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 .
Status of Application/Amendments/Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Applicant’s response filed on 2/3/2026 have been considered. Claims 67-78 and 80-87 are pending. Claims 67 and 68 are amended. Claim 86 is currently withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 67-78, 80-85 and 87 are the subject of the present Official Action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/447,894, 62/447,913, PRO 62/467,062 and PCTUS2018/014116 filed on 1/18/2017, 1/19/2017. 3/3/2017 and 1/17/2018, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 1/18/2017.
Withdrawn Rejections in view of Applicants’ amendment
35 USC § 103
The 35 U.S.C. 103 rejection of claims 67-78, 80-85 and 87 has been withdrawn in light of applicants claim amendments describing the concentration of N-acetyl cysteine during the expanding stage as being at least 5 mM more than the concentration of the transducing stage.
New Claim Rejections in view of Applicants’ amendment
- 35 USC § 112b
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67-78, 80-85 and 87 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. This rejection is newly applied to address applicants claim amendments on 2/3/2026.
Claim 67 describes a method for transducing T cells comprising enriching PBMCs to isolate T cells, activating, transducing and expanding the modified T cells. Claim 67 concludes with a wherein clause describing “the concentration of N-acetyl cysteine” during the expanding stage as being at least 5 mM more than the concentration of the transducing stage. There is a lack of antecedent basis for the concentration of N-acetyl cysteine referenced. It is unclear if the concentration of N-acetyl cysteine referenced is in the culture media at the start of the transducing stage, during or after the 6 to 36 hours, or right after adding the 300 mL of cell expansion media but before the at least 4 days described in the expanding stage. As a result of this indefinite term, one of ordinary skill in the art would not understand which stage in the expanding step must the concentration of N-acetyl cysteine be at least 5mM more than during the transducing step. A claim is indefinite when it contains words or phrases whose meaning is unclear, see MPEP2173.05(e).
Claims 68-78, 80-85 and 87 are rejected for their dependency on indefinite claim 67.
Claim Interpretation
Claim 67 describes activating T cells under “effective activating conditions” comprising an “effective amount of anti-CD3 antibody”. Claim 67 also describes transducing the activated T cells under “effective conditions” comprising incubating the activated T cells in the presence of a replication incompetent recombinant retroviral particle. For the purpose of compact prosecution, the examiner has applied the broadest reasonable interpretation to these effective conditions as being determined by one of ordinary skill through routine optimization since there exist motivation to optimize for T cell transduction efficiency, see MPEP § 2144.05.
The concentration of lactate referenced in claim 82 is interpreted as being derived from metabolites which would inherently be produced as byproducts of normal cellular function. Inherent features need not be recognized at the time of the invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but that the subject matter is in fact inherent in the prior art reference, see MPEP 2112.
New Claim Rejections - 35 USC § 103
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.
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.
Claims 67-78, 80-85 and 87 are newly rejected under 35 U.S.C. 103 as being unpatentable over Frost et al. US 2017/0296678, published 10/19/2017, priority date 3/19/2016 (hereinafter Frost, reference of record) in view of Morgan et al. US 2017/0051252, published 2/23/2017, priority date 4/25/2014 (hereinafter Morgan, reference of record) and Sutton et al. "Bioengineering and serum free expansion of blood-derived γδ T cells." Cytotherapy 18.7 (2016): 881-892 (hereinafter Sutton) as evidenced by ThermoFisher Scientific, 2015 (hereinafter ThermoFisher). This rejection is newly applied to address applicants claim amendments on 2/3/2026.
Claims 67 and 68: Frost describes methods for genetically modifying lymphocytes for adoptive cellular therapies via transducing T cells with recombinant retroviral vectors ex vivo prior to administering the activated T cells into a patient in need thereof (Frost, abstract and para 13-19). In particular, Frost describes the isolation, transduction and expansion of peripheral blood mononuclear cells (PBMCs) using a “closed” bioreactor system (Frost, example 9). Although the majority of the disclosure of Frost is concerned with performing adoptive cellular therapies that include transducing T cells without prior ex vivo stimulation, Frost does provide alternative embodiments describing the ex vivo activation of isolated PBMCs prior to transduction (Frost, example 11 para 626). It is noted that nonpreferred and alternative embodiments constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure, see MPEP 2123. In example 11, Frost describes activating the isolated PBMCs using anti-CD3 antibodies prior to viral transduction which are not attached to or immobilized on a synthetic solid support (Frost, example 11 para 626). Specifically, Frost describes a separate activating step prior to viral transduction wherein 50 ng/mL of anti-CD3 ab (OKT3, Novoprotein) was added to the isolated PBMCs and cultured overnight (~8hrs) in a standard humidified tissue culture incubator at 37°C and 5% carbon dioxide (Frost, para 626). Notably, the activating conditions do not comprise anti-CD28 antibodies (Frost, example 11). Frost describes transducing the activated T cells overnight (~8hrs) with lentiviral particles reading on step (d) (Frost, example 11). Frost describes separate method steps in which the cells are activated, transduced and expanded in the same chamber (Frost, para 626). Frost does not expressly describe adding at least 300 mL of expansion media as described in step (d) but rather teaches a smaller volume of 30 mL (Frost, example 11). Frost does not expressly describe expanding the T cells for at least 4 days prior to harvesting the T cells as described in step (e). Frost does not expressly describe that the concentration of N-acetyl cysteine during at least part of the expanding stage is at least 5mM or more or 10mM more than the concentration during the transducing stage.
Claims 70-73: Frost describes the expansion of isolated PBMCs using media containing IL-2 (100 IU/mL increments) and IL-7 as well as other basal media supplement (Frost, para 626, 629, 638 and Fig 19).
Claims 74-75: Frost describes subsequent steps for transducing the activated PBMCs with replication incompetent lentiviral vectors comprising nucleic acid sequences encoding chimeric antigen receptors (CAR) for expression on the activated PBMCs (Frost, example 3 and 11). Frost provides a detailed description of the CAR construct which contains a microenvironment restricted antigen-specific targeting region (ASTR), a transmembrane domain and an intracellular activating domain (Frost, para 13, 81-84 and claims 1 and 14).
Claim 76: In example 11, Frost describes activating the isolated PBMCs using anti-CD3 antibodies prior to viral transduction which are not attached to or immobilized on a synthetic solid support (Frost, example 11 para 626).
Claim 77: Frost describes incubating the activated T cells in the presence of lentiviral particles at a multiplicity of infection (MOI) of 5 (Frost, para 262 and Fig 20).
Claim 80: Frost describes activating the enriched T cells without previous cryopreservation steps (Frost, para 626).
Claim 81: Frost provides a description of the closed bioreactor system in Example 9. Frost describes gas exchange in the closed system using a gas permeable membrane (Frost, para 291 and example 11).
Claim 82: Frost describes monitoring concentrations of lactic acid or lactate to track mutagenesis or transduction (Frost, para 242).
Claim 85: Frost describes reintroducing the transduced T cells back into the patient as an adoptive cell therapy (Frost, para 19, 45 and claim 14-part c).
Claim 87: Frost describes performing density gradient centrifugation to collect and enrich the PBMCs (Frost, para 275).
Claims 67 and 69: Similar to Frost, Morgan discloses methods for manufacturing adoptive T cell therapies using a closed system process (Morgan, abstract and para 105). Morgan describes various cell culture seeding densities and expansion volume densities (Morgan, para 191, 204 and 226). Specifically, Morgan lists exemplary cell culture volumes of about 500 mL, 750 mL and 100 mL reading on “at least 300 mL of expansion media” as described in claim 67 part (e) (Morgan, para 190, 191, 199 and 237). Morgan states that both activation, transduction and expansion may take place in the same cell culture vessel (Morgan, para 229). Morgan describes expanding the transduced T cells using media containing IL-2 and IL-7 as well as other basal media supplements (Morgan, para 395, 398, 407, 446 and Table 1). Morgan describes the number and density of isolated PBMCs transferred to the culture vessel with alternative embodiments listed, corresponding to the limitations of claim 69 (Morgan, para 204, 237, 255). Morgan states that the T cells may be expanded for periods greater than 4 days, reading on the limitations to claim 67 part (e). Morgan describes harvesting the modified T cells for use as an adoptive immunotherapy (Morgan, para 186, 416).
Claim 83: Morgan describes cryopreserving the harvested T cells (Morgan, para 177, 194).
Claim 84: Morgan describes isolating PBMCs from a patients’ blood to obtain T cells, with blood volumes between 50-300 mL (Morgan, para 172, 179, 444). Morgan describes transferring the isolated PBMCs to a closed-cell processing system for activating and expanding the T cells (Morgan, para 182 and example 1).
It would have been prima facie obvious to one of ordinary skill in the art to use the cell density, expansion culture volumes, expansion culturing times, blood collection volumes and cryopreservation techniques described by Morgan in the closed system process for manufacturing adoptive T cell therapies described by Frost. Both inventors are concerned with similar closed systems for isolating, activating, transducing and expanding CAR T cells using lentiviral vectors. Both inventors’ experiment with different operating conditions and effective concentrations/volumes to optimize T cell transduction efficiencies and yields. Therefore, it would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to adopt the cell density and expansion volumes, blood collection volumes and cryopreservation techniques described by Morgan and apply it to the closed system process for manufacturing adoptive T cell therapies described by Frost. One of ordinary skill in the art would have been motivated to do so in order to optimize T cell yields and transduction efficiencies as well as cryopreserve the transduced T cells for later therapeutic use.
Claims 67 and 68: Sutton describes cell culturing methods to support the ex vivo expansion of γδT cells and describes the use of OpTmizer media which contains N-acetyl-cysteine (Sutton, pg 888). Sutton states that the inclusion of N-acetyl-cysteine in the expansion media can restrict activation-induced cell death (AICD). As evidenced by ThermoFisher, N-acetyl-cysteine is used at a final concentration of 10mM and to help T cell expansion.
It would have been prima facie obvious to one of ordinary skill in the art to include at least 10mM more N-acetyl-cysteine in the expansion stage when compared to the transducing stage as described by Stutton in the methods of T cell transduction of Frost in view of Morgan. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to include N-acetyl-cysteine since it is commercially available in common T cell expansion medias like OpTmizer media provided by ThermoFisher. One of ordinary skill in the art would have been motivated to do so in order to restrict activation-induced cell death (AICD) and improve T cell expansion prior to harvesting. One would have a reasonable expectation of success given that such methods and products are commercially available and used in the prior art. Furthermore, both Frost and Morgan a clear appreciation for varying T cell activation, transduction, and expansion parameters in order to select for T cell subpopulations depending on the therapeutic application (Morgan para 254). Thus, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the transduction incubation time (claim 67), expansion culturing time (Claim 67), expansion cell density (Claim 69), time and general media components (e.g., claims 68-73), and harvesting conditions (e.g., claim 82). "Where 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). One would have a reasonable expectation of success given that both authors use similar close system bioreactors for lentiviral transduction of CAR constructs in isolated T cells and expansion methods. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory 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 Langi, 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 706.02(1)(1) - 706.02(1)(3) 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.
Claim 67 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-61 of copending Application No: 17/272,631 (US Patent Application Publication Number US 2021/0317408). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would anticipate the instant claims if they were available as prior art. This rejection is maintained for the same reasons as described in the Office Action mailed on 8/4/2025. A reply to applicants’ traversal is found below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 67: The copending claims are drawn to a method for genetically modifying T cells comprising collecting blood cells from a subject, contacting the T cells ex vivo in a reaction mixture with a replication incompetent recombinant retroviral particle for transduction (claim 43). The copending claims describe activation elements comprising polypeptides capable of binding CD28 (claim 52 and 53). The copending claims describe a closed cell processing system (Claim 59). Thus, the present invention embraces the copending claims.
Response to Traversal
Applicant requests that the rejection be held in abeyance until allowable subject matter has been indicated.
The rejection is maintained accordingly.
Conclusion
Claims 67-78, 80-85 and 87 are rejected.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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