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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 13, 2025, has been entered.
DETAILED ACTION
Applicant’s response filed on November 13, 2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed May 15, 2025, are hereby withdrawn.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 and 55 were amended. Claims 57-67 are new.
Claims 42-46, 55, and 57-67 are pending and examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on November 13, 2025, has been considered.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42-46, 55, and 57-67 are 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.
Claims 42 and 55 recites the limitation "neurotoxicity" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claims 42 and 55 refer to two distinct types of neurotoxicity, ICANS and non-ICANS. It is unclear whether the inflammatory agent is supposed to reduce ICANS neurotoxicity, non-ICANS neurotoxicity, or both.
Claims 43-46 and 57-58 are also rejected because of their dependency on claim 42.
Claims 59-67 are also rejected because of their dependency on claim 55.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1, 25-28, and 42-46 under 35 U.S.C. 102(a)1 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27: 477.e1-477.e7. March 2021), as evidenced by Santomasso et al. (Cancer Discovery 8: 958-971. 2018), Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019), U.S. Patent Application Publication No. 20200147136 (Albertson), and Zhou et al. ( Front. Immunol. 11: 1-16. 2020) is withdrawn in light of Applicant’s cancellation of claims 1 and 25-28 and the amendments to claim 42 to recite that the method comprises determining non-ICANS neurotoxicity in the selected subject.
Claims 1, 25-28, and 42-48 are rejected under 35 U.S.C. 102(a)1 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27: 477.e1-477.e7. March 2021), as evidenced by Santomasso et al. (Cancer Discovery 8: 958-971. 2018), Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019), U.S. Patent Application Publication No. 20200147136 (Albertson), and Zhou et al. ( Front. Immunol. 11: 1-16. 2020).
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claim 55 under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021) and Santomasso et al. (Cancer Discovery 8: 958-971. 2018), as evidenced by Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019), U.S. Patent Application Publication No. 20200147136 (Albertson), and Zhou et al. ( Front. Immunol. 11: 1-16. 2020) is withdrawn in light of Applicant’s amendments to claim 55 to recite “determining non-ICANS neurotoxicity in the subject by monitoring the subject for symptoms of agraphia, micrographia, dysgraphia, or any combination thereof”.
New 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.
Claims 42-45 and 57-58 rejected under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021) and Santomasso et al. (Cancer Discovery 8: 958-971. 2018). This is a new rejection made in response to Applicant’s amendments to claim 42. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
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).
Regarding claims 42-45, 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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of reducing CRS (and in conjunction neurotoxicities) of Banerjee with method of examining patients for neurotoxicities after they completely resolved CRS and/or ICANS to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to combine the methods of Bannerjee and Santomasso with a reasonable expectation of success because Bannerjee and Santomasso are focused on treating CRS and, by extension, neurotoxicites associated with CAR T-cell therapy using tocilizumab and/or corticosteroids. Furthermore, Santomasso specifically identifies that neurotoxicity sometimes occurred after CRS or neurotoxicity had completely resolved. As such, it would have been obvious to continue to examine these patients even after CRS or ICANS resolved for signs of neurotoxicity as this was a known phenomenon. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 57, Bannerjee, as stated supra, specifically teaches that they treated patients with an initial CRS grade of 2 with tocilizumab (Table 2). Therefore, Bannerjee selected and treated patients with grade 2 or higher CRS.
Regarding claim 58, Banerjee, as stated supra, teaches that several of their patients developed ICANS (Table 2) and Santomasso, as stated supra, teaches that 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.
Therefore, it would have been obvious to continue to examine these patients even after ICANS resolved for signs of neurotoxicity as it was a known phenomenon that neurotoxicity can recur after initially being resolved. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant’s arguments filed November 13, 2025, are acknowledged.
Applicant argues they are the first to identify the correlation between the occurrence of grade ≥ 2 CRS or any grade ICANS with the risk of developing non-ICANS neurotoxicities and developed a mitigating and managing strategy for non-ICANS neurotoxicities. Applicant argues that none of the cited references disclose or even suggest this correlation, much less the specific application of this correlation for mitigating and managing these non-ICANS neurotoxicities by selectively treating a specific patient population as claimed. Applicant argues that Bannerjee and Santomasso do not teach selectively treating patients who develop grade ≥ 2 CRS or grade ≥ 1 ICANS and further monitoring these patients for onset of non-ICANS. Instead, Bannerjee and Santomasso focus on administering mitigating therapeutics for CRS regardless of CRS grade and without any rationale for targeting patients with grade ≥ 2 CRS. Bannerjee and Santomasso do not identify any specific risk associated with grade ≥ 2 CRS compared to grade 1 CRS nor any correlation with the development of non-ICANS. Furthermore, Santomasso does not distinguish between ICANS and non-ICANS neurotoxicities. Instead, Santomasso broadly discusses neurotoxicity without differentiating between ICANS and non-ICANS neurotoxicities (page 6, paragraph 2-page 11, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As stated supra, 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).
Santomasso, as stated supra, 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). Furthermore, 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. Additionally, 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, although Santomasso did not identify their neurotoxicities as non-ICANS neurotoxicity, the neurotoxicities identified by Santomasso fall within the definition of non-ICANS as disclosed by the Applicant.
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. Applicant recites in claim 1 that the mitigating therapeutic treats neurotoxicity. As this is the only treatment step identified, this initial treatment for neurotoxicity is implied to also be responsible for the reduction in the non-ICANS neurotoxicites. As such, even if other methods focused on treating just CRS or just ICANS using anti-inflammatory agents, it is unclear how those methods would not also cause a reduction in non-ICANS as they have followed all the identified steps of claim 1.
Regarding Applicant’s argument that the reference do not suggest selectively treating patients grade ≥ 2 CRS or any grade ICANS, it is noted that claim recites selecting a subject who has been determined to have grade ≥ 2 CRS or grade ≥ 1 ICANS and administering to the selected subject a mitigating therapeutic. Bannerjee and Santomasso teach that they identified patients who developed grade 2 CRS and provided a mitigating therapeutic (tocilizumab and/or corticosteroids). Therefore, Bannerjee and Santomasso do teach identifying subjects with grade 2 CRS and administering to those selected subjects a mitigating therapeutic that is an anti-inflammatory. Although Bannerjee and Santomasso administer the mitigating therapeutics to patients that fall outside of this range, they still teach that they administered the mitigating therapeutic to patients that fall within the required range and, thus, teach selecting patients grade 2 CRS
Thus, Applicant’s arguments are unpersuasive.
Claims 42 and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27: 477.e1-477.e7. March 2021) and Santomasso et al. (Cancer Discovery 8: 958-971. 2018) as applied to claims 42 and 45 above, and further in view of Zhou et al. ( Front. Immunol. 11: 1-16. 2020). This is a new rejection. Applicant’s traversal has been considered and was addressed above.
The teachings of Banerjee and Santomasso are as discussed above.
Banerjee and Santomasso are silent as to the specific corticosteroid used to treat their patients.
Zhou teaches that it was common within the field to treat patients experiencing ICANS with dexamethasone as the corticosteroid treatment (Table 3). Although Banerjee and Santomasso do not specifically identify the corticosteroid used in their clinical trials, it is well understood that dexamethasone would have been one of the known options, and would have been immediately envisioned as a corticosteroid that could be used in the combined method of Banerjee and Santomasso.
Claims 55, 59-61, 63-64, and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021), Santomasso et al. (Cancer Discovery 8: 958-971. 2018), and Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019). This is a new rejection made in response to Applicant’s amendments to claim 55. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written was addressed above.
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).
Regarding claims 55 and 59-61, 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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of reducing CRS (and in conjunction neurotoxicities) of Banerjee with method of examining patients for neurotoxicities after they completely resolved CRS and/or ICANS to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to combine the methods of Bannerjee and Santomasso with a reasonable expectation of success because Bannerjee and Santomasso are focused on treating CRS and, by extension, neurotoxicites associated with CAR T-cell therapy using tocilizumab and/or corticosteroids. Furthermore, Santomasso specifically identifies that neurotoxicity sometimes occurred after CRS or neurotoxicity had completely resolved. As such, it would have been obvious to continue to examine these patients even after CRS or ICANS resolved for signs of neurotoxicity as this was a known phenomenon. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Banerjee and Santomasso do not teach determining non-ICANS neurotoxicity by monitoring the subject for symptoms of agraphia, micrographia, dysgraphia, or any combination thereof after administering the CAR-T cell therapy.
However, 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).
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 reducing neurotoxicity and monitoring for non-ICANS after recovery from CRS of the combined teachings of Banerjee and Santomasso by including assessments for handwriting abilities and dysgraphia to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to make the modification with a reasonable expectation of success because Lee teaches that handwriting abilities are routinely assessed when grading ICANS in patients and that one of the early symptoms of ICANS is dysgraphia. As such, it would have been obvious to assess dysgraphia in this patient population as it is a minimally invasive method of examining and it is an early indicator, allowing for early detection of neurotoxicity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 63, Bannerjee, as stated supra, specifically teaches that they treated patients with an initial CRS grade of 2 with tocilizumab (Table 2). Therefore, Bannerjee selected and treated patients with grade 2 or higher CRS.
Regarding claim 64, Banerjee, as stated supra, teaches that several of their patients developed ICANS (Table 2) and Santomasso, as stated supra, teaches that 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.
Therefore, it would have been obvious to continue to examine these patients even after ICANS resolved for signs of neurotoxicity as it was a known phenomenon that neurotoxicity can recur after initially being resolved. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 66, Bannerjee is silent as to the timeframe associated with examining and identifying ICANS in their patients.
However, Santomasso teaches that they examined their patients for 30 days for neurotoxicity and continued to monitor at least two patients for 39 and 96 days, respectively, as they continued to have at least grade 2 neurotoxicity after 30 days (Figure 1).
Therefore, it would have been obvious to monitor the patients for at least 26 days after CAR T-cell therpay as Santomasso teaches that they monitored each of their patients for 30 days following CAR T-cell therapy for neurotoxicity development including multiple patients that experienced recurrent bouts of neurotoxicity after recovering from an initial bout neurotoxicity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 67, Bannerjee is silent as to the timeframe associated with examining and identifying ICANS in their patients.
However, Santomasso teaches that they examined their patients for 30 days for neurotoxicity and continued to monitor at least two patients for 39 and 96 days, respectively, as they continued to have at least grade 2 neurotoxicity after 30 days (Figure 1).
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 reducing neurotoxicity and monitoring for non-ICANS after recovery from CRS of the combined teachings of Banerjee and Santomasso by monitoring for neurotoxicity after 100 days or more. One of ordinary skill in the art would have been motivated to make the modification with a reasonable expectation of success because Santomasso teaches that they had a patient that continued to experience neurotoxicity 96 days after CAR T-cell treatment. As such, it would have been obvious to continue to assess their patients for neurotoxicity even after 100 days as Santomasso already identifies that neurotoxicity can last for at least 96 days.
Furthermore, although Santomasso teaches that they assessed neurotoxicity after 96 days which is not more than 100 days, the MPEP 2144.05(i) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Waite, 168 F.2d 104, 108, 77 USPQ 586, 590 (CCPA 1948); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Swenson, 132 F.2d 1020, 1022, 56 USPQ 372, 374 (CCPA 1942); In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); Gentiluomo v. Brunswick Bowling and Billiards Corp., 36 Fed. App'x 433 (Fed. Cir. 2002)(non-precedential)(disagreeing with argument that overlapping ranges were required to find a claim prima facie obvious); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 55 and 61-62 are rejected under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021), Santomasso et al. (Cancer Discovery 8: 958-971. 2018), and Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019) as applied to claims 55 and 61 above, and further in view of Zhou et al. ( Front. Immunol. 11: 1-16. 2020). This is a new rejection based on new claim 62.
The teachings of Banerjee, Santomasso, and Lee are as discussed above.
Banerjee and Santomasso are silent as to the specific corticosteroid used to treat their patients.
Zhou teaches that it was common within the field to treat patients experiencing ICANS with dexamethasone as the corticosteroid treatment (Table 3). Although Banerjee and Santomasso do not specifically identify the corticosteroid used in their clinical trials, it is well understood that dexamethasone would have been one of the known options, and would have been immediately envisioned as a corticosteroid that could be used in the combined method of Banerjee and Santomasso.
Claims 55 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Banerjee et al. (Transplantation and Cellular Therapy 27. 477.e1-477.e7. March 2021), Santomasso et al. (Cancer Discovery 8: 958-971. 2018), and Lee et al. (Biol Blood Marrow Transplant 25: 625-638. 2019) as applied to claims 55 and 61 above, and further in view of Gutierrez et al. (Journal of Critical Care 58: 58-64. 2020). This is a new rejection based on new claim 65.
The teachings of Banerjee, Santomasso, and Lee are as discussed above. Santomasso teaches that they performed EEG on 30 of the 33 patients who experienced neurotoxicity including all 22 patients (100%) with severe neurotoxicity, 1 patient with grade 2 neurotoxicity, and 7 patients with grade 1 neurotoxicity (page 960, column 2, paragraphs 2-3).
The combined teachings of Banerjee, Santomasso, and Lee teach all of the elements of the claimed method of reducing neurotoxicity except for imaging the subject's brain via positron emission tomography or magnetic resonance imaging or performing an electroencephalogram (EEG) if they exhibit symptoms of agraphia, micrographia, or dysgraphia.
However, Gutierrez teaches that EEG and MRI are used as diagnostic tests for CAR-T-cell related toxicities (table 4 and page 61, column 2, paragraphs 3-5). Gutierrez teaches that several institutions perform diagnostic EEG recordings at the onset of neurotoxicity or when the ICANS grade is >2 (table 4).
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 combined method of reducing neurotoxicity of Banerjee, Santomasso, and Lee by including EEG and MRI as diagnostic tests for CAR-T-cell related toxicities to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to make the modification with a reasonable expectation of success because Santomasso teaches that they performed EEG on 30 of the 33 patients who experienced neurotoxicity including all 22 patients (100%) with severe neurotoxicity, 1 patient with grade 2 neurotoxicity, and 7 patients with grade 1 neurotoxicity and Gutierrez teaches that several institutions perform diagnostic EEG recordings at the onset of neurotoxicity or when the ICANS grade is >2. Therefore, performing EEGs or MRI after identifying neurotoxicity are a known standard of car within the field. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Furthermore, in regard to claim 65, MPEP 2111.04 (II) indicates that he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631