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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 27, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on May 27, 2026. Claims 33-83 are pending. Claims 33-48, 53, 57-59, 63 and 70-83 are withdrawn. Claims 49-52, 54-56, 60-62, and 64-69 are currently examined.
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.
(Previous rejection-maintained with edition) Claims 49-50, 52, 54-55, 60-62 and 64-68 rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (Mol Ther Methods Clin Dev. 2016 Dec 31; 4:92-101) as evidenced by Aucatzyl-CAR T cell therapy ((https://www.aucatzylhcp.com/dosing-administration/treatment-process/).
The amended base claim 49 is directed to a method for tracking a cell order during an immunotherapy procedure, the method comprising:
initiating a process to create transfected T cells, the initiating comprising:
requesting a timeslot for performing leukapheresis procedure from a remote
computing device,
receiving indicia responsive to the requesting, wherein the timeslot is
available to perform the leukapheresis procedure, and
confirming acceptance of an available timeslot with the remote computing
device;
obtaining T cells by leukopheresis at a material extraction site from a patient's blood collected at the material extraction site.
transferring the collected T cells to a container that is labeled with a patient specific identifier;
transmitting the labeled collected T cells to a manufacturing facility;
creating transfected T cells by transfecting the labeled collected T cells with a polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) to obtain an immune-oncology agent;
receiving the immune-oncology agent from the manufacturing facility; and infusing the immune-oncology agent into the patient,
wherein a tracking event is recorded for each step of the method, each tracking event including the patient specific identifier, and
wherein the tracking events comprise a chain of custody of the patient's T cells during the method.
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Levine et al. reviews the global manufacturing of CAR T cell therapy and teaches that Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. They disclose the steps involved in the cell processing of the technology, including the use of an optimal vector for consistent cell processing, along with addressing the challenges of expanding chimeric antigen receptor T cell therapy to a global patient population. (See Abstract).
Levine et al. teaches obtaining T cells from a patient's blood by leukopheresis (See Figure 1, page 93 and above). After a sufficient number of leukocytes have been harvested, the leukapheresis product is enriched for T cells., The cells are washed and separated by size, density and cell viability (See page 92, right column, paragraph 1), where the separated T cells are obviously in a container. Because the T cell is from the patient, it would be obvious that a patient identity will be included on the container such as the global regulation including donor screening and testing, traceability and labeling, patient confidentiality, and apheresis requirements (See page 98, right column, paragraph 1). Here the description teaches the “transferring the collected T cells to a container that is labeled with a patient specific identifier” as claimed.
One of the limitations of the base claim 49 is for “transmitting the labeled collected T cells to a manufacturing facility”, Levine et al. teaches the limitation by stating that they describe the process of manufacturing CAR T cells, and discuss regulatory concerns that must be addressed to successfully produce CAR T cells for larger numbers of patients (See page 92, left column, paragraph 2). Levine et al. also teaches that it is important to establish quality control testing for safety, sterility, purity, potency, identity, and titer so that manufacturing centers can be assured that each batch of vector meets defined standards before it is used to transduce T cells (See page 95, left column, paragraph 1) and discloses the T cell transition to a commercial manufacturing (See Figure 4, page 97 and below).
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Levine et al. also teaches the limitation “creating transfected T cells by transfecting the labeled collected T cells with a polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) to obtain an immune-oncology agent” by disclosing that the chimeric antigen receptor T cells are generated by removing T cells from a patient’s blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells (See Abstract), where the generation of chimeric antigen receptor (CAR) is engineered through transfection with a viral vector such as the Lentiviral vectors. The gene transfer also include the Sleeping Beauty transposon system or mRNA transfection and transient mRNA transfection (See page 93, left column, paragraph 1).
As for the receiving the immune-oncology agent from the manufacturing facility and infusing the immune-oncology agent into the patient as claimed, Levine et al. reviews the application of the immune-oncology agent, the CD19 chimeric antigen receptor T cell therapy CTL019, and teaches acquiring the immune-oncology agent from the GMP cell processing facility (See Figure 3, page 96 and below) and teaches that when the cell expansion process is
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finished, the cell culture, which may reach a volume of up to about 5 L, must be concentrated to a volume that can be infused into the patient (See page 93, right column, paragraph 2).
As for the requirements at “wherein a tracking event is recorded for each step of the method, each tracking event including the patient specific identifier, and wherein the tracking events comprise a chain of custody of the patient's T cells during the method”, Levine et al. teaches that the producing of the immune-oncology agent is under GMP regulation, it would be obvious that each step will be followed by the regulation with recording and tracking. Levine et al. also teaches in contrast to the final CAR T cell product, which must be individually generated for each patient, the viral vector encoding the CAR can be made in large quantities and stored at -80oC for 4 years. Other reports suggest that frozen viral vector stocks are stable for up to 9 years at this temperature. As with the CAR T cell manufacturing process, generation of the vector stocks must take place in Good Manufacturing Practice (GMP) facilities (See page 94, left column, paragraph 2), which indicates the tracking events comprise a chain of custody of the patient's T cells during the method.
As for the limitation at “obtaining T cells by leukopheres is at a material extraction site from a patient's blood collected at the material extraction site”, it is obvious that patient’s blood collection needs to be in a specific site such as hospital or a research or clinical center that includes the site name, address and patient’s personal information. As a type of material extraction, leukapheresis can be performed at the site of patient’s blood collection place. Levine teaches that the challenges of taking a chimeric antigen receptor T cell manufacturing process from a single institution to a large-scale multi-site manufacturing center must be addressed (See Abstract), which indicates the risk of transferring the leukapheresis site without quality ensuring (See page 97, right column, paragraph 2). Nevertheless, Levin teaches that “first, the process involves using leukapheresis to remove blood from the patient’s body, separate the leukocytes, and return the remainder of the blood to the circulation. After a sufficient number of leukocytes have been harvested, the leukapheresis product is enriched for T cells” (See page 92, right column, paragraph 1), which indicates that the material extraction site is the same as the patient’s blood collect site.
As for the new added limitations of “initiating a process to create transfected T cells”, “requesting a timeslot”, “receiving indicia responsive” and “confirming acceptance of an available timeslot with the remote computing device”, although Levine does not use the identical “term” and phrases” as amended in their study, Levine’s discloses teaches all the newly amended limitations by stating that “First, the process involves using leukapheresis to remove blood from the patient’s body, separate the leukocytes, and return the remainder of the blood to the circulation (See page 92, right column, paragraph 1) that indicates an initiation of a CAR T cell therapy. The Figure 1 and 4 of Levine teaches the CAR T therapy process is involved in a process including patient’s identity, blood collection, manufacturing transferring, transfected T cells and leukapheresis to ensure quality of product in moving from a single institution to a multi-site, large-scale manufacturing process. Here the teachings indicate a timeslot is required, requested and confirmed for all the procedure and coordination. It is obvious that the CAR T cell therapy is needed to be performed by a remote computing device. Levine also teaches that a major challenge with scaling out the production of CAR T cell therapies is the transition from a flexible process at a single academic institution to a highly controlled process that can be implemented across many collection, manufacturing, and treatment sites. Therefore, effective coordination among the collection, manufacturing, and treatment sites involved is crucial to ensure that the material is handled correctly and patients are appropriately scheduled throughout the therapeutic process (See page 97, right column, paragraph 2). Here it further teaches that a “initiating process”,” requesting a timeslot”, “receiving indicia responsive” and “confirming acceptance” are needed and required. By transferring among locations for T cell collection, transfection/transduce, delivering to patient and infusion, a remote computing device will be needed. Levine also teaches the order/prescription in Figure 4 that indicates a timeslot has been confirmed. These steps can be also evidenced by AUCATZYL treatment process (See Below) that include patient’s identity, time management and leukapheresis and manufacturing where the patient’s mononuclear cells are enriched for T cells, activated, and transduced with a replication-incompetent lentiviral vector containing the CD19 CAR transgene (See the website).
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Thus, the invention as a whole is clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 50 and 60-62, Levine et al. teaches a CAR comprising an antigen binding molecule that specifically binds to the target CD19, where the generation of the CD19-targeting therapy CTL019 is conducted by delivering the transgene to the T cell using a single vector source (See page 95, left column, paragraph 2) and discloses that Lentiviral vectors, which have a safer integration site profile than gammaretroviral vectors, are commonly used in clinical trials of CAR T cell therapies, including CTL019 (See page 93, right column), where the CTL09 teaches the T cells with the polynucleotide encoding the CAR comprising CD19-target molecule as claimed in claim 50, where the CD19 is a tumor-associated antigen such as the surface protein in B cell of acute lymphoblastic leukemia (claim 62). CTL09 also teaches the polynucleotide transfected into T cell is a component of lentiviral vector claimed in claim 60 and 61.
Regarding claims 52, Levine et al. teaches that CTL019 is a type of CAR T-cell therapy to specifically target and eliminate cancer cells expressing the CD19 protein, for example, CAR T cell therapy has demonstrated complete response rates of 69%–90% in pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) in phase 1 trials (See page 92, left column, paragraph 2).
Regarding claims 54 and 55, Levine et al. teaches that Chimeric antigen receptor (CAR) T cell therapy is a cellular therapy that redirects a patient’s T cells to specifically target and destroy tumor cells. CARs are genetically engineered fusion proteins composed of (1) an antigen recognition domain derived from a monoclonal antibody and (2) intracellular T cell signaling and costimulatory domains (See page 92, left column, paragraph 2), which teaches claim 54. Levine et al. also teaches that the starting cell population used for many CAR T cell therapies consists of CD4+ and CD8+ T cells at the ratio present in the peripheral blood of the patient (See page 98, right column, paragraph 2), which teaches claim 55.
Regarding claim 64, Levine et al. teaches that the CAR T cell therapy process involves using leukapheresis to remove blood from the patient’s body (See page 92, right column, paragraph 1) and T cell transfection such as the viral vector uses viral machinery to attach to the patient cells (See Figure 3 above; page 93, eft column, paragraph 1), it is obvious and necessary that the process include a cell order request to create the transfected T cells for the patient because the CAR T cell must be individually generated for each patient (See page 94, left column, paragraph 1 and Figure 4 above, page 97).
Regarding claims 65-67, these claims require a computer device to record each step for T cell transfection, transferring and storage.
Based on the description above, Levine et al. teaches a Global Manufacturing of CAR T Cell Therapy including the transition to Commercial Manufacturing (See Figure 4). It would be obvious that the commercial systems involving using computer for monitor and track each step in the process (claim 65) as a success in developing a global manufacturing process of CAR T cells will be driven by a robust understanding of both the product and the process in order to establish the target product profile and critical quality attributes (See page 97, right column, paragraph 2). In figure 4, Levine et al. teaches that the first site is the tissue or cell source site with the order, and then other sites including clinical site for infusing to the patient (claim 66). Levine et al. also teaches a transition to Commercial Manufacturing (See Figure 4 above and page 97) and discloses that a major challenge with scaling out the production of CAR T cell therapies is the transition from a flexible process at a single academic institution to a highly controlled process that can be implemented across many collection, manufacturing, and treatment sites (Figure 4). Therefore, effective coordination among the collection, manufacturing, and treatment sites involved is crucial to ensure that the material is handled correctly and patients are appropriately scheduled throughout the therapeutic process. Success in developing a global manufacturing process of CAR T cells will be driven by a robust understanding of both the product and the process in order to establish the target product profile and critical quality attributes (See page 97, right column, paragraph 2), which indicates that a device such as computer is needed to stock and track each step in the process for matching the GMP regulations. Furthermore, Levine et al. also teaches that FDA recommends that patients be followed for RCRs/RCLs for up to 15 years to monitor any potential delayed adverse event related to these vectors and United States (USA) trial has been developed to monitor patients who received the CD19 CAR T cell therapy CTL019 for 15 years after treatment (NCT02445222) (See page 97, left column). Here the descriptions further indicate that the computing device is needed for storing and tracking events in an ordered sequence and teaches claim 67.
Regarding claim 68, Levine et al. teaches that effective coordination among the collection, manufacturing, and treatment sites involved is crucial to ensure that the material is handled correctly and patients are appropriately scheduled throughout the therapeutic process (See page 97, right column, paragraph 2) that includes donor screening and testing, traceability and labeling, patient confidentiality, and apheresis requirements (See page 98, right column, first paragraph 1). Here the descriptions are obvious to include patient ID in each step of the therapy.
(Previous rejection-maintained with edition) Claims 51 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (Mol Ther Methods Clin Dev. 2016 Dec 31; 4:92-101) as evidenced by Aucatzyl-CAR T cell therapy ((https://www.aucatzylhcp.com/dosing-administration/treatment-process/) as applied to claims 49-50, 52, 54-55, 60-62 and 64-68 above and in view of Grupp et al. (Blood, Volume 122, Issue 21, page 67).
Claims 51 and 69 require the antigen binding molecule or CAR being scFv.
Levine et al. teaches a method for immunotherapy procedure as claimed, however, it is silent on the scFv in the CAR.
Grupp et al. teaches that the CTL019 cells are T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB costimulatory domains. These cells can undergo robust in-vivo expansion and can persist for 15 mo or longer in pts with relapsed ALL. CTL019 therapy is associated with a significant CRS that responds rapidly to IL-6-targeted anti-cytokine treatment. This approach has promise as a salvage therapy for patients who relapse after allo-SCT, and collection of tolerized cells from the recipient appears to have a low risk of GVHD. CTL019 cells can induce potent and durable responses for patients with relapsed/refractory ALL (See Conclusions, last page).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the anti-CD19 scFv of Grupp into Levine’s study to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because these cells with the anti-CD19-scFv can undergo robust in-vivo expansion and can persist for 15 mo or longer in pts with relapsed ALL. There would be a reasonable expectation of success to develop a CAR with scFv based on the methods developed in Levine and Grupp.
(Previous rejection-maintained with edition) Claim 56 is rejected under 35 U.S.C. 103 as being unpatentable over Levine et al. (Mol Ther Methods Clin Dev. 2016 Dec 31; 4:92-101) as evidenced by Aucatzyl-CAR T cell therapy ((https://www.aucatzylhcp.com/dosing-administration/treatment-process/) as applied to claims 49-50, 52, 54-55, 60-62 and 64-68 above and in view of Orentas et al. (WO2015069922A2, published on May 14, 2015).
Claim 56 requires at least one costimulatory domain comprises a sequence of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, or SEQ ID NO. 14.
Levine et al. teaches a method for immunotherapy procedure as claimed, and the CAR further comprises at least one costimulatory domain that can be the CD28 or CD8. However, it is silent on a specific SEQ ID NO for the costimulatory domain.
Orentas et al. teaches a novel nucleic acid molecule encoding chimeric antigen receptor (CAR), useful for preparing the chimeric antigen receptor for treating tumor. The nucleic acid molecule comprises an antigen binding domain, transmembrane domain, and at least one intracellular T-cell signaling domain (See Summary). Orentas et al. teaches the SEQ ID NO: 29, an amino acid sequence of exemplary CD28 transmembrane and signaling domains, is identical to the claimed SEQ ID NO: 2 (See Table 1 below), where the CD28 is one of the costimulatory molecules (See page 29, lines 30-40).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Orentas and Levine to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to use the known sequence of the costimulatory molecule CD28, and there would be a reasonable expectation of success to develop a CAR comprising the costimulatory domain of CD28 as claimed.
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Responses to Applicant’s Remarks
Applicant’s arguments filed on May 27, 2026 has been received and fully considered.
Applicant’s arguments on the rejections under 35 U.S.C. § 103 are not found persuasive.
1). Applicant argued that Levine does not disclose or suggest each and every feature recited in present claim 49 (See Remarks, page 13).
Applicant’s argument is not persuasive.
Although Levine does not use the identical terms claimed in the amended base claim 1, Levine’s teachings indicate all the limitation features. Levine teaches the “leukapheresis removes immune cells from the patient’s blood” (See Figure 1) that indicates a patient identification has been confirmed and a timeslot is requested and confirmed and cell tracking is started because the time for T cell culture and transfection /transduction is limited and need to be scheduled.
2). Applicant argued that Levine merely discloses a method for producing CAR T cells (See Remarks, page 13, paragraph 3).
Applicant’s argument is not persuasive.
Levine does not only teach a method for producing CAR T cells, but also teaches the global regulatory expectations for successful implementation of CAR T Cell therapies (See page 98, left column), the importance for effective coordination among the collection, manufacturing, and treatment sites involved is crucial to ensure that the material is handled correctly and patients are appropriately scheduled throughout the therapeutic process (See page 97, right column, paragraph 2), the harmonized regulations established among the donor screening and testing, traceability and labeling, patient confidentiality, and apheresis requirements (See page 98, right column), and patients being followed for RCRs/RCLs for up to 15 years to monitor any potential delayed adverse event related to these vectors (See page 97, left column, paragraph 1).
3). Applicant argued that none of Levine, Grupp, and Orentas disclose or suggest a method for tracking a cell order during an immunotherapy procedure wherein the process is initiated (See Remarks, page 14).
Applicant’s argument is not persuasive.
Based on the description above, Levine teaches a method and system for tracking a cell order during an immunotherapy procedure by disclosing patient’s blood collection, patient confidential, harmonized regulations for the leukapheresis and T Cell isolation (See Figure 1), the Lentiviral Vector Manufactured by Oxford BioMedica Ltd (See Figure 3) and bedside transferring (See Figure 4) and the Long-Term patient follow-up.
For Grupp and Orentas, they support the primary reference of Levin to teach the specific limitation on a ScFv target molecule and a specific costimulatory domain sequence, respectively. It is applicable for them to be combined as the prior art references in the current office action.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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