DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Priority
The instant application, filed 09/03/2020, claims domestic benefit to US provisional applications 62/944,884, filed 12/06/2019 and 62/895,972, filed 09/04/2019.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 11/12/2025 is acknowledged. Claim 11 is amended; claims 1-10, 13-18, and 20-26 are cancelled; and claims 29-31 are new. Claims 11-12, 19, and 27-31 are currently pending.
Claim 28 remains withdrawn as being drawn to an unelected species.
Claims 11-12, 19, 27, and 29-31 are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 08/15/2025,
Claim 3 was rejected under 35 USC 112(d). The cancellation of claim 3 has rendered the rejection moot and the rejection is withdrawn.
Claims 3-5, 11-13, 19, and 27 were rejected under 35 USC 103 over Kloss, Posey, WO’564, NCBI_001328609.1, Jensen, Brogdon, NCT’442, Wells Fargo, Townsend, and Sun. The cancellation of claims 3-5 and 13 has rendered the rejection of these claims moot and the rejections are withdrawn. The rejections over claims 11-12, 19, and 27 are also withdrawn in view of applicant’s amendment to independent claim 11 remove recitation of the nucleic acid sequence of SEQ ID NO: 37; an amendment which has rendered the use of the NCBI_001328609.1 reference unnecessary. The rejection has been amended to remove the extraneous reference.
The following grounds of rejections are necessitated by applicant’s amendment to the claims.
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 for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 11-12, 19, 27, and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Kloss, C.C., et al (2018) Dominant-Negative TGF-β receptor enhances PSMA-Targeted human CAR T cell proliferation and augments prostate cancer eradication Molecular Therapy 26(7); 1855-1866 in view of Posey, A.D. and C.H. June (2015) 211. CD2, the first identified T cell co-stimulator, demonstrates more effective chimeric antigen receptor activity over CD28 and 4-1BB Molecular Therapy 23(Supplemental 1); S83, WO 2017/120546 (Tauton, J.W., et al) 13 July 2017, WO 2017/165571 A1 (Jensen, M. and R. Gardner) 28 SEPT 2017, US 2016/0046724 A1 (Brogdon, J., et al) 18 Feb 2016, NCT03549442 (Sponsor: University of Pennsylvania) v2, 19 JUNE 2018, Wells Fargo (2017) Deep dive on emerging cell therapies for cancer Equity Research; 1-94, Townsend, M.H., et al (2018) The expansion of targetable biomarkers for CAR T cell therapy Journal of Experimental & Clinical Cancer Research 37(163); 1-23, and Sun, S., et al (2018) Immunotherapy with CAR-modified T cells: Toxicities and Overcoming Strategies Journal of Immunology Research 2386187; 1-10.
Kloss teaches that cancer has an impressive ability to evolve multiple processes to evade therapies and that, while immunotherapies and vaccines have shown great promise in the treatment of solid tumors such as prostate cancers, they have been met with resistance. In the case of prostate cancer, the cancer secretes transforming growth factor β (TGF-β) as a means to inhibit immunity while allowing for cancer progression. Kloss further teaches that blocking TGF-β signaling in T cells increases their ability to infiltrate, proliferate, and mediate antitumor response in prostate cancer models (abstract). Kloss teaches that studies in the 1990s demonstrated that TGF-β signaling can be blocked by using a dominant-negative TGFRβRII, which is truncated and lacks the intracellular domain necessary for downstream signaling. Expression of the dnTGFβRII enhances antitumor immunity and can lead to autoimmunity (page 1855, right column, paragraph 2).
Kloss studied whether the potency of CAR T cells directed to PSMA could be enhanced by the co-expression of a dominant negative TGF-βRII (dnTGF-βRII) and teaches that the co-expression of the receptor increased proliferation of the lymphocytes and enhanced cytokine secretion, resistance to exhaustion, long-term in vivo persistence, and the induction of tumor eradication in aggressive human prostate cancer and mouse models (abstract).
The CAR taught by Kloss was designed and synthesized utilizing the heavy and light chain variable regions of the J591 antibody fused to a 4-1BB costimulatory domain sequence and a CD3ζ intracellular signaling domain (page 1856, left column, paragraph 3; pages 1862-1863, Vector Design). The CAR was then transduced into T cells using a lentiviral vector (page 1863, Lentiviral vector production and CAR T cell production).
Based on the encouraging preclinical results reported, Kloss discloses the initiation of a clinical trial to infuse the dnTGF-βRII-T2A-PBBZ CAR T cells in a first-in-human study in patients with refractory castration resistant metastatic prostate cancer (page 1862, right column, paragraph 2).
Kloss teaches that glutamate carboxypeptidase II or prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein that has been studied within the prostate cancer field for three decades as a tumor-associated antigen for prostate cancer. There is low-level expression in some normal tissues, for example astrocytes, neurons, kidney, epithelium, and salivary glands (page 1856, left column, paragraph 1).
Kloss, however, does not disclose that the costimulatory domain in the CAR is CD2 comprising the amino acid sequence of SEQ ID NO: 36. Kloss also does not disclose that the CAR T cells are administered as a split dose with 30% of the total dose of cells administered in a first administration and 70% of the total dose administered in a subsequent administration at least five days after the first dose, the monitoring of CRS, immune-cell associated neurological toxicities, and/or on-target off-tumor or that the split dose administration results in the reduced development of these side effects compared to a single dose of cells/a single dose regimen.
Posey teaches that CD2, first identified as T11 sheep erythrocyte receptor protein, was originally classified as the trigger for an alternative T cell activation pathway and later as a costimulatory molecule that synergized with CD3 activation. Co-stimulation of T cells with CD2 augments CD3-mediated signaling cascades, IL-2 production, and proliferation. The field dedicated to the development of novel second- and third-generation chimeric antigen receptors (CARs) has focused on the inclusion of endodomains from CD28 superfamily and TNFRSF members as costimulation, but the use of CD2/SLAM family of costimulatory molecules had not yet been explored. Posey studied a CAR comprising the endodomain of CD2 juxtaposed to the CD3z activation domain (SS1CD2z). Human T cells modified with SS1CD2z demonstrate comparable cytotoxicity of tumor cell lines in vitro as SS1z, SS1BBz, and SS128z. SS1CD2z T cells proliferated similar to SS128z and better than SS1BBz in vitro. Importantly, SS1CD2z cells produced minimal quantities of TNFα similar to SS1BBz cells; contrary to SS128z cells, which produced large quantities of the neurotoxic cytokine. SS1CD2z T cells exhibited a fast and durable anti-tumor response against a subcutaneous mesothelioma xenograft model, while both SS128z and SS1BBz T cells lagged in terms of response rate. These results suggest that CAR co-stimulation with CD2 can produce potent antitumor activity, T cell proliferation and favorable cytokine profiles (abstract, S83, right column).
WO’546 teaches costimulatory domains for use in CARs in Table 1 (page 114, [00394]) which includes the costimulatory domain of CD2 (page 294 Figure page 49/124, Fig. 27, 2nd to last row). The costimulatory domain of CD2 is identical to instant SEQ ID NO: 36 as shown in the alignment below:
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Jensen teaches methods for preventing or ameliorating toxicity caused by or due to a therapy such as an immunotherapy or a cell therapy. Jensen further teaches that the cell therapy is one in which the cells express recombinant receptors including chimeric antigen receptors. Jensen teaches methods for pre-emptive or early administration of toxicity-targeting agent(s) in an effort to lower toxicity while maintaining persistence and efficacy of the administered cells (abstract).
Jensen teaches that adoptive cell therapies, including CAR T cell therapy, can be effective in the treatment of cancer and other diseases. Jensen further teaches that optimal efficacy can depend on the ability of the administered cells to recognize and bind to a target, e.g., target antigen, activate, and expand allowing for the exertion of various effector functions, including cytotoxic killing and secretion of various factors such as cytokines (page 19, [0081]). Jensen teaches that the efficacy of adoptive cell therapy may be limited by the development of toxicities in the subject which, in some cases, can be severe and/or life threatening. Jensen teaches that, for example, in some cases, administering a dose of cells expressing a CAR can result in CRS or neurotoxicity (pages 19-20, [0082]; page 22, [0091]).
Jensen teaches that the cell therapy is administered to a subject to treat or prevent diseases including solid tumors, such as prostate cancer (page 61, [0239]; page 62, [0242]). Jensen further teaches that the antigen associated with the disease is selected from a group which includes prostate specific antigen (PSMA) (page 63, [0244]). Alternatively, Jensen teaches that the antigen may be CD19 and the disease may be multiple myeloma (page 63, [0244]; page 62, [0242]).
Jensen teaches that in the context of adoptive cell therapy, administration of a given dose encompasses administration of the given amount or number of cells as a split dose (page 66, [0259]). Jensen teaches that the dose may be administered to the subject over 2 or 3 days and exemplary methods include administering 25% of the dose on the first day and the remaining 75% of the dose on the second day or 33% of the dose on the first day and the remaining 67% of the dose on the second day (page 66, [0261]).
Thus, Jensen teaches a split dose of 33% and 67%, which is close to the claimed 30% and 70% split dose, rendering the claimed dosing obvious as a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I).
Jensen further teaches that one or more consecutive or subsequent doses of cells can be administered to the subject and that the dose of cells can be more than, approximately the same, or less than the first dose. Jensen teaches that the administration of the T cell therapy, such as the administration of the first and/or second dose of cells can be repeated (page 67, [0263]), demonstrating the use of a dosing regimen.
Jensen further teaches the administration of a chemotherapeutic agent, e.g., a conditioning chemotherapeutic agent, to reduce tumor burden prior to administration. Jensen teaches that the lymphodepleting or chemotherapeutic agents include cyclophosphamide, fludarabine, or a combination thereof which are administered to a subject prior to the initiation of the cell therapy; for example, at least 2 days before, such as at least 3, 4, 5, 6, 7 days prior (page 64, [0251]-[0252]). Jensen further teaches an example in which subjects were treated with 30 mg/m2 of fludarabine daily for 3 days and 300 mg/m2 cyclophosphamide daily for 3 days (page 105, [0345]). Jensen teaches that the agents can be given daily (page 65, [0253]-[0254]) indicating consecutive days.
Brogdon teaches compositions and methods for treating diseases associated with BCMA expression in a subject comprising the administration of genetically modified T cells expressing a CAR (abstract). Brogdon teaches that the subject being treated has a solid tumor and that the disease associated with BCMA may be prostate cancer, including castrate-resistant or therapy-resistant prostate cancer, or metastatic prostate cancer (page 11, [0065]; page 137, [0798]). Brogdon also teaches that a disease associated with BCMA may be multiple myeloma (page 11, [0064]). Brogdon teaches that the CAR-expressing cells are administered to the subject according to a dosing regimen comprising a total dose of cells administered to the subject by dose fractioning, e.g., one, two, three or more separate administrations of a partial dose. Brogdon further teaches that a first percentage of the total dose is administered on a first day of treatment and a second percentage of the total dose is administered on a subsequent, e.g., second, third, fourth, fifth, sixth, or seventh or later, day of treatment (page 12, [0077]).
NCT’442 is a clinical trial evaluating anti-BCMA and CD19 CAR T cells in high-risk multiple myeloma (title). NCT’442 teaches split-dose infusions after lymphodepletion chemotherapy comprising cyclophosphamide + fludarabine (page 3, study description). NCT’442 teaches a split dose infusion comprising 3 infusion days with day 1 comprising 10% of the dose, day 2 comprising 30% of the dose, and day 3 comprising 60% of the dose. NCT’442 teaches that infusion days may be spread over 7 calendar days due to scheduling constraints or to allow for observation of suspected early cytokine release syndromes or other toxicities (page 4, assigned interventions).
Wells Fargo provides a detailed review of adoptive cellular therapy encompassing CAR-T, engineered T-cell receptors, and tumor infiltrating lymphocyte therapeutics for the treatment of cancers and discusses more than 250 ongoing trials and more than 100 investigational new drug applications that are pending (page 1, first bullet point). Wells Fargo teaches that ultimately, the greatest opportunity for adoptive cellular therapy (ACT) lies within the larger category of solid tumors, where exclusive targets have been more elusive and where early patient deaths have highlighted the huge challenge (page 2, first bullet point).
Wells Fargo teaches that following administration of adoptive cell therapies (ACT), it is hoped that the cells find their target antigens leading to activation and clonal expansion of the ACT, resulting in rapid destruction of the tumor cell; however, their use has shown unique and different safety profiles (page 23, paragraph 6). Wells Fargo teaches that for CAR and TCR products, rapid destruction of tumors can lead to acute inflammation, resulting in cytotoxic release syndrome (CRS), or at its worst, macrophage activation syndrome (MAS), which is potentially fatal (page 23, paragraph 8). Wells Fargo teaches that toxicities associated with CAR-T cells include CRS, neurotoxicity, and on-target off-tissue related toxicities (Exhibit 11, page 24). In their summary of ACT related toxicities, Wells Fargo discloses that CRS and neurotoxicity related to ACT typically correlates with peak CAR-T levels at days 7-10 post infusion (page 24, exhibit 11, rows 1 and 2). Wells Fargo teaches that CRS has long been recognized as a common and potentially fatal side effect associated with the release of acute phase reactants and has been associated with very high temperature and low blood pressure and that groups have studied methods of monitoring and predicting oncoming CRS using various methods including cytokine signatures which will allow for early intervention (page 24, paragraph 2).
Wells Fargo teaches that investigators for the TRANCEND NHL-01 trial presented data on 28 subjects enrolled in an ongoing trial studying the CD19 directed CAR, JCAR017, in the treatment of NHL. In the trial, a 33% rate of grade 3/4 neurotoxicity was noted for JCAR017 given as a single dose. Split dosing reduced the rate of severe neurotoxicity to 14% (page 64, paragraph 4).
Townsend teaches that CAR T cell therapy has been revolutionary in the treatment of hematological malignancies but has had difficulties translating to solid tumors due to the lack of cancer-specific tumor targets. Townsend teaches that biomarker discovery and specificity is essential for further CAR T cell development and success teaching that some of the struggles facing CAR T cell therapy include on-target off-tumor cytotoxicity, persistence in vivo, immunosuppressive tumor microenvironment, and cytokine release syndrome (page 1, right column, paragraph 1). Townsend provides a review of biomarkers for CAR T cell therapy (abstract).
Townsend teaches that PSMA is expressed in normal prostate epithelium and has been shown in 90% of human prostate tumors including their metastatic sites. Townsend teaches that PSMA is also expressed in low levels in salivary glands, brain, and kidneys. Townsend discloses that in pre-clinical models, PSMA CAR T cells were able to effectively target and eliminate 60% of tumors in treated animals improving overall survival and that in phase I clinical trials, 40% of patients achieved clinical partial responses. Townsend further teaches PSMA CAR T cells have also been designed to resist TGFβ suppression, which is commonly found in prostate cancers, via a negative TGFβII receptor II (page 10, right column, paragraph 2).
Sun teaches that the most striking toxicity specific to genetically targeted T cells is on-target off-tumor toxicity resulting from a direct attack on normal tissues that have shared expression of the target antigen. Considering the potency of redirected T cells, toxicity on nonpathogenic tissues expressing low levels of the antigen can be highly detrimental. With these toxicities in mind, the selection of target antigen, which is strictly specific to the tumor, is probably the most critical determinant to broaden the application. Indeed, such antigens have been difficult to identify, particularly in the settings of solid malignancies. Moreover, a study proved that the substantial dose of infused CAR T cells could potentially provoke this toxicity. In a study lower doses of HER2/neu-specific CAR T cells were safe compared to higher dosages. (paragraph bridging pages 2 and 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the 4-1BB costimulatory domain in the dnTGF-βRII-T2A-PBBZ CAR T cells in the method taught by Kloss with a CD2 costimulatory domain as disclosed by Posey using the CD2 costimulatory domain amino acid sequence disclosed by WO’546. It would have further been obvious to administer the CAR T cells using a split dose regimen, such as a first dose of 33% and a second dose of 67%, as disclosed by Jensen with the second, consecutive, or subsequent percentage of the CAR T cells administered on the fifth, sixth, or seventh day after administration of the first dose as taught by Brogdon while monitoring the development on-target off-tumor toxicity based on the teachings of NCT’442 and supported by the combination of applied references.
An ordinarily skilled artisan would have been motivated to substitute a CD2 costimulatory domain in place of the 4-1BB costimulatory domain as Posey teaches that CARs using a CD2 costimulatory domain were more effective and exhibited faster and more durable anti-tumor response against tumors compared to CARs comprising a 4-1BB costimulatory domain. An ordinarily skilled artisan would have had a reasonable expectation of success as Posey demonstrates CD2 as an alternative costimulatory domain to 4-1BB and demonstrates the costimulatory domain with a CD3z intracellular signaling domain, which is the same signaling domain in the dnTGF-βRII-T2A-PBBZ CAR T cells.
It would have been obvious to use the CD2 amino acid sequence taught by WO’546 as the sequence is recognized as the costimulatory domain of CD2 and had been considered for use in CAR production. An ordinarily skilled artisan would have had a reasonable expectation of success as Posey demonstrates the use of the costimulatory domain of CD2 in CAR T cells and WO’546 provides the amino acid sequence of the CD2 costimulatory domain.
An ordinarily skilled artisan would have been motivated to administer the CAR T cells of Kloss using the split dose regimen of Jensen at least five days apart as taught by Brogdon in order to monitor for signs of toxicities, as suggested by NCT’442. Particularly as these toxicities were known to be associated with CAR T cell therapy and could be severe and life-threatening as taught by Wells Fargo, Townsend, and Sun. For instance, Townsend establishes that on-target off-tumor toxicity is a potential toxicity that could be associated with anti-PSMA CAR T cells, such as those disclosed by Kloss, as PSMA is expressed in low levels in normal tissue including the salivary glands, brain, and kidneys. An ordinarily skilled artisan would have had a reasonable expectation of success in using the suggested split dosing strategies as each of the applied references are teaching the administration of CAR T cell therapy for the treatment of cancer. Additionally, Jensen teaches that the CAR therapy can alternatively target PSMA or CD19 and treat cancers including prostate cancer or multiple myeloma; Brogdon teaches anti-BCMA CARs and the treatment of prostate cancer and multiple myeloma; and NCT’442 teaches cancer treatment, specifically multiple myeloma, with anti-BCMA and anti-CD19 CARs demonstrating treatment of overlapping cancers with CARs having overlapping targets. Jensen teaches a split dose of 33% and 67% which is close to the claimed 30% and 70% split, rendering the claimed dosing obvious as a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05 (I).
An ordinarily skilled artisan would have reasonably expected that the split dose administration would result in a reduction in on-target off-tumor toxicity, compared to a single dose or single dose regimen based on the teachings of Wells Fargo and Sun. Wells Fargo teaches a CAR T cell trial in which incidence of neurotoxicity of grades 3/4 reduced from 33% to 14% when a split dosing regimen was used compared to a single dosing regimen, demonstrating that toxicities can be reduced compared to a single dose regimen by using a split dose regimen. While these results were determined during treatment of NHL and not specifically a solid tumor/prostate cancer, an ordinarily skilled artisan would still have reasonably expected a reduction in toxicity when a split dose is used compared to a single dose in the treatment of a solid tumor as Wells Fargo teaches that toxicities result from activation and clonal expansion of the ACT resulting in rapid destruction of tumor cells and correlates with peak CAR T cell levels, which are factors that would still be relevant during the treatment of solid cancers. Additionally, Sun teaches that on-target off-tumor toxicity can occur when normal tissues express even low levels of the target antigen and that a study has demonstrated that a substantial dose of infused CAR T cells could potentially provoke this toxicity while lower doses were safer. Therefore, an ordinarily skilled artisan would reasonably expect that by splitting the dosage of CAR T cells, as suggested, toxicity would be reduced as lower dosages of CAR T cells are administered at a time.
Additionally, the reduction in these adverse events would flow naturally from the administration of the CAR T cells using the split dosing regimen suggested and, therefore, cannot be the basis for patentability when the differences would have otherwise been obvious.
MPEP 2145 II. states “The fact that appellant 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.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Regarding claim 19, it would have been prima facie obvious to delay the consecutive dosage of the CAR T cells until toxicity has been treated or subsided based on the teachings of NCT’442 which teaches spreading the infusion days to allow for observation of toxicity (page 4, top right box of table) and Jensen, which teaches early or preemptive interventions (page 61, [0239]). An ordinarily skilled artisan would have had a reasonable expectation of success as the combination of applied prior art demonstrates that methods of monitoring and treating CAR T cell associated toxicities were known and practiced in the prior art.
Response to Arguments
Applicant’s arguments in the response of 11/12/2025 have been fully considered, but were not persuasive.
Applicant argues that the Office specifically chooses a discrete portion of Posey (the CD2 domain) to be used as a substitution for the 4-1BB costimulatory domain in the CAR of Kloss without fully considering each of the references as a whole. Applicant argues that Kloss does not teach or suggest changing the structure of the CAR to ameliorate the observed toxic effects of the dnTGF-bRII-T2A-Pbba CAR T cells. Specifically, applicant argues that Kloss does not teach or suggest that replacing the 4-1BB costimulatory domain with a CD2 costimulatory domain would address toxic effects.
The instant claims, however, do not require that the use of the CD2 costimulatory domain in place of the 4-1BB costimulatory domain ameliorate toxic effects of the CAR as argued by applicant. Nor is this rationale used in the rejection to demonstrate obviousness in substituting the CD2 costimulatory domain in place of the 4-1BB costimulatory domain. Rather, the claims only require that the use of the claimed split dose of cells reduce toxicity. Specifically, the claim recites “wherein administering the first dose of cells and the consecutive dose of cells results in a reduced on-target off-tumor toxicity when compared to results for administering a single dose of cells; and wherein administering the first dose of cells and consecutive dose of cells results in a reduced on-target off-tumor toxicity when compared to the results for administering a single dose regimen.” At no point does the claim require that the CD2 costimulatory domain further decrease toxicity.
Additionally, even if applicant proposes use of the CD2 costimulatory domain as a means to reduce toxicity, the reason to combine the references does not need to be the same reason as that of applicant. MPEP 2144 IV. states “[t]he reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”
The rejection relies on the teachings of Posey for motivation to substitute the 4-1BB costimulatory domain in the CAR of Kloss with a CD2 costimulatory domain. Specifically, Posey teaches that the CD2 costimulatory domain was more effective and exhibited faster and more durable anti-tumor response against tumors compared to CARs comprising a 4-1BB costimulatory domain. Additionally, Posey teaches the use of the CD2 costimulatory domain with a CD3z intracellular signaling domain, which is the same intracellular signaling domain in the dnTGF-βRII-T2A-PBBZ CAR T cells of Kloss.
In response to this, which was previously discussed in the office action of 08/15/2025 response to arguments, applicant argues that the entirety of Kloss and Posey must be considered as a whole, and a motivation to substitute the 4-1BB costimulatory domain of Kloss for the CD2 domain of Posey be shown. Applicant argues that there has not been a sufficient demonstration of such motivation.
It is first noted that explicit motivation in the prior art is not required in order establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art. The rejection of the instant office action relies on substitution of the 4-1BB costimulatory domain in the CAR T cells of Kloss with the CD2 costimulatory domain, a substitution which is motivated by teachings in Posey in which it is demonstrated that CAR T cells with a CD2 costimulatory domain exhibited a fast and durable anti-tumor response compared to those with a 4-1BB costimulatory domain. While applicant argues that Kloss and Posey must be considered as a whole, applicant does not specifically identify any portion of Kloss or Posey which are contradictory to the motivation used in the rejection or the reasonable expectation of success in substituting one known costimulatory domain for another. As discussed in detail above, the motivation to combine the references in the rejection does not need to be the same reason or to achieve the same advantage or result discovered by applicant.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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