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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 19, 2025, has been entered.
The amendment filed December 19, 2025, is acknowledged and has been entered. Claims 1, 15-17, 21, 23 and 28-30 have been amended. Claim 33 has been newly added.
Claims 1-2, 4-6, 9-18 and 21-23 and 25-33 are pending. Claims 31-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected species of the invention, there being no allowable generic or linking claim.
Claims 1-2, 4-6, 9-18, 21-23, 25-30 and 33 are under examination.
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 1-2, 4-6, 9-18, 21-23, 25-30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Calissano et al (US 2012/0128586 A1, IDS), Brentjens et al (H, (1):143-151, 2012), Till et al (B, doi:10.1182/blood-2011-10-387969, pages 1-36, 2012) and June et al (US 2013/0287748 A1, IDS).
The claims are herein drawn to methods of treating a B cell malignancy in a subject with a combination therapy, comprising first administering to said subject a first chimeric antigen receptor (CAR) that specifically binds to a first antigen that is CD19, wherein after this step the B cell malignancy has relapsed, is refractory, or persists, and then administering to said subject a second chimeric antigen receptor (CAR) that specifically binds to a second antigen that is CD20, wherein the first CAR and the second CAR each comprises an intracellular region that comprises the amino acid sequence of a) a 4-1BB or CD28 costimulatory domain, and b) a CD3 zeta signaling domain, the second CAR comprises at least one domain of the intracellular region that is identical in amino acid sequence to a corresponding region of the first CAR. Notably, the claimed invention encompasses switching to a new chimeric antigen receptor (CAR) that specifically binds to a second antigen that is CD20 to treat B cell malignancy, when the first chimeric antigen receptor (CAR) that specifically binds to a CD19 does not work, no longer works, or is not 100% effective (the cancer persists) as long as both CARs comprise at least one domain of the intracellular region that is identical in amino acid sequence.
While new claim 33 encompasses such methods set forth above, it is noted that claim 33 is broader as it does not recite administration of the CD20 CAR after the CD19 CAR does not work, no longer works, or is not 100% effective or that both CARs comprise at least one domain of the intracellular region that is identical in amino acid sequence.
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. Calissano et al teach these methods include targeting one or more of CD19 and CD20 (see claims and pages 2-3). Calissano et al teach that CLL relapses and teach targeting therapy at the time of relapse and that CLL expresses CD19 and CD20 (see pages 1 and 5-7).
Brentjens et al teach clinical studies of treating B cell malignancies such as lymphoma and CLL with by administering autologous T cells expressing CD19 CARs, including a 4-1BB and CD3 zeta containing CD19 CAR that resulted in partial or complete responses (see pages 145-148). 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 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).
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 4-1BB signaling domain and the intracellular signaling domain can be a CD3 zeta signaling domain (see pages 2, 4, 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 and claims).
Accordingly, it would have been prima facie obvious to treat B-cell malignancies including lymphomas and leukemias, such as CLL, in patients that have a B cell malignancy that has relapsed, is refractory or persists (partial response) or not (see new claim 33) after administration of T cells expressing a CD19 CAR by then administering for the first time autologous T cells expressing a CD20 CAR, wherein the CAR further comprises a hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB signaling domain and a CD3 zeta intracellular signaling domain that are identical in amino acid sequence 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 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 signaling domain and a CD3 zeta intracellular signaling domain for targeting CD19 and CD20, the second CAR comprises at least the 4-1BB and CD3 zeta regions that are identical with the first CAR. Then as amended claims 15-16 and 29-30 also recite an identical transmembrane domain in combination with a 4-1BB signaling domain and the intracellular signaling domain can be a CD3 zeta signaling domain, it is noted that June et al teach that the hinge and transmembrane region of the CD19 CAR can be from CD8 alpha, the costimulatory domain can be a 4-1BB signaling domain and the intracellular signaling domain can be a CD3 zeta signaling domain, such that one of skill in the art would have been motivated to use these domains from June also in the CD20 CAR because they were taught in the art as being effective domains for use in chimeric antigen receptors. Additionally, using identical intracellular domains would allow faster production of the CD20 CAR as only the CD20 binding domain would need to be swapped by cloning it into the CD19 binding domain spot. Accordingly, using identical domains would be seen as combining prior art elements according to known methods to yield predictable results.
One would have also been motivated to do so because a CAR targeting CD20 and a CAR targeting CD19 both have been individually taught in the prior art to be effective at treating cancers, including chronic lymphocytic leukemia. 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 refractory CLL that had been treated with a CD19 CAR by then administering a CD20 CAR.
Then with respect to the timing and dosages administered, the art recognized that timing and dosages are routinely optimized in treating cancer with CARs and are within the purview of one skilled in the art of medicine.
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 for the first time autologous T cells expressing a CD20 CAR, wherein the CAR 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 with the same domain in order to best treat a patient that needs additional patients. 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 that “nothing in Brentjens discloses or suggests administering CD20 CAR-T cells after the failure of CD19 CAR-T therapy, nor any therapeutic sequencing”, that the disclosure of Till “is not a teaching of treating CD19-CAR-relapsed malignancy”, “the present claims do not require targeting a second antigen other than CD19 or CD20, which defeats the primary purpose of Calissano that is to target the proliferative compartment of CLL cells” and that “June does not teach administering CD20 CAR-T after relapse from CD19 CAR-T, does not identify relapse biology as a rationale for switching antigens, and does not teach designing two separate CARs with shared intracellular domain(s) for sequential therapeutic use”.
the relevant disclosure of Brentjens “does not teach treating the same individual with a CD20-CAR therapy who have been previously treated with a CD19-CAR therapy”.
In response, the prior art recognized that patients can relapse from a first CD19 CAR T cell therapy and recognized and suggested that such patients can be treated with additional therapies, including additional second CAR T cell therapies, wherein the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR such as a CD20 CAR, wherein the CAR further comprises a hinge and transmembrane region from CD8 alpha, a costimulatory 4-1BB signaling domain and a CD3 zeta intracellular signaling domain. Furthermore, Callisano specifically discloses and claims treating CLL with one or more agents that target cell surface antigens wherein the antigens are CD19 and CD20 (see page 2 and claims 1-3) and in combination with other agents, as are encompassed by the instant claims which recite “open”, comprising language, while June discloses and claims treating diseases expressing tumor antigens, such as refractory CLL, with a combination of agents that target CD19 and CD20 (see page 2 and claims 47-49). Doctors are motivated to continue treating cancer patients with multiple therapies and the art cited above recognizes that and suggests treatment with a second CAR T cell therapy in a subject that has received, but has relapsed from, a first CAR T cell therapy, wherein the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR and also suggests combing the therapies in patients in general as claimed in new claim 33.
Notably, as set forth in the Supreme Court decision in KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007):
“A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 550 U.S. at ___, 82 USPQ2d at 1397. “[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. (see e.g., abstract, page 141-143 and Table 142).
In this case, based on the knowledge in the art that patients can relapse from a first CD19 CAR T cell therapy and that there are other CAR T cell targets for therapy, like a CD20 CAR, one of skill in the art using ordinary creativity and inferences would have been motivated to administer a second CAR T cell therapy in a subject that has received, but has relapsed from, a first CAR T cell therapy, wherein the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR, in order to treat the relapsed cancer.
"The test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965).
"There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. v. lnterdiqital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
With respect to the proposition that it is obvious to combine two treatments individually known to be useful for the same purpose, Applicant submits that reliance on In re Kerkhoven is inapt because “Sequential CAR-T administration is fundamentally different: it is a complex, patient-specific clinical decision, not the simple combination of interchangeable compositions for a non-clinical use. CAR-T treatments are not additive or substitutable ingredients; their use depends on many factors such as disease burden, relapse biology, CAR persistence, and profound toxicity risks.
Moreover, the purpose of the two CAR-T therapy are also different at least because the second CAR-T therapy was for treating a patient population that have failed the first CAR-T therapy. As shown in a study, while the overall survival rates for childhood B-ALL is 90%, in relapsed B-ALL there was an overall survival of only 30%. See Woo et al. Exp Hematol Oncol. 2014 Jun 13;3:16, first full paragraph at right column on page 2 and third full paragraph at left column on page 10 (submitted along with this response in IDS). This study evidenced that treating a B cell malignancy that has failed a prior therapy can be much more difficult.”
In response, it is recognized that treating cancer in general is a patient-specific clinical decision as is evidenced by the references. Notably, the references evidence that patients can relapse from treatment and those patients can then be treated with other therapies. Neither the claims, nor the rejection require treating every patient that relapses from CD19 CAR therapy with a CD20 CAR therapy. The claims do not even require relapse, but include patients that are refractory to treatment or patients where the B cell malignancy persists. Oncologists routinely treated cancer patients with multiple agents as is evidenced by the references, especially when the first agent was not 100% effective, and treating diseases with multiple agents by doctors was common at the time the instant application was filed, and none of the references teach away from combining CD20 CAR T cell therapy with CD19 CAR T cell therapy, especially after the CD19 CAR T cell therapy was not 100% effective. It is precisely because “treating a B cell malignancy that has failed a prior therapy can be much more difficult” that one would be motivated to target CD20 with CAR T cells in patients with a B cell malignancy that expresses CD20 that had failed CD19 CAR T cell therapy.
Applicant further submits that “The Examiner asserts that because the art recognized that B-cell malignancies often relapse and require multiple treatments, the skilled artisan would have been motivated to administer a CD20 CAR-T product to a subject who relapsed after CD19 CAR-T therapy. This assertion lacks evidentiary support. None of the cited references, singly or in combination, identify or suggest a sequential CAR-T cell therapy as a solution for a patient population who have failed a CAR-T therapy. The cited reference in totality only shows clinical trials that are limited to CAR-T cells targeting a single antigen. There was no evidence on record that supports that a sequential CAR-T administration that target two different antigens was effective or even safe.”
In response, as set forth above ““A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 550 U.S. at ___, 82 USPQ2d at 1397. “[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. (see e.g., abstract, page 141-143 and Table 142).
In this case, based on the knowledge in the art that patients can relapse from a first CD19 CAR T cell therapy and that there are other CAR T cell targets for therapy, like a CD20 CAR, one of skill in the art using ordinary creativity and inferences would have been motivated to administer a second CAR T cell therapy in a subject that has received, but has relapsed from, a first CAR T cell therapy, wherein the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR, in order to treat the relapsed cancer. One would expect that treatment to be effective in treatment because it was targeting a different antigen on the B cell malignancy and to be safe in patients that had already received a different CAR without complications that had stopped treatment with the first CAR. There is no evidence of record that such a combination would not be effective or would be unsafe.
Applicant further argues that “the Examiner concludes that because the art taught CARs comprising 4-1BB and CD3ζ domains, the second CAR inherently comprises "at least one region identical in amino acid sequence" to the first CAR. This conclusion is incorrect as a matter of fact and law. The art discloses families of costimulatory and signaling domains, many with different sequence variants, structures, and configurations. June itself teaches a CD3z domain with a specific sequence that is different from the natural CD3ζ sequence. Nothing in the art suggests designing two different CAR constructs, which were administered at separate times, to share identical intracellular domain sequences. The Examiner's reasoning impermissibly constructs Applicant's claim requirements into disparate art disclosures using hindsight. As stated in KSR, obviousness cannot be based on "the distortions caused by hindsight bias," 550 U.S. at 421”
In response, the claims (except claim 33) are not directed to any particular 4-1BB and CD3z domains, just that one or the other or some undefined intracellular region of the CARs have identical amino acid sequences, while the art taught that the intracellular domains to be used in CD19 CARs include 4-1BB and CD3ζ domains such that using the identical domains in each CAR would be obvious because those domains were used in the CD19 CARs that had been administered to the patient. By way of further explanation, the CD19 CAR had been successfully administered to the patient, such that those 4-1BB and CD3ζ domains were known to be tolerated by the patient which provides further motivation to use identical domains. Furthermore, using identical intracellular domains would allow faster production of the CD20 CAR as only the CD20 binding domain would need to be swapped by cloning it into the CD19 binding domain spot. Here using identical domains would be seen as combining prior art elements according to known methods to yield predictable results.
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 1-2, 4-6, 9-18, 21-23, 25-30 and 33 are provisionally rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over claims 92-94, 96-100, 102-109, 112-115 and 117-118 of US application 17/588,149 in view of Calissano et al (US 2012/0128586 A1, IDS). Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons:
The claims of US application 17/588,149 recite methods of treatment, comprising administering cells expressing a second chimeric antigen receptor (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 96) 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 96); and the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR.
The claims of US application 17/588,149 further recite the additional limitations instantly claimed such that they anticipate the instant methods except they do not recite that the B cell malignancy is CLL as recited in instant claims 11 and 18.
However, 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).
Accordingly, while the copending claims do not recite CLL, it would have been prima facie obvious to treat B-cell malignancies including lymphomas and leukemias, such as CLL, based on the teachings of Calissano that CLL is a B cell malignancy that can be treated with T cells that express a CAR that binds CD20 because CLL is a cancer that can be treated by the copending claims.
Applicant requests that the rejection be held in abeyance.
In response, the rejection will be maintained until appropriately addressed.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, this rejection is being maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
August 15, 2026
Prosecution Insights