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 .
The amendments and remarks filed 4/1/26 is acknowledged. Claims 1 and 9-10 have been amended. Claim 4 has been canceled. Claims 1-3 and 5-20 are pending and under examination.
Maintained Rejections
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.
Claim(s) 1-2 and 11-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Davilla et al. (Sci Transl Med. 2014 Feb 19;6(224):224ra25) in view of Lee et al. ((Blood.2014; 124(2):188-195).
The instant claims are drawn to a method of treating or delaying the development of cytokine release syndrome (CRS) in a subject, wherein the subject has received a chimeric antigen receptor (CAR) T cell therapy, the method comprising administering an agent comprising tocilizumab to the subject when the subject has no greater than grade 2 CRS, wherein the grade 2 CRS comprises hypoxia or hypotension, and wherein the agent comprising tocilizumab is administered to the subject within 24 hours after onset of fever or hypotension.
Davilla et al. teach that patients with B-ALL were treated with 19-28z CAR T cell (See page 2-3 and 8). Davilla et al. teach that patients with sCRS were treated with tocilizumab alone (Fig. 2), which reduced patients’ fevers and sCRS symptoms within 1 to 3 days similar to steroid therapy, but did not result in dampened expansion of the 19-28z CAR T cells measured in the peripheral blood (See page 5). Davilla et al. teach that diagnosis of sCRS is based on the presence of fevers (38oC), elevation of characteristic cytokines, and clinical toxicities (See table 3). Davilla et al. teach that patients with evidence of CRS have fevers that start about 24 hours after infusion with 19-28z CAR T cells and can persist for several days (See page 5). Davilla et al. teach that patients with sCRS universally exhibited at least one of the following clinical manifestations: hypoxia, hypotension, and /or neurologic changes (See page 5). Davilla et al. teach that sCRS can be managed with high-dose steroids and/or tocilizumab (See page 8). Davilla et al. teach that administration of tocilizumab as a first-line therapy for sCRS in patients MSK-ALL13, MSK-ALL14, and MSK-ALL17 similarly reduced fevers and ameliorated clinical symptoms without apparent effect on 19-28z CAR T cell expansion and persistence (See page 7 and figure 2). Davilla et al. teach that tocilizumab should be used in the first-line treatment of sCRS, with high-dose steroids being reserved for those patients with severe life-threatening CRS unresponsive to tocilizumab (See page 8).
Davilla et al. do not teach administering tocilizumab to the subject when the subject has no greater than grade 2 CRS, wherein the grade 2 CRS comprises hypoxia or hypotension; wherein the agent comprising tocilizumab is administered to the subject within 24 hours after onset of fever or hypotension; wherein the agent comprising tocilizumab is administered to the subject when the subject has no greater than grade 1 CRS, wherein the grade 1 CRS comprises a fever, nausea, fatigue, headache, myalgia, or malaise.
Lee et al. teach an algorithm for the management of CRS (see figure 2). Lee et al. teach that grade 2 CRS is characterized by hypotension that responds to fluids or one low dose vasopressor, hypoxia that responds to <40% O2, and grade 2 organ toxicity (See figure 2). Lee et al. teach that tocilizumab and/or corticosteroids can be used to treat patients with grade 2 CRS (See page 192). Lee et al. teach that the decision to intervene with immunosuppressive agents for patients with grade 2 CRS is influenced by the degree to which the patients is judged to be able to tolerative the altered hemodynamics and organs stresses associated with the syndrome (See page 191). Lee et al. teach that in older patients and patients with significant comorbidities, depending on clinical judgment, it may be appropriate to intervene with immunosuppression in patients with grade 2 CRS (See page 191). Lee et al. teach that in patients with CRS who respond to tocilizumab, fever and hypotension often resolve within a few hours, and pressors and other supportive care measures can be weaned quickly thereafter (See page 192). Lee et al. teach that in some cases, however, symptoms may not completely resolve, and continued aggressive support may be necessary for several days (case 3) (See page 192). Lee et al. teach that if the patient’s condition does not improve or stabilize within 24 hours of the tocilizumab dose, administration of a second dose of tocilizumab and/or a second immunosuppressive agent, such as corticosteroids, should be considered (See page 192). Lee et al. teach that corticosteroids are effective treatment of CRS, and a rapid steroid taper can generally be accomplished within several days without recurrence of the CRS (See page 193). Lee et al. teach that in some settings it may be beneficial to use both tocilizumab over corticosteroids in cases of severe or life-threatening CRS (See page 193).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Davilla to administer tocilizumab to a subject having no greater than grade 2 CRS because Lee et al. teach that tocilizumab can be used to treat grade 2 CRS. One of ordinary skill in the art would be motivated to administer tocilizumab to a subject following CAR T cell therapy when the subject has no greater than grade 2 CRS because doing so would reduce the subjects’ fevers and sCRS symptoms without dampening expansion of the CAR T cells in the blood. One of ordinary skill in the art would have a reasonable expectation of success because it is known in the art that IL-6R blockade via tocilizumab rapidly resolves sCRS.
Furthermore, optimizing the timing of administration of the tocilizumab such that it is administered when the subject has no greater than grade 2 CRS would be within “the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA1955). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Applicant’s Arguments
Applicant argues that Davila also teaches away from premature and/or early intervention based on fever alone and does not teach the amended "within 24 hours after onset of fever or hypotension" limitation. Applicant argues that Davila’s discussion of tocilizumab is presented in the context of managing sCRS, not early treatment within 24 hours after fever onset. Applicant argues that Lee emphasizes limiting early immunosuppression and does not teach the amended "within 24 hours after onset of fever or hypotension" limitation, nor the claimed combination with "no greater than grade 2 CRS". Applicant argues that Lee frames early immunosuppression as potentially compromising efficacy and recommends symptomatic treatment for grade 1 CRS, with immunosuppression directed to preventing life-threatening CRS. Applicant argues that the record does not support optimizing the timing of tocilizumab administration because Davila and Lee repeatedly emphasize uncertainty and risk associated with earlier immunosuppression, including concerns that premature intervention could diminish T cell persistence and/or efficacy and that early aggressive immunosuppression could limit efficacy.
Applicant argues that Nellan's discussion does not connect the "first sign of fever" to the claim's particular clinical constraints (e.g., no greater than grade 2 CRS; and administration within 24 hours after onset of hypotension). Applicant argues that Jensen does not present "early tocilizumab" as a settled, predictable approach with established safety for preserving CAR T therapeutic outcomes. Instead, Jensen frames "pre-emptive" early intervention as something done in select, worrisome cases and expressly acknowledges the need for further analysis to avoid compromising efficacy.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The references are not anticipatory, and were used in an obviousness rejection. Thus, Applicant’s arguments regarding the deficiencies of each reference are not persuasive.
In response to Applicant’s argument that the references do not support that one of skill in the art could optimize the administration of the tocilizumab, given the teachings of the prior art, one of skill in the art would be capable of optimizing the timing of administration of the tocilizumab. Specifically, Davilla et al. teach that patients with evidence of CRS have fevers that start about 24 hours after infusion with 19-28z CAR T cells and can persist for several days. Nellan and Lee teach that it is suggested to treat with prophylactic tocilizumab in patients with high burden disease to reduce toxicities of CRS (See page 518). Nellan and Lee teach that the Seattle group has begun to treat patients with tocilizumab at the first sign of fever, the harbinger of CRS (See page 518). Jensen (2015, Enhancing the IQ of CAR T cells using the synthetic biology tool box, Jensen Lab, PowerPoint presentation, 39 pp.) teach that two patients were treated pre-emptively with early tocilizumab and then dexamethasone and more tocilizumab, and dexamethasone on the upswing of their CAR T cells engraftment. Jensen teach that the CAR T cell engraftment was very robust in the patients, and the treatment did not collapse the CAR T cell population, they achieve B cell aplasia for long periods of time and engraftment (See page 36). Thus, the references in the reference would suggest to one of skill in the art that tocilizumab within 24 hours after onset of fever. One of ordinary skill in the art would be motivated to administer tocilizumab within 24 hours after the onset of fever for the benefit of treating toxicities associated with CAR T cell engraftment. Furthermore, Applicant has not demonstrated criticality of the claimed timing, and determining the optimal time to administer the tocilizumab would be well within the knowledge of the skilled artisan.
Claim(s) 3 and 5-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Davilla et al. (Sci Transl Med. 2014 Feb 19;6(224):224ra25) in view of Lee et al. ((Blood.2014; 124(2):188-195), as applied to claims 1-2 and 11-20 above, and further in view of Nellan and Lee ((2015) Current Opinion in Hematology, 22(6):516-520) and Jensen (2015, Enhancing the IQ of CAR T cells using the synthetic biology tool box, Jensen Lab, PowerPoint presentation, 39 pp).
Davilla et al. teach that patients with B-ALL were treated with 19-28z CAR T cell (See page 2-3 and 8). Davilla et al. teach that patients with sCRS were treated with tocilizumab alone (Fig. 2), which reduced patients’ fevers and sCRS symptoms within 1 to 3 days similar to steroid therapy, but did not result in dampened expansion of the 19-28z CAR T cells measured in the peripheral blood (See page 5).
Davilla et al. teach that diagnosis of sCRS is based on the presence of fevers (38oC), elevation of characteristic cytokines, and clinical toxicities (See table 3). Davilla et al. teach that patients with evidence of CRS have fevers that start about 24 hours after infusion with 19-28z CAR T cells and can persist for several days (See page 5). Davilla et al. teach that patients with sCRS universally exhibited at least one of the following clinical manifestations: hypoxia, hypotension, and /or neurologic changes (See page 5). Davilla et al. teach that
Davilla et al. teach that sCRS can be managed with high-dose steroids and/or tocilizumab (See page 8). Davilla et al. teach that administration of tocilizumab as a first-line therapy for sCRS in patients MSK-ALL13, MSK-ALL14, and MSK-ALL17 similarly reduced fevers and ameliorated clinical symptoms without apparent effect on 19-28z CAR T cell expansion and persistence (See page 7 and figure 2). Davilla et al. teach that tocilizumab should be used in the first-line treatment of sCRS, with high-dose steroids being reserved for those patients with severe life-threatening CRS unresponsive to tocilizumab (See page 8).
Davilla et al. do not teach administering tocilizumab to the subject when the subject has no greater than grade 2 CRS, wherein the grade 2 CRS comprises hypoxia or hypotension; wherein the agent comprising tocilizumab is administered to the subject when the subject has no greater than grade 1 CRS, wherein the grade 1 CRS comprises a fever, nausea, fatigue, headache, myalgia, or malaise; wherein the agent comprising tocilizumab is administered to the subject within 24 hours after onset of fever or hypotension.
Lee et al. teach an algorithm for the management of CRS (see figure 2). Lee et al. teach that grade 2 CRS is characterized by hypotension that responds to fluids or one low dose vasopressor, hypoxia that responds to <40% O2, and grade 2 organ toxicity (See figure 2). Lee et al. teach that tocilizumab and/or corticosteroids can be used to treat patients with grade 2 CRS (See page 192). Lee et al. teach that the decision to intervene with immunosuppressive agents for patients with grade 2 CRS is influenced by the degree to which the patients is judged to be able to tolerative the altered hemodynamics and organs stresses associated with the syndrome (See page 191). Lee et al. teach that in older patients and patients with significant comorbidities, depending on clinical judgment, it may be appropriate to intervene with immunosuppression in patients with grade 2 CRS (See page 191). Lee et al. teach that in patients with CRS who respond to tocilizumab, fever and hypotension often resolve within a few hours, and pressors and other supportive care measures can be weaned quickly thereafter (See page 192). Lee et al. teach that in some cases, however, symptoms may not completely resolve, and continued aggressive support may be necessary for several days (case 3) (See page 192). Lee et al. teach that if the patient’s condition does not improve or stabilize within 24 hours of the tocilizumab dose, administration of a second dose of tocilizumab and/or a second immunosuppressive agent, such as corticosteroids, should be considered (See page 192). Lee et al. teach that corticosteroids are effective treatment of CRS, and a rapid steroid taper can generally be accomplished within several days without recurrence of the CRS (See page 193). Lee et al. teach that in some settings it may be beneficial to use both tocilizumab over corticosteroids in cases of severe or life-threatening CRS (See page 193).
Davilla and Lee do not teach wherein the tocilizumab is administered within 24 hours after the onset of fever or within 16 hours after the onset of fever.
Nellan and Lee teach that it is suggested to treat with prophylactic tocilizumab in patients with high burden disease to reduce toxicities of CRS (See page 518). Nellan and Lee teach that the Seattle group has begun to treat patients with tocilizumab at the first sign of fever, the harbinger of CRS (See page 518).
Jensen (2015, Enhancing the IQ of CAR T cells using the synthetic biology tool box, Jensen Lab, PowerPoint presentation, 39 pp.) teach that two patients were treated pre-emptively with early tocilizumab and then dexamethasone and more tocilizumab, and dexamethasone on the upswing of their CAR T cells engraftment. Jensen teach that the CAR T cell engraftment was very robust in the patients, and the treatment did not collapse the CAR T cell population, they achieve B cell aplasia for long periods of time and engraftment (See page 36).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer tocilizumab when the subject within 24 hours after onset of fever because Nellan and Lee teach that patients can be treated with tocilizumab at the first sign of fever. Given that the art establishes that (i) fever is the hallmark of CRS, (ii) fevers start about 24 hours after infusion with 19-28z CAR T, and (iii) tocilizumab can be administered to reduce fever and treat sCRS symptoms that develop after anti-CD19 CAR T infusion, it would be obvious to administer the tocilizumab as early as possible when the subject has no greater than grade 2 CRS and at the first sign of fever and to prevent the progression of CRS to a higher, and more severe, grade. One of ordinary skill in the art would be motivated to administer tocilizumab when the subject has no greater than grade 2 CRS and within 24 hours after the first sign of fever following administration of anti-CD19 CAR T cell therapy because doing so would reduce the fever, as well as prevent the progression to more severe CRS. One of ordinary skill in the art would have a reasonable expectation of success because Davilla et al. teach that administration of tocilizumab reduces patients’ fevers and sCRS symptoms, without affecting 19-28z CAR T cell expansion and persistence. Similarly, Jensen teaches that preemptive treatment with tocilizumab and dexamethasone does not affect CAR T cell engraftment.
Furthermore, optimizing the timing of administration of the tocilizumab such that it is administered within 24 hours after the onset of fever would be within “the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA1955). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Applicant’s Arguments
Applicant argues that Davila also teaches away from premature and/or early intervention based on fever alone and does not teach the amended "within 24 hours after onset of fever or hypotension" limitation. Applicant argues that Davila’s discussion of tocilizumab is presented in the context of managing sCRS, not early treatment within 24 hours after fever onset. Applicant argues that Lee emphasizes limiting early immunosuppression and does not teach the amended "within 24 hours after onset of fever or hypotension" limitation, nor the claimed combination with "no greater than grade 2 CRS". Applicant argues that Lee frames early immunosuppression as potentially compromising efficacy and recommends symptomatic treatment for grade 1 CRS, with immunosuppression directed to preventing life-threatening CRS. Applicant argues that the record does not support optimizing the timing of tocilizumab administration because Davila and Lee repeatedly emphasize uncertainty and risk associated with earlier immunosuppression, including concerns that premature intervention could diminish T cell persistence and/or efficacy and that early aggressive immunosuppression could limit efficacy.
Applicant argues that Nellan's discussion does not connect the "first sign of fever" to the claim's particular clinical constraints (e.g., no greater than grade 2 CRS; and administration within 24 hours after onset of hypotension). Applicant argues that Jensen does not present "early tocilizumab" as a settled, predictable approach with established safety for preserving CAR T therapeutic outcomes. Instead, Jensen frames "pre-emptive" early intervention as something done in select, worrisome cases and expressly acknowledges the need for further analysis to avoid compromising efficacy.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s argument that the references do not support that one of skill in the art could optimize the administration of the tocilizumab, given the teachings of the prior art, one of skill in the art would be capable of optimizing the timing of administration of the tocilizumab. Specifically, Davilla et al. teach that patients with evidence of CRS have fevers that start about 24 hours after infusion with 19-28z CAR T cells and can persist for several days. Nellan and Lee teach that it is suggested to treat with prophylactic tocilizumab in patients with high burden disease to reduce toxicities of CRS (See page 518). Nellan and Lee teach that the Seattle group has begun to treat patients with tocilizumab at the first sign of fever, the harbinger of CRS (See page 518). Jensen (2015, Enhancing the IQ of CAR T cells using the synthetic biology tool box, Jensen Lab, PowerPoint presentation, 39 pp.) teach that two patients were treated pre-emptively with early tocilizumab and then dexamethasone and more tocilizumab, and dexamethasone on the upswing of their CAR T cells engraftment. Jensen teach that the CAR T cell engraftment was very robust in the patients, and the treatment did not collapse the CAR T cell population, they achieve B cell aplasia for long periods of time and engraftment (See page 36). Thus, the references in the reference would suggest to one of skill in the art that tocilizumab can be administered within 24 hours after onset of fever. One of ordinary skill in the art would be motivated to administer tocilizumab within 24 hours after the onset of fever for the benefit of treating toxicities associated with CAR T cell engraftment. Furthermore, Applicant has not demonstrated criticality of the claimed timing, and determining the optimal time to administer the tocilizumab would be well within the knowledge of the skilled artisan.
Claim Status
No claims are allowed.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa L. Ford can be reached at (571)272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SANDRA CARTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights