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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 2, 2025, has been entered.
The amendment filed September 2, 2025, is acknowledged and has been entered. Claims 92-95 have been amended. Claims 101, 110-111 and 116 have been canceled. Claims 117-118 have been newly added.
Claims 92-100, 102-109, 112-115 and 117-118 are pending and are under examination. The species under consideration are the first CAR binding CD19 and the second CAR binding CD22 or CD20.
Information Disclosure Statement
The information disclosure statement has been considered.
Grounds of Rejection Maintained
Claim Rejections - 35 USC § 103
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 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.
Claims 92-94 and 96-100, 102-109, 112-115 and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Brentjens et al (H, (1):143-151, 2012), Till et al (B, doi:10.1182/blood-2011-10-387969, pages 1-36, 2012), Calissano et al (US 2012/0128586 A1, IDS) and June et al (US 2013/0287748 A1, IDS).
Brentjens et al teach clinical studies of treating B cell malignancies such as lymphoma and CLL by administering autologous T cells expressing CD19 CARs that resulted in partial or complete responses and that CARs can comprise a CD28, 4-1BB and CD3 zeta domain (see pages 145-148 and Figure 1). Brentjens et al teach that the CD20 antigen is an additional antigen that can be targeted on B cell malignancies (see page 148).
Till et al teach a clinical study administering T cells expressing a CD20 specific CAR comprising a CD28, 4-1BB and CD3 zeta domain to patients with relapsed B cell lymphoma that had not previously been treated with T cells expressing a CD20 specific CAR (see entire document, e.g., abstract).
Calissano et al teach methods of treating B cell CLL by administering T cells that express a chimeric CAR that binds CD19 and T cells that express a CAR that binds CD20 to treat B-cell CLL (see claims and pages 2-3). Calissano et al teach that CLL relapses and teach targeting therapy at the time of relapse (see pages 1 and 5-7).
June et al administering autologous T cells expressing a chimeric antigen receptor that binds antigen CD19 and autologous T cells expressing chimeric antigen receptor that binds antigen CD20 in combination to treat B-cell CLL. (see pages 1 and 2). June et al teach that the hinge and transmembrane region of the CAR can be from CD8 alpha, the costimulatory domain can be a CD28 and 4-1BB signaling domain and the intracellular signaling domain can be a CD3 zeta signaling domain (see pages 2, 4, 5, 10 and 12). June et al teach administering the CAR T cells in compositions comprising cell numbers at ranges encompassing the instantly claimed number of cells and that “the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient” and that the “optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly” (see pages 19 and 20). June et al teach that the leukemia can be refractory CD19+ leukemia and treating with CAR T cells that target CD19 (see page 2).
Accordingly, it would have been prima facie obvious to treat B-cell malignancies including lymphomas and leukemias in patients with relapsed, refractory or persistent malignancy by administering T cells expressing a CD19 CAR and then administering autologous T cells expressing a CD20 CAR, wherein both CARs further comprises an identical hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB and CD28 signaling domain and a CD3 zeta intracellular signaling domain and in combination with other treatments because the art recognized that B-cell malignancies including lymphomas and leukemias often require multiple treatments over time as they often relapse such that administering autologous T cells expressing a CD20 CAR, wherein the CAR further comprises a hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB and CD28 signaling domain and a CD3 zeta intracellular signaling domain would be recognized as another treatment to administer to patients that still have the disease after administration of T cells expressing a CD19 CAR. Furthermore, as the art taught using CARs with a costimulatory 4-1BB and CD28 signaling domain and a CD3 zeta intracellular signaling domain for targeting CD19 and CD20, the second CAR comprises at least hinge and transmembrane regions from CD8 alpha, the 4-1BB, CD28 and CD3 zeta regions that are identical.
Notably, the prior art recognized that targeting CD19 and CD20 with CARs could be used to treat lymphomas or CLL in humans or model systems of these cancers, such that it would be obvious to target CD20 to better treat lymphomas or CL that had relapsed after targeting CD19. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven,205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to for a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant process claims, one of ordinary skill in the art would have reasonably expected to treat cancers, including lymphomas and CLL by administering autologous T-cells that express a CAR that binds CD19 and separate autologous T-cells that express a CAR that binds CD20 when the CD19 therapy fails by methods taught and suggested by the prior art.
Then with respect to the timing and dosages administered the art recognized that timing and dosages are routinely optimized in treating cancer with CARs.
In this case the art identified that often patients with B cell malignancies have a partial response, a relapse or refractory B cell malignancy and they need multiple treatments, so one of skill in the art would not have found it inventive to use multiple different treatments including administering autologous T cells expressing a CD20 CAR and autologous T cells expressing a CD20 CAR, wherein CARs further comprises a hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB signaling domain and a CD3 zeta intracellular signaling domain after administration of T cells expressing a CD19 CAR in order to best treat a patient that needs additional treatment. Furthermore, the prior art also recognized that the clinician can determine the timing and amounts to be administered and each patient would need to be individually evaluated for timing and amount administered, so the timing and dosage administered would be considered to be routine optimization of a results effective variables (see MPEP 2144.05). Here, it was recognized that treatment regimens must be optimized so one of skill in the art would have been motivated to optimize the administrations, and any particular claimed dosage and timing of administration would be seen as obvious, absent a showing otherwise.
In the response, Applicant traverses the rejection and submits:
“the present application provides that immune responses were truly identified in patients against CARs with non-naturally occurring domain. As discussed in Trede Declaration submitted along with last response, at the time of filing the instant application one skilled in the art would have expected that such immune response may neutralize activity of the second CAR T cell therapy and minimize its effectiveness. Accordingly, one skilled in the art would not have had a reasonable expectation of success at the time of the present application. See e.g., Trede Declaration, paragraph 11. The Examiner responds that previous claims encompass CARs with naturally occurring domains such as intracellular costimulatory signaling domain which is not a concern in the prior art or the Declaration. See first paragraph on page 7 of the Office Action.
Solely in an effort to advance prosecution, and without acquiescing to the rejection, present independent claims 92-94 have been amended to recite that the first CAR and the second CAR each comprises an intracellular signaling domain that comprises the amino acid sequence of a) a 4-1BB or CD28 costimulatory domain, and b) a CD3 zeta signaling domain, thereby obviating the rejection.”
In response this argument is not found persuasive because while the specification identified anti-CAR immune responses in two of the four patients, these immune response were “against peptides with sequences within the VH portion of the scFv of the CAR” for two of the four patients or “against two overlapping 15-mer peptides, each containing the junction between the transmembrane domain and costimulatory domain of the CAR” in only one of the four patients (see paragraph [0375] of the present application), while the instant claims only recite a shared 4-1BB or CD28 costimulatory domain, and a CD3 zeta signaling domain such which were not shown to generate an immune response. These domains are from human proteins which would be expected to be seen as self-antigens.
Furthermore, the claims are not limited to treating patients that developed immune responses against regions of a first CAR, there is only a probability that such an immune response may occur, such that one of skill in the art would have still been motivated and expected success in treating relapsed patients with a second CAR targeting a different antigen, even when the CARs shared domains, for example, because those CARs are targeting a different antigen.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Claims 92-100, 102-109, 112-115 and 117-118 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al (EOBT, 14(1):37-49, 2014, published online Nov 2013, IDS), Cheadle et al (JI, 184:1885-1896, 2010, IDS),Calissano et al (US 2012/0128586 A1, IDS), June et al (US 2013/0287748 A1, IDS) and Long et al (OI, 2(4):e23641:1-2, 2013, IDS).
Gill et al teach administering a chimeric antigen receptor expressed on T cells that binds CD19 to treat B-cell malignancies including CLL and ALL (see abstract, table 1 and pages 37-38). Gill et al teach that relapses are to be expected in view of limited T-cell persistence and that relapses to such therapy has been detected and that the relapsed cancerous cells can be CD19 negative (See page 46). As a result of the relapse being CD19 negative, Gill et al teach that “treatment of B-cell malignancies could also be enhanced by sequential or simultaneous administration of T cells targeted to additional B-cell antigens, such as CD20” (see page 46).
Cheadle et al teach that natural expression of CD19 limits long-term persistence of T cells bearing an anti-CD19 CAR (see abstract).
Calissano et al teach administering multiple agents to treat B-cell CLL wherein the agent can be a chimeric antigen receptor expressed on T cells that binds CD19 and another agent is a chimeric antigen receptor expressed on T cell that binds to CD20 (see pages 1 and 2). With respect reciting that the first CAR is administered prior to the second CAR, Calissano et al teach that agents that treat CLL can be administered prior to, following or in combination with other therapeutic agents (see page 3). Calissano et al teach that CLL relapses and teach targeting therapy at the time of relapse (see pages 5-7).
June et al administering autologous T cells expressing a chimeric antigen receptor that binds antigen CD19 and autologous T cells expressing chimeric antigen receptor that binds antigen CD20 in combination to treat B-cell CLL. (see pages 1 and 2). June et al teach that the hinge and transmembrane region of the CAR can be from CD8 alpha, the costimulatory domain can be a CD28 and 4-1BB signaling domain and the intracellular signaling domain can be a CD3 zeta signaling domain (see pages 2, 4, 5, 10 and 12). June et al teach administering the CAR T cells in compositions comprising cell numbers at ranges encompassing the instantly claimed number of cells and that “the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient” and that the “optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly” (see pages 19 and 20). June et al teach that the leukemia can be refractory CD19+ leukemia and treating with CAR T cells that target CD19 (see page 2).
Long et al teach that chimeric antigen receptors expressed on T cells that bind CD22 have therapeutic potential for the treatment of B-ALL (see e23621-2). Long et al teach that CD19-targeting CARs have achieved clinical success (see e23621-1).
Accordingly, it would have been prima facie obvious to treat patients with B-cell leukemia or lymphoma in patients with relapsed, refractory or persistent malignancy with one CAR that binds CD19 and a second CAR that binds CD22 or CD20 both in T cells that are autologous and administer the CAR that binds CD19 and then if or when the malignancy has relapsed administer the second CAR that binds CD22 or CD20, where each CAR comprises identical domains such as transmembrane domains. Notably, the art recognized that the B-cell malignancy can relapse and the relapse can be CD19 negative, so one of skill in the art using common sense would recognize that the malignancy would need to be treated with a different therapy after relapse, such as an anti-CD20 CAR-expressing T cell or an anti-CD22 CAR-expressing T cell. Furthermore, the art recognized that anti-CD19 CAR T cells do not necessarily have long-term persistence which can also lead to relapse, so one of skill in the art would have been motivated to treat with a CAR that targets a different antigen after relapse when anti-CD19 CAR T are ineffective because even if the malignancy still expresses CD19, the fact that the therapy was ineffective the first time would indicate a high-likelihood that the same therapy would be ineffective a second time. Notably, while prior art also suggested simultaneous administration of two CARs, it is noted that these therapies are expensive and patients do not always relapse, so administering the 2 CARs at the same time would result in a waste of resources and unnecessary expense, such that one of skill would have been motivated to administer the second CAR after relapse from the first CAR had been detected except in cases that had been determined to require simultaneous treatment, such as a highly aggressive cancer that had relapsed multiple times or a cancer where two distinct clones had been detected where one clone expressed CD19, but not CD20 or CD22 and the other clone expressed CD20 or CD22, but not CD19. In this case the art identified a finite number of predictable antigens that could be targeted on B-cell cancers, like CLL or ALL, signaling domains and transmembrane domains that could be used, such that one of skill in the art would not have found it inventive to use art known solutions in constructing CARs for use in treatments suggested by the art.
Notably, the prior art recognized that targeting CD19 and CD20 or CD22 with CARs could be used to treat CLL or ALL in humans or model systems of these cancers, such that it would be obvious to target CD320 or CD22 to better treat CLL or ALL that had relapsed after targeting CD19. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven,205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to for a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant process claims, one of ordinary skill in the art would have reasonably expected to treat cancers, including CLL and B-ALL by administering autologous T-cells that express a CAR that binds CD19 and separate autologous T-cells that express a CAR that binds CD20 or CD22 when the CD19 therapy fails by methods taught and suggested by the prior art.
Then with respect to the timing and dosages administered the art recognized that timing and dosages are routinely optimized in treating cancer with CARs.
In this case the art identified that often patients with B cell malignancies have a partial response, a relapse or refractory B cell malignancy and they need multiple treatments, so one of skill in the art would not have found it inventive to use multiple different treatments including administering autologous T cells expressing a CD20 CAR and autologous T cells expressing a CD20 CAR, wherein CARs further comprises a hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB signaling domain and a CD3 zeta intracellular signaling domain after administration of T cells expressing a CD19 CAR in order to best treat a patient that needs additional treatment. Furthermore, the prior art also recognized that the clinician can determine the timing and amounts to be administered and each patient would need to be individually evaluated for timing and amount administered, so the timing and dosage administered would be considered to be routine optimization of a results effective variables (see MPEP 2144.05). Here, it was recognized that treatment regimens must be optimized so one of skill in the art would have been motivated to optimize the administrations, and any particular claimed dosage and timing of administration would be seen as obvious, absent a showing otherwise.
In the response, Applicant traverses the rejection essentially for the reasons set forth above.
In response this argument is not found persuasive because while the specification identified anti-CAR immune responses in two of the four patients, these immune response were “against peptides with sequences within the VH portion of the scFv of the CAR” for two of the four patients or “against two overlapping 15-mer peptides, each containing the junction between the transmembrane domain and costimulatory domain of the CAR” in only one of the four patients (see paragraph [0375] of the present application), while the instant claims only recite a shared 4-1BB or CD28 costimulatory domain, and a CD3 zeta signaling domain such which were not shown to generate an immune response. These domains are from human proteins which would be expected to be seen as self-antigens.
Furthermore, the claims are not limited to treating patients that developed immune responses against regions of a first CAR, there is only a probability that such an immune response may occur, such that one of skill in the art would have still been motivated and expected success in treating relapsed patients with a second CAR targeting a different antigen, even when the CARs shared domains, for example, because those CARs are targeting a different antigen.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 92-100, 102-109, 112-115 and 117-118 are provisionally rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over claims 1-18 and 21-30 of US application 18/491,633 in view of June et al (US 2013/0287748 A1, IDS). Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
Claims 1-18 and 21-30 of US application 18/491,633 recite methods of treatment, comprising administering cells expressing a second chimeric antigen receptor that binds CD20 (CAR) to a subject that has previously received an administration of cells expressing a first CAR, wherein: the first CAR specifically binds CD19 (see claim 1) to an antigen associated with a B cell malignancy; the second CAR, which is distinct from the first CAR, specifically binds to the antigen specifically bound by the first CAR or a different antigen associated with the B cell malignancy (CD20, see claim 1); and the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR (see claim 2).
The claims of US application 18/491,633 further recite the additional limitations instantly claimed such that they anticipate the instant claims except they do not recite a CD22 CAR as required by instant claims 95 and 116.
June et al teach administering multiple agents to treat B-cell CLL or B cell ALL, wherein the agent can be a chimeric antigen receptor expressed on T cells that binds CD19 and another agent is a chimeric antigen receptor expressed on T cell that binds to CD20 or CD22 and wherein the T cells are autologous (see pages 1, 2 and 18-19). June et al teach that the transmembrane domain can be from CD28 or other transmembrane domains and using a 4-1BB signaling domain or other signaling domains including ITAMs (see pages 11 and 12). June et al teach administering the CAR T cells in compositions comprising cell numbers at ranges encompassing the instantly claimed number of cells and that “the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient” and that the “optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly” (see pages 19 and 20). June et al teach that the leukemia can be refractory CD19+ leukemia and treating with CAR T cells that target CD19 (see page 2).
Accordingly, while the copending claims do not recite CD22, it would have been prima facie obvious to treat B-cell malignancies including lymphomas and leukemias additionally with a CAR that binds CD22 as that is another known antigen that is expressed by B cell malignancies which could be further targeted a CAR to treat leukemias and lymphomas that are being treated or have been treated with a CD19 CAR.
Applicant submits that the terminal disclaimed filed July 28, 2025, has obviated the rejection.
In response, the terminal disclaimed filed July 28, 2025, was not approved because the “Incorrect TD form was submitted. Please resubmit on PTO/AIA /26 (04-14). No additional fee is required with the resubmission.”
Accordingly, the rejection will be maintained until appropriately addressed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached on Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
October 5, 2026
