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
Acknowledgement is hereby made of receipt and entry of the communication filed on Oct. 21, 2025. 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 Claims 33-48, 53, 57-59, 63 and 70-83 are withdrawn.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) 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).
The amended base claim 49 is directed to a method for tracking a cell order during an immunotherapy procedure, the method comprising:
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 new 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.
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.
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 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.
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 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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Double Patenting (withdrawn)
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(The Double Patenting is withdrawn) Claims 49-52, 54, 60, 62 and 66-69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16--19, 21, 23, 25 and 27-30 of co-pending Application No. 16646239 (reference application).
The Double Patenting is withdrawn in view of applicant’s remark filed on Oct. 21, 2025.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Oct. 21, 2025 has been received and fully considered.
1). Applicant’s argument for the Double patenting is considered. The Double patenting rejection is withdrawn.
2). Regarding the rejections under 35 U.S.C. § 103, Applicant argued that Levine does not disclose or suggest that the patient's blood is collected at a material extraction site and the leukapheresis procedure is also performed at the same material extraction site to obtain patient-specific T cells (See Remarks, pages 12-13).
Applicant’s argument is not persuasive.
The instant specification discloses that the user interface module 108a requests confirmation of the material extraction site (e.g., site name, address, contact information) for drop-off of an extraction kit (e.g., leukapheresis kit) and confirmation of the altered material delivery and treatment site (e.g., site name, address, contact information) for delivery of the material (e.g., transfected T cells) from the manufacturing facility (See [0145]), which indicates that the material extraction site is a facility or center.
The instant specification also discloses that “once the cell order process is complete as described above, a process 206 is initiated to perform the biological material extraction procedure at the extraction site, ship the extracted material to the manufacturing facility for modification, and send the modified material back to a delivery site for infusion back into the patient's bloodstream. First, the patient arrives at the material extraction site and a procedure (e.g., a leukapheresis procedure) is performed (206a) on a sample of the patient's blood to collect T cells from the sample…” (See [0146]).
Based on the description, Levin’s review for the leukapheresis and extraction site teaches the newly amended limitation (See page 92, right column, paragraph 1). Levin teaches collecting patient’s blood, which obviously implies a “material extraction site”. Levin teaches that “…separate the leukocytes, and return the remainder of the blood to the circulation…” (See page 92, right column, paragraph 1) that indicates that the leukapheresis and the blood collection can be performed at the same site.
3). For the 103 rejections of claims 51, 56 and 69, Grupp and Orentas 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 a combination prior art in the current office action.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 date of this final action.
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-5:00 pm, EST.
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672