverse Events) and specifically states “Given the exploratory nature of the analysis with multiplicity and the small number of events (i.e., movement and neurocognitive TEAEs), results were intended for hypothesis generating and should be interpreted with caution” (paragraph 00106).
Example 5 identifies that the Clinical Study protocols were amended to incorporate the recommendation for early and aggressive steroid treatment of and grade ICANS in an effort to evaluate whether this intervention may decrease the risk of movement and neurocognitive TEAEs developing after CRS resolution (point 8), Table 13 identifies a cluster of other neurotoxicities associated with movement and neurocognitive TEAEs were observed at higher frequency in participants with high burden of disease and in participants experiencing higher grade CRS (grade 2 and above_ or any grade ICANS. This may be indicative that Grade 2 or above CRS and any grade ICANS are early indicators for the development of other neurotoxicity after a period of recovery from CRS and/or ICANS. Therefore, this may represent an opportunity for early intervention and more aggressive supportive care (including steroids) to mitigate the risk for developing other neurotoxicities (Table 13 under Other Neurotoxicities).
Example 5 does state that the mitigation strategies that they cited to were initiated for all ongoing cilta-cel studies and that the incidence of movement and neurocognitive adverse events has decreased from 5% to 1% (paragraph 00150).
The statement from paragraph 00150 is the only statement regarding a reduction in the incidence of other neurotoxicites. However, this statement is related to all the mitigating strategies and is not specific to treatment with anti-inflammatories. Furthermore, as identified by the Applicant, the data should be interpreted with caution due to the small sample size.
As such, there is nothing within Applicant’s clinical data cited throughout the specification that shows that treating CRS/ICANS with an anti-inflammatory reduced the risk of developing non-ICANS neurotoxicities. Although Applicant has shown a correlation with grade 2 or above CRS and any grade ICANS and the development of non-ICANS neurotoxicites, there’s no comparative data with patients that received anti-inflammatories and those that didn’t to treat CRS and/or ICANS to show that anti-inflammatories reduce the likelihood of non-ICANS development. Anti-inflammatories are a known common treatment method for CRS and ICANS, and it appears that all the patients that experienced CRS/ICANS in Applicant’s cited studies received anti-inflammatories. Furthermore, at multiple points within Applicant’s examples, they state the potential for these mitigating strategies to reduce the risk for developing other neurotoxicities without identifying that this is actually what is occurring based on the data they have collected. Therefore, the Applicant has not shown that treating with anti-inflammatories reduces the risk of non-ICANS development.
Quantity of experimentation needed: In light of the above factors, the applicant has not provided enablement for reducing the likelihood of developing non-ICANS neurtoxicity. As such, there would be undue experimentation related to reducing the likelihood of developing non-ICANS neurtoxicity to practice the scope of the claim.
Furthermore, it is worth addressing that Applicant’s arguments (page 9, paragraph 2) cite to the preventative nature of the claimed method. However, there are no known methods to test for and provide evidence for prevention of development of non-ICANS as there’s no way to know who would otherwise develop non-ICANS if not for being administered the anti-inflammatories. It is unclear how one would determine whether a subject was going to develop non-ICANS absent the treatment versus a subject that was never going to develop non-ICANS. As identified in the specification in Example 1, not all patients that had CRS/ICANS ended up with non-ICANS neurotoxicities. As such, this results in unpredictability on how someone could prevent non-ICANS development using the claimed method as there are unknown experimental methods related to determining prevention of the development of non-ICANS
Claims 43-46 and 68-69 are also rejected because of their dependency on claim 42. Claims 56-67 are also rejected because of their dependence on claim 55.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KEENAN A BATES/Examiner, Art Unit 1631
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