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
This action is in response to the papers filed May 14, 2026.
Amendments
Applicant's response and amendments, filed May 14, 2026, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2, 6-8, 10-11, 13-15, 17-18, and 20, amended Claims 1, 4-5, 12, and 16, and added new claims, Claims 21-31.
Claims 1, 3-5, 9, 12, 16, 19, and 21-31 are pending and under examination.
Priority
This application is a continuation of application 16/307,462 filed on December 5, 2018, now abandoned, which is a 371 of PCT/US2017/036231 filed on June 6, 2017. Applicant’s claim for the benefit of a prior-filed application provisional applications:
62/429,737 filed on December 3, 2016;
62/417,292 filed on November 3, 2016; and
62/346,547 filed on June 6, 2016,
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on May 14, 2026 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claims 1 and 12 are objected to because of the following informalities:
As a first matter, the phrase “or between at or about” is grammatically awkward and suffers from a lack of punctuation between “cells or” (Claim 1, line 12; Claim 12, line 14).
As a second matter, where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m). The first T cell dose recited using “viable” language should be separated from the second T cell dose recited using “cells/kg” language by line indentation.
For example, the dose of T cells comprises:
(a)….viable….; or
(b)….cells/kg….
Appropriate correction is required.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
2. The prior rejection of Claim(s) 1, 3-5, and 7-11 under AIA 35 U.S.C. 103 as being unpatentable over Kochenderfer et al (Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor, J. Clin. Oncol. 33(6): 540-549, 2015; available online August 25, 2014; of record in IDS) in view of Novartis (NCT02445248, Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET), May 15, 2015; of record in IDS), Kandalaft et al (2012; of record in IDS), Brudno et al (available online May 20, 2016; of record in IDS), and Geyer et al (available online May 20, 2016; of record in IDS) is withdrawn in light of Applicant’s amendment to independent Claim 1 to recite the CD4+ to CD8+ ratio of about 5:1 to about 1:5, a limitation not taught/disclosed by Kochenderfer et al, Novartis, Kandalaft et al, Brudno et al, and Geyer et al
3. Claim(s) 1, 3-5, 9, 12, 16, 19, and 21-31 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kochenderfer et al (2015; available online August 25, 2014; of record in IDS) in view of Novartis (NCT02445248 (JULIET), May 15, 2015; of record in IDS), Kandalaft et al (2012; of record in IDS), Brudno et al (available online May 20, 2016; of record in IDS), Geyer et al (available online May 20, 2016; of record in IDS), Lee et al (available online October 13, 2014; of record in IDS), and Turtle et al (December 6, 2014; Applicant’s own work; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Kochenderfer et al is considered relevant prior art for having taught a method of treating DLBCL in a subject, the method comprising the step(s) of:
administering a dose of T cells expressing an anti-CD19 CAR (e.g. Abstract) comprising a CD3zeta intracellular signaling domain and a costimulatory receptor signaling domain (e.g. Figure 1a).
Similarly, Novartis is considered relevant prior art for having taught a method of treating DLBCL patients (e.g. “histologically confirmed DLBCL”), the method comprising the step of administering CD19 CAR T cells (e.g. “the CTL019 cell product”, “keywords CART19) to the patients. The art recognized that CTL019 CD19 CAR inherently comprises:
an extracellular antigen binding domain that is an scFv derived from FMC63;
a CD3zeta signaling domain; and
a 4-1BB costimulatory domain.
Neither Kochenderfer et al nor Novartis teach wherein the CD19 CAR T therapy is administered to the patients via outpatient delivery.
However, prior to the effective filing date of the instantly claimed invention, Kandalaft et al is considered relevant prior art for having taught a method of CAR T therapy for the treatment of cancer, the method comprising the steps of:
i) preconditioning the patient with a lymphodepleting therapy (Abstract, Design); and
ii) administering to the preconditioned patient a dose of T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the cancer (Abstract, Rationale, Design), wherein said CAR comprises a CD3zeta signaling domain and a cytoplasmic signaling domain derived from 4-1BB (Abstract).
Kandalaft et al taught wherein the administration of the cell dose and/or the lymphodepleting therapy is carried out via outpatient delivery (pg 4, col. 1-2, joining para, Regimen).
While Kandalaft et al taught that lymphodepletion is performed via outpatient delivery, and would reasonably imply or infer that the CAR T cells are also administered via outpatient delivery, Kandalaft et al do not teach ipsis verbis that the CAR T cells are also administered via outpatient delivery.
However, prior to the effective filing date of the instantly claimed invention, Brudno et al (co-authors to Kochenderfer et al) is considered relevant prior art for having taught methods of CAR-T therapy in clinical medicine, whereby “at other centers, CAR T-cell infusions are performed on an outpatient basis” (pg 3326).
Brudno et al taught that CD19 CAR T therapies have been used in clinical medicine for the treatment of relapsed or chemotherapy-refractory acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) (e.g. pg 3321, introduction).
Similarly, Geyer et al is considered relevant prior art for having taught methods of CD19 CAR-T therapy for the treatment of relapsed or refractory CLL, whereby the patients received doses CD19 CAR T cells as outpatients (“outpatient CAR T cell therapy”; “received… 19-28z T cells, administered outpatient” (Methods), wherein the CD19 CAR comprises a CD3zeta signaling domain and a CD28 costimulatory domain (19-28z).
Neither Kochenderfer et al, Novartis, Kandalaft et al, Brudno et al, nor Geyer et al teach wherein the dose of CAR T cells comprises a CD4+ CAR-expressing cells to CD8+ CAR-expressing cells to be at or about 5:1 to at or about 1:5.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 1, 12, and 16, Lee et al is considered relevant prior art for having taught a method of treating a subject having relapsed or refractory ALL or relapsed or refractory non-Hodgkin lymphoma (NHL), (e.g. Summary Background; pg 517, col. 2, Introduction; pg 518, col. 1), the method comprising the steps of:
i) preconditioning the patient with a lymphodepleting therapy comprising the administration of fludarabine (Summary Methods); and
ii) administering to the preconditioned patient a dose of T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL (Summary Methods).
Lee et al taught wherein the infused dose comprises a CD19 CAR-T CD4+ to CD19 CAR-T CD8+ ratio of 2.6 to 1 (Supplementary Figure 3, “infused CD19-CAR cells”).
Lee et al taught wherein the CD19 CAR comprises an CD3zeta intracellular signaling domain and a costimulatory receptor signaling domain (pg 518, col. 2, Procedures, FMC63-28Z).
Similarly, Turtle et al is considered relevant prior art for having taught a method of treating a subject having chronic lymphocytic leukemia (CLL) or a non-Hodgkin lymphoma (NHL), the method comprising the step of administering a CD19 CAR-T dosage, wherein the relative ratio of CD19 CAR-T CD4+ to CD19 CAR-T CD8+ cells to be administered is about 1:1 (Methods).
The CD19 chimeric antigen receptor of Turtle et al (Juno Therapeutics) naturally comprises an IgG4 hinge domain.
With respect to the limitation wherein the subject has relapsed following remission after treatment with, or become refractory to, one or more prior therapies,
Kochenderfer et al taught wherein the patients with DLBCL had chemotherapy-refractory lymphoma (e.g. pg 541, col. 2, Patient Characteristics), having received 2, 3, 4, 5, or even 12, prior therapies (e.g. Table 1).
The Novartis (NCT02445248, Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET)) includes patients with relapsed or refractory DLBCL (Title).
Brudno et al taught that CD19 CAR T therapies have been used in clinical medicine for the treatment of relapsed or chemotherapy-refractory acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) (e.g. pg 3321, introduction).
Lee et al taught wherein the patients had relapsed or refractory disease (e.g. Abstract Methods, “relapsed or refractory” ALL or NHL).
Turtle et al taught wherein the patients had relapsed or refractory ALL, CLL, or NHL (e.g. pg 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The specification fails to disclose an element of criticality for the treatment of relapsed or refractory DLBC from at least one prior therapies, as opposed to the treatment of relapsed or refractory DLBC from at least one, two, or more, prior therapies taught by the prior art.
With respect to the limitation wherein the dose of the T cells comprises about 2.5x10^7, about 5x10^7, about 1x10^8, or about 2x10^8 viable CAR-expressing T cells,
Those of ordinary skill in the art recognize that the average body mass for adults in the Unites States naturally ranges from 77kg to 91kg.
Thus, Kochenderfer et al taught wherein the dose ranges from about 7.7x10^7 to about 2.3x10^8 CD19 CAR T cells.
Kandalaft et al taught wherein the dose of total CAR-T cells comprises 1x10^6 cells, 3x10^6 cells, or 1x10^9 cells (pg 4, col. 1, standard escalation phase).
Geyer et al taught wherein the dose comprises about 3x10^6, 1x10^7, or 3x10^7 CAR T cells (Results).
Lee et al taught dose 1 of 1x10^6 cells/kg = 7.7x10^7 cells to 9x10^7 cells.
Lee et al taught dose 2 of 3x10^6 cells/kg = 2.3x10^8 cells to 2.7x10^8 cells.
Turtle et al taught a dose of 2x10^5, 2x10^6, or 2x10^7 cells/kg (e.g. pg 2), which is/are equivalent to 1.5x10^7 to 1.8x10^9 cells.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The specification fails to disclose an element of criticality for a dose of about 1x10^7 to about 2.5x10^7, 5x10^7, 1x10^8, or about 2x10^8 total viable CAR-expressing cells, as opposed to the 1x10^6, 3x10^6, 1x10^7, 3x10^7, and/or 1x10^9 total viable CAR T cells taught by the prior art.
With respect to the limitation wherein the dose of the T cells comprises about 5x10^5 to 2x10^6 viable CAR-expressing T cells/kg body weight,
Kochenderfer et al taught administering a CD19 CAR T dose ranging from 1x10^6 to 2.5x10^6 cells/kg (e.g. Table 1).
Kandalaft et al taught wherein the dose of CAR-T cells comprises 1x10^6 cells/kg (dose 1) or 3x10^6 cells/kg (dose 2) (Summary Methods) about 2x10^5 to about 2x10^6 of the cells/subject kg. Kandalaft et al taught wherein the dose of total CAR-T cells comprises 1x10^6 cells, 3x10^6 cells, or 1x10^9 cells (pg 4, col. 1, standard escalation phase).
Geyer et al taught wherein the dose comprises about 3x10^6, 1x10^7, or 3x10^7 CAR T cells (Results).
Those of ordinary skill in the art recognize that the average body mass for adults in the Unites States naturally ranges from 77kg to 91kg. Lee et al taught dose 1 of 1x10^6 cells/kg.
Lee et al taught dose 2 of 3x10^6 cells/kg.
Turtle et al taught a dose of 2x10^5, 2x10^6, or 2x10^7 cells/kg (e.g. pg 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The specification fails to disclose an element of criticality for a dose of about 5x10^5, 1x10^6, and/or 5x10^6 viable CAR T cells/kg, as opposed to the 2x10^5, 1x10^6, 2x10^6, 3x10^6, and/or 2.5x10^7 viable CAR T cells/kg taught by the cited prior art.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and chimeric antigen receptor T cell therapies. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify a CD19 CAR-T immunotherapy method of treating a subject having DLBCL, as per Kochenderfer et al and/or Novartis, to comprise the steps of performing the CD19 CAR-T administration step via outpatient delivery with a reasonable expectation of success because those of ordinary skill in the art previously practiced outpatient administration of CAR-T cells for immunotherapy in clinical trials, as taught by Brudno et al and Geyer et al, being motivated to do so because such had already been successfully reduced to practice in the art.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to try outpatient administration of a CD19 CAR-T immunotherapy in a method of treating a subject having DLBCL with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” One of ordinary skill in the art would have understood that there are only two known options for administration of CAR-T cells to the subject, via inpatient or outpatient settings, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success, as taught by Brudno et al and Geyer et al.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first B-cell hematological cancer disease, e.g. ALL, CLL, and/or NHL, as taught by Brudno et al and Geyer et al, with a second B-cell hematological cancer disease, i.e. DLBCL, as taught by Kochenderfer et al and/or Novartis, in a method of treating a subject having a B-cell hematological cancer disease comprising the step(s) of administering to said patient via outpatient therapy a dose of anti-CD19 CAR T cells with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first B-cell hematological cancer disease, e.g. ALL, CLL, and/or NHL, as taught by Brudno et al and Geyer et al, with a second B-cell hematological cancer disease, i.e. DLBCL, as taught by Kochenderfer et al and/or Novartis, in a method of treating a subject having a B-cell hematological cancer disease comprising the step(s) of administering to said patient via outpatient therapy a dose of anti-CD19 CAR T cells because Brudno et al and Geyer et al taught that clinical medicine practice already performed CAR T-cell infusions, including CD19 CAR T cells, as either inpatient or an outpatient basis to patient’s suffering from B-cell hematological cancer disease, whereby outpatient administration of CD19 CAR T cells is well-tolerated in patients (Geyer et al), and whereby supportive care in response to adverse side effects can be addressed via inpatient contexts as needed, e.g. fevers as a result of cytokine release syndrome (Geyer et al).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to practice a CD19 CAR-T immunotherapy method of treating a B-cell hematological cancer in a subject comprising the step of administering a dose comprising a CD19 CAR-T CD4+ to CD19 CAR-T CD8+ ratio of about 1:1 with a reasonable expectation of success, and being motivated to do so, because both Applicant (Turtle et al) and Lee et al successfully demonstrated a reduction to practice administering a CD19 CAR-T dosage comprising a CD4+ to CD8+ ratio of 2.6 to 1 (Lee et al) to about 1:1 (Turtle et al). Turtle et al taught that adoptive immunotherapy with CD19 CAR T cells of defined subset, and at a CD4+ to CD8+ ratio of about 1:1 is feasible and safe in a majority of heavily pretreated patients with refractory B cell malignancies and has potent anti-tumor activity (Conclusion).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The prior art teaches a CD19 CAR-T CD4/CD8 ratio dosage used for a similar purpose as the instantly claimed invention(s), with a specific embodiment within the claimed range, whereby the size of the claimed range is small and the ordinary artisan would have found the relative ratios to be predictable across the range. Instant specification fails to disclose an element of criticality for the claimed CAR-T CD4/CD8 ratio. The specification fails to disclose an element of criticality for the broadly recited CD4+ to CD8+ CAR T cell ratio of about 5:1 to about 1:5, as opposed to the prior art reduction to practice of a CD4+ to CD8+ CAR T cell ratio of about 2.6:1 or about 1:1.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 3, Kochenderfer et al taught wherein the CAR comprises a CD28 costimulatory signaling domain (e.g. Figure 1a).
The Novartis CTL019 CD19 CAR inherently comprises a cytoplasmic signaling domain derived from 4-1BB.
Kandalaft et al taught wherein CAR comprises a CD3zeta signaling domain and a cytoplasmic signaling domain derived from 4-1BB (Abstract; Figure 1).
Geyer et al taught wherein the CAR comprises an scFv specific for the antigen (anti-CD19 scFv) linked to a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, to wit, CD3zeta, a CD28 costimulatory signaling domain (Methods, 19-28z).
Lee et al taught wherein the CAR comprises a CD28 costimulatory signaling domain (e.g. Abstract Methods).
Turtle et al taught wherein the CAR comprises a 4-1BB costimulatory signaling domain (e.g. pg 2).
With respect to Claims 4-5, Kochenderfer et al taught wherein the CAR comprises a CD19 antigen binding domain from FMC63 (e.g. Figure 1a), which is an art-recognized scFv, as discussed above.
The Novartis CTL019 CD19 CAR inherently comprises an extracellular antigen binding domain that is an scFv derived from FMC63.
Lee et al taught wherein the CAR comprises a CD19 antigen binding domain from FMC63 (e.g. pg 518, col. 2, Procedures), which is an art-recognized scFv, as discussed above.
Turtle et al taught wherein the CAR comprises a CD19 antigen binding domain from FMC63 (e.g. pg 2), which is an art-recognized scFv, as discussed above.
With respect to Claims 23 and 29, Kochenderfer et al taught wherein the B cell lymphoma is DLBCL or PMBCL (e.g. Table 1).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that DLBCL and residual CLL are not interchangeable or substitutable to yield predictable results for purposes of outpatient delivery because, e.g. Kochenderfer reports approximately 87% of DLBCL patients experience grade 3 or higher toxicities in an inpatient setting.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims are merely directed to a method of outpatient delivery of CD19 CAR T cells. The independent claims, and also dependent claims therefrom, fail to recite any particular therapeutic effect and/or patient response to the outpatient delivery of the CD19 CAR T cells. To put it another way, the instant claims do not prohibit or exclude DLBCL patients experience grade 3 or higher toxicities as a result of the outpatient delivery of the CD19 CAR T cells.
Further, as taught by Brudno et al, those of ordinary skill in the art previously recognized clinical practices to manage CAR-T therapy-induced toxicities, whereby “the threshold for transfer to an ICU will clearly vary among institutions” (e.g. pg 3326, col. 2).
See also Maus et al (2016; of record), whereby those of ordinary skill in the art previously understood that after outpatient CAR-T administration, said patients are monitored for a few hours to ensure not acute reaction develops requiring hospitalization so that the patient may return home (e.g. pg 612, col. 2).
See also Slovin et al (2013; of record), whereby those of ordinary skill in the art previously understood that after outpatient CAR-T administration, said patients are monitored (e.g. col. 5, “outpatient Center for T cell infusion,…, clinical monitoring, and bloodwork for immune monitoring”).
See also Stiff et al (2006; of record), whereby those of ordinary skill in the art previously understood “To improve patient satisfaction and resource utilization,… our center developed a comprehensive care protocol for our outpatient transplant center that included performing all [transplants] when feasible in a totally outpatient setting” (e.g. pg 757, col. 2), providing, e.g. nursing/physician assessment, lab tests, antibiotics, etc…, designed to treat patients with total management of nearly all transplant complications, including benign arrythmias, fever, neutropenia, anemia, transfusion support, infection, and pain (e.g. pg 758, col. 1). Patients are admitted to the in-patient unit only for care that would typically be provided in an ICU (e.g. pg 758, col. 1).
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
Applicant provides no objective evidence that symptoms such as grade 3 or higher toxicities such as fever, headache, nausea, or infection absolutely prohibit and/or preclude outpatient delivery of CD19 CAR-T cells to DLBCL and/or PMBCL patients.
Applicant argues that DLBCL and residual CLL are not interchangeable or substitutable to yield predictable results for purposes of outpatient delivery because, e.g. Geyer et al caution that greater disease burden may limit [CAR-T] efficacy
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims are merely directed to a method of outpatient delivery of CD19 CAR T cells. The independent claims, and also dependent claims therefrom, fail to recite any particular therapeutic effect and/or patient response to the outpatient delivery of the CD19 CAR T cells. Kochenderfer et al clearly demonstrated the ability of the CD19 CAR-T cell therapy to elicit complete or partial remissions in most DLBCL and/or PMBCL patients.
Applicant argues that outpatient delivery of CAR T cell therapy is desired and of interest because it addresses several practical and clinical constraints of traditional inpatient delivery including access and cost, among others.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that outpatient delivery of CAR T cell therapy is desired and of interest because it addresses several practical and clinical constraints of traditional inpatient delivery including access and cost, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Stiff et al (2006; of record) taught that those of ordinary skill in the art previously understood “To improve patient satisfaction and resource utilization,… our center developed a comprehensive care protocol for our outpatient transplant center that included performing all [transplants] when feasible in a totally outpatient setting” (e.g. pg 757, col. 2), providing, e.g. nursing/physician assessment, lab tests, antibiotics, etc…, designed to treat patients with total management of nearly all transplant complications, including benign arrythmias, fever, neutropenia, anemia, transfusion support, infection, and pain (e.g. pg 758, col. 1). Patients are admitted to the in-patient unit only for care that would typically be provided in an ICU (e.g. pg 758, col. 1).
Outpatient CAR-T administration, including CD19 CAR-T administration, had previously been suggested and/or successfully reduced to practice (Kandalaft et al; Brudno et al; and Geyer et al).
See also Maus et al (2016; of record) and Slovin et al (2013; of record).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific, clinical, and technical concept of administering CAR T therapy to patients in an outpatient setting.
Applicant argues that CAR T cell therapy is only a viable option if an acceptable safety profile, referring to the avoidance of CAR T cell-mediated toxicities including cytokine release syndrome and neurotoxicity, can be reasonable expected.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., an acceptable safety profile, including, but not limited to, avoidance of CAR T cell-mediated toxicities including cytokine release syndrome and neurotoxicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As evidenced by Kochenderfer et al (Table 1), the CD19 CAR T cell therapy doses encompassed by instant claims is/are able to achieve complete or partial remission of DLBCL and/or PMBCL, even if said patients present with grade 3 toxicities.
Applicant argues secondary consideration that instant application Example 2 demonstrates a majority of treated subjects (74%) achieved an objective response rate, with 44% achieving complete remission, and very few exhibiting toxicity.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, Example 2 speaks to a mixed patient population, including those who suffered from non-DLBCL and/or non-PMBCL disease, e.g. instead were treated for NHL, TCHRBCL, Burkitt lymphoma, mantle cell lymphoma, or follicular lymphoma (e.g. [0359]).
However, the specification fails to disclose the actual response rate(s) for the instantly claimed DLBCL and/or PMBCL patient subpopulations of the Example 2 study. Thus, one simply cannot properly assess the asserted secondary considerations as it pertains to the instantly claimed invention.
The Examiner notes that Example 2 discloses the CD19 CAR T cell formulary was administered with a CD4+: CD8+ ratio of 1:1 (e.g. [0360]). However, instant claims (5:1 to 1:5, and/or 3:1 to 1:3) are far broader in scope than 1:1 ratio.
Applicant argues that there is no reasonable expectation of success for administering CD19 CAR T cells to DLBCL patients via outpatient settings.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s argument is contradicted by the fact that those of ordinary skill in the art had previously recognized and successfully reduced to practice in clinical medicine outpatient CD19 CAR T administration for the treatment of relapsed or chemotherapy-refractory acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) (Brudno et al, Geyer et al).
Applicant argues that the standard of care therapy for DLBCL-RS, a form of DLBCL upon transformation of CLL disease, shifts to more aggressive immunotherapy, and still achieves poor outcomes, with complete remission rates of only about 20%, and less than 20% long-term survival.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., DLBCL-RS, complete remission rate(s), and/or long-term survival rate(s)) are not recited in the rejected independent claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Citation of Relevant Prior Art
4. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Vairy et al (CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia, Drug Design, Development and Therapy 12: 3885-3898, 2018; of record in IDS) is considered relevant art for evidencing that the Juno Therapeutic’s CD19 chimeric antigen receptor (as taught by Turtle et al, 2014; of record) naturally comprises an IgG4 hinge domain (e.g. Table 1).
June et al (U.S. 2014/0227237; effective priority to 61/535,608, filed September 16, 2011) is considered relevant prior art for having disclosed a CAR-T immunotherapy method, wherein the CAR may be an anti-CD19 CAR (e.g. Figure 34; [0073]; as also disclosed in ‘608, e.g. pg 6, lines 2-3 and 15-16), and wherein the CAR-T cell dose is administered to the patient in an outpatient setting (e.g. [0379, 382]; as also disclosed in ‘608, e.g. pg 86, lines 3-5; pg 87, lines 5-6).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the scientific, clinical, and technical concept of administering CAR T therapy to patients in an outpatient setting.
See also previously cited Meisenberg et al (1998; of record), Stiff et al (2006; of record), Butler et al (2013; of record), Slovin et al (2013; of record), and Mous et al (available online March 23, 2016; of record).
Conclusion
5. No claims are allowed.
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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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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