DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 2, 6, 8, 12, 15, 18, 21, 35, 36, 38, 42, 45, 54, 62 and 63-70 are pending.
Claims 15, 21, 36, 38, 62, 63 and 64 have been withdrawn.
Claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 are under examination
Priority
Claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 have been assigned the priority date of August 30, 2016, the filing date of the provisional application 62,381,153
35 USC § 101 rejections withdrawn
The rejections of claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 as not being directed to patent eligible subject matter under 35 USC § 101 are withdrawn in view of Applicant’s amendments to the claims.
35 USC § 112(b) rejections withdrawn
The rejection of claim 35 under 35 USC 112(b) is withdrawn in view of Applicant’s arguments.
35 USC § 103 rejections maintained
The rejection of claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 under 35 U.S.C. 103(a) as being unpatentable over Maude et al (Cancer J, 20:119-122, 2014, IDS) and Patel et al (Immunother, 6:675-678, 2014, IDS) in view of Teachey et al (Inflammation Research Vol. 64, Supp1 1 August 8, 2015, IDS) and Lee et al (Blood,124:188-195, 2014, IDS) are maintained.
The claims are drawn to a method for treating a subject having a cancer, comprising administering to the subject a therapeutically effective dose of a CAR-expressing cell therapy; and acquiring a cytokine release syndrome (CRS) risk status for the subject, wherein said CRS risk status comprises a measure of or soluble IL6 receptor (s1L6R) in a sample from the subject, wherein the CRS risk status is indicative of the subject's risk for developing CRS and wherein the subject is identified as being at risk of developing CRS if the level or activity of sIL6R is greater than a reference level or activity; and wherein the method further comprises, responsive to a determination of the CRS risk status administering to the subject a therapy to treat CRS.
Maude disclose administering to the subject with acute lymphoblastic leukemia (ALL) a therapeutically effective dose of a CAR-expressing cell therapy comprising CART19 and measuring the level of the cytokines such as IL-6 in patients with cytokine release syndrome, and administering the anti-IL-6R antibody, tocilizumab to patients with severe cytokine release syndrome (page 2, paragraphs 1- 3; page 3, paragraph 2 to page 5, paragraph 2). Maude discloses that severe CRS started a median of 1 day after infusion, whereas cytokine-release syndrome that was not severe started a median of 4 days after infusion (page 5, 3rd paragraph). Maude discloses treatment for patients with severe CRS (page 8).
Patel discloses administering 19-28z CAR-T cell immunotherapy to patients with relapsed or refractory B-ALL, measuring CRP in serum, and treating patients with severe cytokine release syndrome with tocilizumab (page 2, 3rd paragraph to page 3, 3rd paragraph). Patel disclose monitoring cytokine levels to determine severe CRS from normal CRS (page 6). Patel disclose treatment of patients with severe CRS (Abstract; page 3).
One of ordinary skill in the art would have been motivated to combine Maude, and Patel because they both relate to the development of severe CRS in patients treated with anti-CD19 CAR T immunotherapy and treatments.
However, neither Maude, Patel and Lee specifically disclose that sIL-6R levels are elevated in severe CRS in refractory ALL treated with CAR-T cell that recognize the B-lymphocyte surface antigen, CD19.
However, this is made up by Teachey that disclose the that sIL-6R levels were markedly elevated in patients with grade 4 CRS treated with an anti-CD19 CAR T cell, CTL019, the same CAR T cells used in Maude. Teachey disclose that IL-6 trans-signaling is clinically relevant.
One of ordinary skill in the art would have been motivated to apply Teachey’s disclosure that sIL-6R is elevated in patients with grade 4 CRS treated with an anti-CD19 CAR T cell, CTL019 with Maude and Patel’s method for detecting markers that indicate the development of severe CRS in patients treated with anti-CD19 CAR T immunotherapy because Maude, Patel and Teachey disclose measuring markers of severe CRS following treatment of patients with B-ALL with an anti-CD19 CAR T immunotherapy. Maude and Teachey also disclose that IL-6 and sIL-6R can initiate trans-signaling to induce proinflammatory responses. Patel disclose monitoring cytokine levels to determine severe CRS from normal CRS while Teachey disclose that levels of sIL-6R and IL-6 are elevated in severe CRS.
Furthermore, Lee describes clinical manifestations of severe CRS as well as cytokine levels such as IL-6 following treatment with CAR T cells (page 3). Lee discloses that circulating cytokine levels could be used to diagnose syndrome severity (page 4, 4th paragraph to page 5, 2nd paragraph). Lee also disclose that when IL-6 and soluble IL-6R can initiate trans-signaling to induce proinflammatory responses (page 4, 1st paragraph).
Thus, it would have been prima facie obvious to combine Maude, Patel and Teachey’s disclosures relating to the development of severe CRS in patients treated with CAR T immunotherapy to have a method for treating a subject having a cancer, comprising administering to the subject a therapeutically effective dose of a CAR-expressing cell therapy; and acquiring a cytokine release syndrome (CRS) risk status for the subject, wherein said CRS risk status comprises a measure of or soluble IL6 receptor (s1L6R) in a sample from the subject, wherein the CRS risk status is indicative of the subject's risk for developing CRS and wherein the subject is identified as being at risk of developing CRS if the level or activity of sIL6R is greater than a reference level or activity; and wherein the method further comprises, responsive to a determination of the CRS risk status administering to the subject a therapy to treat CRS.
With regards to claim 18, determining levels of sIL-6 greater than at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 500, 1000-fold or more greater, relative to the reference level or activity, the cutoff level of sIL-6R for determining selectivity for determining risk status is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
With regards to claim 70, Maude discloses that severe CRS started a median of 1 day after infusion, whereas cytokine-release syndrome that was not severe started a median of 4 days after infusion. Thus, it would have been obvious for the subject to be evaluated 10 days or less after infusion with the CAR-expressing cell therapy.
Applicant states that the present application is based, at least in part, on the discovery that several biomarkers, including sIL6R, can predict CRS early on during the course of a therapy, e.g., an immune cell-based therapy (e.g., a CART cell treatment). Such early detection of biomarkers can occur before a subject shows symptoms, or becomes ill, from CRS, e.g., within the first 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 day, or less, of CAR T cell administration.
Applicants state that the pending claims are not simply directed to a method for treating a subject who has severe CRS but rather are drawn to a method for treating a subject who has been identified as being at risk of developing CRS. Applicant argues that not only do Maude, Patel and Lee fail to disclose that sIL6R levels are elevated in severe CRS, but also offer no teaching or suggestion of determining a CRS risk status, which is indicative of the subject's risk for developing CRS, by measuring the level or activity of sIL6R.
Applicant argues that Lee actually teaches away from the instant claims. Applicant argues that Lee states that "although scientific and clinical evidence implicates a relationship between inflammatory cytokine levels and CRS severity, it remains unclear whether severity in an individual patient can be predicted based on cytokine levels." Lee further states "we conclude that real-time analysis of a broad panel of cytokines will not significantly impact management of individual patients with CRS
at the current time and recommend that treatment decisions be based on clinical parameter.
Applicant argue that according to the Office, Teachey discloses that "sIL-6R levels were markedly elevated in patients with grade 4 CRS treated with an anti-CD19 CART cell ... Applicant argues that Teachey merely states that "[b]oth IL6 and IL6R were markedly elevated in patients with CRS4. Applicant argues that Teachy describes measuring cytokine levels in patients with CRS but does not provide that measuring the level or activity of any cytokine, let alone sIL6R as recited in the instant claim, is capable of determining a CRS risk status for a subject after receiving a CAR T cell therapy.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Maude, Patel, Teachey and Lee 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).
Maude discloses that severe cytokine-release syndrome started a median of 1 day after infusion, whereas cytokine-release syndrome that was not severe started a median of 4 days after infusion following CAR T therapy. Thus, cytokine levels start to become elevated soon after treatment with antibody-based immunotherapy. It is noted that most of the claims do not specify when the levels of sIL-6R are being measured. Only claim 70 recites a time, 10 days. Based on Maude the severe cytokine-release syndrome would already be underway by the time sIL-6R levels were being detected if measurements were made within the first few days following CAR T therapy. Given that sIL-6R was known to be elevated in cytokine-release syndrome and that severe cytokine-release syndrome started a median of 1 day after infusion of the antibody-based therapy, it would have been obvious to measure levels of sIL-6R within days of treatment to acquire a cytokine release risk status for the subject. Furthermore, given, that a time for measuring the sIL-6R levels is not recited in the claims measuring high levels of sIL-6R well after the CAR-expressing cell therapy had been initiated would indicate a severe cytokine-release syndrome, based on the teachings of Maude and Teachey.
FIG. 14 of the specification discloses that the levels of 4 cytokines (IFNy, IL6, sIL6R, and sgp130) over time in the 14 grade 4-5 subjects treated with tocilizumab. It is not clear from the specification whether levels of sIL-6R were measured within days of CAR T cell therapy and could be used, by itself to demonstrate the development of severe cytokine-release syndrome. The specification discloses that peak levels of 24 cytokines, including IFNy, IL6, ILS, sIL2Ra, sgp130, sIL6R, MCPl, MIPla, MIP1J3, and GM-CSF sent in the first month after CTL019 were associated with grade 4-5 CRS compared to grade 0-3 CRS and significant by the Holm's adjusted p-value. The specification discloses that IFNy and sgp130, rise very early and that these two cytokines were the only ones differently elevated for severe versus non-severe CRS in the first 3 days after infusion and prior to patients becoming critically ill after adjustment for multiple comparisons (page 275, line 19 to page 276, line 1; page 285, lines 15-22)). With a 3 variable regression model, found by forward selection, we accurately predicted which patients developed severe CRS using IFN-gamma, sgpl30, and ILlRa (PPV 75%, NPV 94%, sensitivity 86%, specificity 89%, AUC=0.93) (Id). Thus, it is not clear from the specification whether sIL-6R was able to predict severe CRS, by itself. It further appears that the ability of a particular cytokine or cytokines to predict severe CRS was dependent on the timing for measuring the cytokines following the administration of the CAR T therapy as well as the concentration of CAR expressing cell.
In response to Applicant’s argument that Teachy describes measuring cytokine levels in patients with CRS but does not provide that measuring the level or activity of any cytokine, let alone sIL6R as recited in the instant claim, is capable of determining a CRS risk status for a subject after receiving a CAR T cell therapy, Teachey disclose the that sIL-6R levels were markedly elevated in patients with grade 4 CRS treated with an anti-CD19 CAR T cell while Maude discloses that severe cytokine-release syndrome started a median of 1 day after infusion, whereas CRS that was not severe started a median of 4 days after infusion with the same CAR T cells used in Teachey. It would have been obvious to measure sIL-6R levels soon after treatment with anti-CD19 CAR T cell and have a reasonable expectation of success that elevated sIL-6R levels would be indicative of the patient’s risk for developing CRS.
In response to Applicant’s argument that Lee actually teaches away from the instant claims, Lee does not does not criticize, discredit, or otherwise discourage the use of sIL-6R for predicting the severity of CRS.
MPEP 2143.01 (I)states that
The disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention. In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004), the claims of a utility patent application were directed to a shoe sole with increased traction having hexagonal projections in a "facing orientation." 391 F.3d at 1196-97, 73 USPQ2d at 1142. The Board combined a design patent having hexagonal projections in a facing orientation with a utility patent having other limitations of the independent claim. 391 F.3d at 1199, 73 USPQ2d at 1144. Applicant argued that the combination was improper because (1) the prior art did not suggest having the hexagonal projections in a facing (as opposed to a "pointing") orientation was the "most desirable" configuration for the projections, and (2) the prior art "taught away" by showing desirability of the "pointing orientation." 391 F.3d at 1200-01, 73 USPQ2d at 1145-46. The court stated that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." Id. In affirming the Board’s obviousness rejection, the court held that the prior art as a whole suggested the desirability of the combination of shoe sole limitations claimed, thus providing a motivation to combine, which need not be supported by a finding that the prior art suggested that the combination claimed by the applicant was the preferred, or most desirable combination over the other alternatives. Id. See also In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016).
Lee does disclose that measuring cytokines in cancer patients is particularly challenging in patients with cancer, wherein baseline inflammatory cytokine levels can be very high due to their underlying disease (page 5). Lee discloses that fold increases, net increases, or rate of change in cytokine levels may provide better correlates of CRS severity than absolute cytokine levels. Lee further discloses that diagnostic utility could require a profile of several different cytokines rather than changes in only 1 level. This would be consistent with the present invention given that the specification proposes the use of cytokines, including IFNy, IL6, ILS, sIL2Ra, sgp130, sIL6R, MCPl, MIPla, MIP1J3, and GM-CSF to predict severity of CRS.
Furthermore, it appears that the ability of a particular cytokine or cytokines to predict severe CRS was dependent on the timing for measuring the cytokine or cytokines following the administration of the CAR-expressing cell therapy as well as the concentration of CAR-expressing cell.
Unexpected Results
Applicant argues that Example 2 of the present application describes the identification of predictive biomarkers for CRS after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. In this study, Applicants discovered that several cytokines, including those recited in the claims, in the first month after infusion were highly associated with severe CRS. Using regression modeling, it could be accurately predicted which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Applicant argues that as provided in the present application, "[t]hese comprehensive profiling data provide novel insights into CRS biology, and importantly represent the first data that can accurately predict which patients have a high probability of becoming critically ill." Applicant argues that the study "establishes that concentrations of sIL6R and sgp130 are likely clinically and biologically relevant, as this is the first work that has systemically evaluated sIL6R and sgp130 after CART cells."
Applicant’s arguments have been considered but are not persuasive. Footnote 24 states “ it establishes that concentrations of sIL6R and sgp130 are likely clinically and biologically relevant, as this is the first work that has systemically evaluated sIL6R and sgpl30 after CAR T cells”. This does not state that sIL-6R was capable of by itself indicative of determination of the CRS risk status. The specification does not appear to demonstrate that sIL-6R was used individually to determine the risk status of a subject for developing CRS. The specification does not disclose that levels of sIL-6R can accurately predict which patients have a high probability of becoming critically ill.
It is noted that claim 2 recites the limitation “the CRS risk status is indicative of whether the subject is at high risk or low risk of developing severe CRS.
Furthermore, as discussed previously, the ability of a particular cytokine or cytokines to predict severe CRS would be dependent on the timing for measuring the cytokine or cytokines following the administration of the CAR-expressing cell therapy as well as the concentration of CAR-expressing cell.
Maude discloses that severe cytokine-release syndrome started a median of 1 day after infusion, whereas cytokine-release syndrome that was not severe started a median of 4 days after infusion while Teachey disclose the that sIL-6R levels were markedly elevated in patients with grade 4 CRS treated with an anti-CD19 CAR T cell, CTL019, the same CAR T cells used in Maude. Thus, it would have been obvious to measure sIL-6R levels to indicate a subject’s risk for developing CRS. Applicant has not demonstrated that sIL-6R levels were superior to any other cytokine for determining a subject’s risk for developing CRS. In fact it appears as if the specification suggests that measuring the levels of a panel of cytokines including IFNy, IL6, ILS, sIL2Ra, sgp130, sIL6R, MCPl, MIPla, MIP1J3, and GM-CSF would be the best way to determine the CRS risk status for a subject following the administration of a CAR-expressing therapy.
Double Patenting rejections maintained
The rejections of claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 4 of U.S. Patent No. 11,747,346 are maintained.
Applicant request that the double patenting rejections be held in abeyance until the rejections outstanding in the instant application are overcome.
Summary
Claims 2, 6, 8, 12, 18, 35, 42, 45, 54 and 65-70 stand rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646