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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/08/2026 has been entered.
Claim 11 is amended; claims 1-10, and 12-26 are cancelled; and claims 32-33 are new. Claims 11 and 27-33 are currently pending.
Claim 28 remains withdrawn as being drawn to an unelected species.
Claims 11, 27, and 29-33 are examined on the merits herein.
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.
Withdrawn Objections and Rejections
In the office action of 01/12/2026,
Claims 11-12, 19, 27, and 29-31 were rejected under 35 USC 103 over Kloss, Posey, WO’546, WO’571, US’724, NCT’442, Wells Fargo, Townsend, and Sun. The rejections are withdrawn in favor of the modified rejections below.
The following rejections are new.
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, 27, and 29-33 are rejected under 35 U.S.C. 103 as being unpatentable over 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, US 2016/0206656 A1 (Gilbert, M.J.) 21 July 2016, 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 from CD2 comprising the amino acid sequence of SEQ ID NO: 36. Kloss also does not disclose the administration regimen instantly claimed in which a first dose comprising 30% of the total dose is administered, the development of an on-target off-tumor toxicity resulting from the first dose is monitored, specifically a neurological toxicity associated with expression of PSMA in a normal tissue, and a consecutive dose comprising 70% of the total dose is administered 5-7 days later at a time when the on-target off-tumor toxicity has been treated or has subsided, wherein this regimen has a reduced on-target off tumor toxicity compared to the results for administering a single dose of cells.
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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US’656 teaches methods for administering multiple doses of cells, such as T cells, to a subject for cell therapy. The cells generally express recombinant receptors, such as chimeric antigen receptors (CARs). The methods generally involve administering a first dose and at least one consecutive dose of the cells. Timing of the doses relative to one another and/or the size of the doses provide various advantages such as lower or reduced toxicity and improved therapeutic efficacy. In some embodiments, the first dose is a relatively low dose thereby improving the efficacy of consecutive or subsequent doses. US’656 further teaches that the timing of the consecutive dose is designed to minimize risk of toxicity and/or host immune response to the cells by the subject, thereby improving persistence and efficacy (page 1, [0003]).
US’656 further teaches that the time between the administration of the first dose, e.g., the initiation of the administration of the first dose, and the initiation of the consecutive dose is greater than about 4 days, e.g., greater than about 5, 6, 7, 8, or 9 days (page 2, [0017]). The timing of the consecutive dose disclosed by US’656 overlap with the instantly claimed ranges of 5-7 and 5-6 days and, also lie within the claimed ranges including 5, 6, and 7 days. As such, the timing of the consecutive dose disclosed by US’656 renders the instantly claimed timing obvious as per MPEP 2144.05 I as any of the times between dosages disclosed by US’656 would have been reasonably expected to be effective.
US’656 further teaches that the consecutive dose is larger than the first dose and that the increased number of cells is 2-fold, 5-fold, or 10-fold (page 4, [0029]). US’656 teaches the administration of a single dose unit in the first infusion and that the consecutive infusion can comprise a dose containing 1, 2, 3, or even more unit doses of the cells (page 44, [0549] and [0553]). US’656 teaches that the size of the consecutive dose is patient-specific and is based on tumor burden, presence of an anti-CAR immune response, and the level of toxic outcomes (page 44, [0553]). Based on the consecutive dose being a 2-fold increase, US’656 teaches a first dose of 1/3 of the total cells and a consecutive dose of 2/3 of the total cells (a 2-fold increase in the consecutive dose), or approximately 33% and 67%. These percentages are also supported by the administration of a single dose unit of the cells followed by a 2 dose unit of the cells, in which case the total dosage would be 3 units with 1/3 administered first and 2/3 administered consecutively. As such, US’656 suggests a first dose of approximately 33% and a second dose of approximately 67%, which is close to the 30% and 70% first and consecutive dosages of the instantly claimed invention rendering the claimed percentages obvious per MPEP 2144.05 I.
US’656 also teaches that the consecutive dose is administered at a time in which the clinical risk for neurotoxicity, cytokine release syndrome, macrophage activation syndrome, or tumor lysis syndrome is not present or has passed or has subsided following administration of the first dose. US’656 further provides methods of monitoring such toxicities, including biochemical readouts or identification of factors associated with toxicity in the serum (page 2, [0013]). US’656 teaches that following administration of the first dose, the subjects receive physical examinations and are monitored for any symptoms of toxicity or toxic outcomes, such as fever, hypotension, hypoxia, neurologic disturbances or an increase serum level of inflammatory cytokines. If necessary, anti-IL-6, or other CRS therapy, is administered to reduce signs of CRS (page 44, [0550]). US’656 teaches that the subject is treated with such therapy following the first dose and the consecutive dose is administered only if and when the CRS-associated symptom(s) are reduced or declining or declined below an acceptable level following such treatment (page 18, [0172]).
US’656 also teaches methods of monitoring neurotoxicity or neurological complications, including symptoms of confusion, aphasia, seizures, convulsions, lethargy, and/or altered mental status, graded based on severity (page 45, [0558]).
US’656 teaches that the methods are used to treat a disease or condition, such as cancer, including prostate cancer (page 3, [0020]). US’656 further teaches that the CAR targets an antigen associated with the disease and the antigen associated with the disease can be PSMA (page 44, [0547] and page 12, [0103]).
US’656 teaches that the methods provide advantages over single-dose administrations, which can lead to severe toxicity, unwanted outcomes, and/or lower efficacy, particularly in the case of high disease burden. They can also be advantageous over methods administering the subsequent dose(s) too soon following an initial dose- increasing the risk of unwanted side effects – or too late, e.g., after establishment of an immune response to a previous dose. The provided method extends exposure to the therapeutic cells, improving durability and extent of clinical response and/or patient survival, while reducing toxic outcomes (page 11, [0092]).
US’656 also teaches that the methods disclosed offer advantages over other approaches aiming to address the risk of toxic outcomes and/or improving efficacy. Many such approaches have focused, for example, on targeting downstream effects of toxicity, such as cytokine blockade and/or delivering agents such as high-dose steroids which can also eliminate or impair the function of administered cells. Many of these other approaches also do not prevent other forms of toxicity such as neurotoxicity which can be associated with cell therapy. On the other hand, administering relatively low doses of cells (e.g., CAR expressing cells) may decrease the risk but may not be completely effective. Delivery of subsequent doses of cells, for example, after relapse following an initial administration has also not been entirely satisfactory as such approaches can lead to limited or ineffective responses due to host immune responses mounted against the first dose. The methods disclosed by US’656 minimize the risk of toxicity while maximizing efficacy (page 8, [0075]-[0076]).
US’656 further teaches that preconditioning subjects with immunodepleting, e.g., lymphodepleting, therapies can improve the effects of adoptive cell therapy (ACT). Preconditioning with lymphodepleting agents, including combinations of cyclosporine and fludarabine, have been effective in improving the efficacy of transferred TIL cells in cell therapy, including improved responses and/or persistence of transferred cells (page 13, [0118]). Thus, in some embodiments, the method includes administering a preconditioning agent, such as a lymphodepleting or chemotherapeutic agent, such as cyclophosphamide, fludarabine, or combinations thereof to a subject prior to the first dose. For example, the subject may be administered a preconditioning agent at least 2 days prior, such as at least 3, 4, 5, 6, or 7 days prior, to the first or subsequent dose. In some embodiments the preconditioning agent is administered no more than 7 days prior to the first dose. US’656 further teaches that fludarabine can be administered at a dose of 30 mg/m2 and given daily (page 13, [0119]-[0122]). US’656 also teaches the combination of cyclophosphamide and fludarabine (page 13, [0122]).
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 the methods disclosed by US’656, while monitoring specifically for on-target off-tumor neurologic toxicity associated with the expression of PSMA in a normal tissue as suggested by Kloss and Sun. An ordinarily skilled artisan would have had a reasonable expectation of success that the administration of the first and consecutive dose of cells would result in a reduction in the on-target off-tumor toxicity compared to the administration of a single dose of cells based on the teachings of Kloss, US’656, and Sun.
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. Additionally, Posey teaches that CAR T cells with a CD2 costimulatory domain produced minimal quantities of TNFα, similar to those with 4-1BB costimulatory domains, which Posey suggests is a neurotoxic cytokine, suggesting that the safety profile between CD2 costimulatory domain and 4-1BB costimulatory domain containing CARs are comparable. 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 using the methods disclosed by US’656 as US’656 teaches that the methods have advantages over single-dose administrations, which can lead to severe toxicity, unwanted outcomes and/or lower efficacy. Particularly, US’656 teaches that the methods taught extend exposure to therapeutic cells, improves durability, and the extent of clinical response and/or patient survival, while reducing toxic outcomes. An ordinarily skilled artisan would have had a reasonable expectation of success as US’656 is teaching methods of treating cancer using CAR T cells and also teaches that the CAR T cells can target PSMA and be used to treat prostate cancer, which is the same CAR antigen target and cancer type disclosed by Kloss. It would have also been obvious to have the toxicity that is monitored in US’656 be on-target off-tumor neurologic toxicity associated with the expression of PSMA in a normal tissue as Kloss teaches that there is low-level expression of PSMA on normal tissues including astrocytes and neurons, both of which are components of the central nervous system and Sun teaches that on-target off-tumor toxicity can occur when normal tissues express even low levels of the target antigen. An ordinarily skilled artisan would have had a reasonable expectation of success as all of Kloss, US’656, and Sun are related to CAR T cell administration for the treatment of cancers and US’656 demonstrates methods of monitoring toxicity between the first and consecutive dose as a means to increase efficacy and reduce toxicity.
An ordinarily skilled artisan would have reasonably expected that the administration of the first and consecutive dose of cells would result in a reduced on-target off-tumor toxicity compared to the administration of a single dose of cells, specifically a neurologic toxicity associated with the expression of PSMA in a normal tissue, based on the teachings of Kloss, US’656, and Sun. For instance, as discussed above, Kloss teaches the expression of PSMA on normal tissues including cells of the central nervous system and Sun teaches on-target off tumor toxicity resulting from even low-expression of target antigen on normal tissues. Sun also teaches a study suggesting that a substantial dose of infused CAR T cells could potentially provoke this toxicity while lower doses could be safer. This reduction in toxicity is also supported by US’656 which teaches that using the first and consecutive dosing regimen disclosed can reduce toxicity, including neurotoxicity, compared to single-dose administrations. Thus, an ordinarily skilled artisan would have reasonably expected the claimed outcomes.
Additionally, the reduction in on-target off-tumor neurologic toxicity associated with the expression of PSMA in a normal tissue would flow naturally from the administration of the CAR T cells using the first and consecutive dose regimen suggested by US’656 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.”
Furthermore, one of ordinary skill in the art would have been able to use the first and consecutive dosing percentages and timing disclosed by US’656 as a starting point for routine optimization in order to determine the optimal percentages and timing for administering the dnTGF-βRII PSMA CAR T cells in the method suggested by the combination of applied references.
MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, as discussed in detail above, US’656 suggests a first dose of 1/3 the total dose (~33%) and a consecutive dose of 2/3 the total dose given (~67%). US’656 also suggests administration of the consecutive dose greater than about 4 days, e.g., greater than about 5, 6, 7, 8, or 9 days, following administration of the first dose. The teachings of US’656 also demonstrate that these were recognized as result effective variables. Specifically, US’656 teaches that the size of the consecutive dose is patient-specific and is based on tumor burden, presence of an anti-CAR immune response, and the level of toxic outcomes (page 44, [0553]). US’656 also teaches that if the consecutive dose is administered too close to the first dose, there is an increased risk of unwanted side effects, but, if administered too late, an immune response could be established to the previous dose lowering efficacy (page 11, [0092]). US’656 also teaches that the consecutive dose is administered at a time in which the clinical risk for toxicity is not present, has passed, or has subsided following the administration of the first dose (page 3, [0013]). Such teachings in US’656 demonstrate that the time between the first and consecutive dose as well as the amount of dosing in each administration is a result effective variable that can be optimized to achieve the best outcomes.
Claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over 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, US 2016/0206656 A1 (Gilbert, M.J.) 21 July 2016, and Sun, S., et al (2018) Immunotherapy with CAR-modified T cells: Toxicities and Overcoming Strategies Journal of Immunology Research 2386187; 1-10 as applied to claims 11 and 29 above, and in further view of WO 2017/165571 A1 (Jensen, M. and R. Gardner) 28 SEPT 2017.
It is noted that claims 30-31 were rejected above over Kloss in view of Posey, WO’546, US’656, and Sun. The claims are further rejected here to demonstrate that the dosages of cyclophosphamide and fludarabine recited in claim 30, parts (c) and (d) would have been obvious to use as a lymphodepleting regimen. These dosages, specifically 300 mg/m2/day of cyclophosphamide and 30 mg/m2/day of fludarabine, were elected in the species election response of 10/25/2022.
The combination of Kloss, Posey, WO’546, US’656, and Sun teach the method of claim 29 as discussed in detail above.
As discussed in detail above, US’656 teaches the administration of lymphodepletion chemotherapy prior to the administration of the CAR T cells and teaches that the lymphodepletion chemotherapy comprises cyclophosphamide and fludarabine.
The combination of applied references, however, do not disclose that cyclophosphamide is administered at a dose of 300 mg/m2/day and fludarabine is administered at a dose of 30 mg/m2/day.
WO’571 teaches methods for therapy with CAR T cells (abstract) including CARs targeting PSMA (page 63, [0244]). WO’571 teaches that preconditioning subjects with immunodepleting, e.g., lymphodepleting therapies, can improve the effects of adoptive cell therapy (page 64, [0251]). Thus, WO’571 teaches administration of a preconditioning lymphodepleting chemotherapeutic agent, such as cyclophosphamide, fludarabine, or combinations thereof prior to the initiation of cell therapy. For example, the subject may be administered the preconditioning agent at least 2 days, such as at least 3, 4, 5, 6, or 7 days prior to the initiation of cell therapy (page 64, [0252]). WO’571 exemplifies an embodiment of lymphodepletion in which, prior to administration of the CAR expressing T cells, subjects were treated with 30 mg/m2 fludarabine daily for 3 days and 300 mg/m2 cyclophosphamide daily for 3 days (page 105, [0345]).
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 modify the method taught by the combination of Kloss, Posey, WO’546, US’656, and Sun by administering 30 mg/m2 fludarabine daily for 3 days and 300 mg/m2 cyclophosphamide daily for 3 days as the lymphodepletion chemotherapy as disclosed by WO’571. It would have been obvious to use this lymphodepletion regimen as WO’571 demonstrates that the dosages of fludarabine and cyclophosphamide were considered effective for lymphodepletion prior to CAR T cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’571 teaches the same chemotherapeutics for lymphodepletion as US’656, which also suggests a combination of fludarabine and cyclophosphamide.
Response to Arguments
Applicant’s arguments in the response filed 04/08/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but are not persuasive.
Applicant argues that neither Kloss nor Posey teaches or suggests administering a first partial dose of cells comprising the claimed CAR, monitoring the development of a PSMA-associated neurologic on-target off-tumor toxicity after that first dose, and administering the second dose only when that toxicity has been treated or has subsided.
It is first noted that neither Kloss nor Posey, or any of the other cited references alone, are individually required to teach each and every limitation of the claimed method as the rejection is based on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. See MPEP 2145 (IV).
In the rejection, Kloss is applied to demonstrate that methods of treating the claimed patient population with the claimed CAR was taught by the prior art. Posey is applied to demonstrate that the use of CD2 costimulatory domains in CARs had been studied and compared to a 4-1BB costimulatory domain, which is the costimulatory domain in the CAR disclosed by Kloss. Neither of these references are required to teach the claimed administration regimen as these limitations are met by US’656 and Sun as discussed in detail in the rejection of the instant office action.
Applicant further argues that, in the advisory action (dated 03/17/2026), it is stated that one of ordinary skill in the art would have expected that the regimen would reduce toxicity relative to a single dose regardless of whether the CAR used a 4-1BB or CD2 costimulatory domain, but that there is no identification of what reference teaches this. Applicant argues that the Office has not pointed to a teaching in the cited art that teaches that the regimen would reduce a neurologic on-target off-tumor toxicity associated with normal PSMA expression or that such would be true irrespective of the costimulatory domain.
The limitation recited in the instant claims regarding reduced toxicity states “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 the results for administering a single dose of cells”. Such limitation only requires that the prior art references provide a reasonable expectation that the claimed regimen would reduce this toxicity compared to a single dose of cells. As discussed in detail in the rejections of the instant office action, US’656 establishes methods in which a first dose is applied, toxicities are monitored, and, when toxicities have subsided or been treated, a consecutive dose is administered. US’656 directly teaches that such an administration method results in reduced toxicity compared to a single dose of CAR T cells. An outcome which is further supported by Sun, which suggests that on-target off-tumor toxicity could be caused by high CAR T cell dosages and reduced by using lower dosages. Additionally, the teachings of Sun specifically demonstrate that on-target off-tumor toxicity is a result of T cells attacking normal tissues that have the shared expression of the target antigen, further suggesting that this toxicity is a result of the antigen target of the CAR. Such teachings indicate that, by using a lower dose of cells in the first administration and a consecutive administration of the cells, toxicities can be reduced including on-target off-tumor toxicity. Furthermore, US’656 teaches that the administration methods disclosed can be used for CARs targeting PSMA and includes prostate cancer as a cancer that can be treated demonstrating a further nexus among the art.
It is also noted that the standard for obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required in order to determine a prima facie case of obviousness. See MPEP 2143.02(I).
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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