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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/17/2025 has been entered.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1 and 4-10 under 35 USC 103 over Barbera-Guillem, in view of Stice et al, Hyde et al, Powell et al, and Wilson et al: Upon reconsideration, the previous rejection is withdrawn.
New/Modified Grounds of Rejection
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.
Claims 1, 4 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Lamers et al (Cancer Gene Therapy, 2002), in view of Wilson et al (US 2005/0106717).
Lamers et al seek to optimize generation of therapeutically useful cytotoxic T lymphocytes, specifically by optimizing parameters for activation, transduction and expansion (See abstract). Lamers et al generate scFvG250 ch-Recpos T lymphocytes which have specificity for a renal cell carcinoma tumor associated antigen. The optimized protocol is described at Pg. 621-622, and briefly summarized as:Step 1: Activate in vitro patient PBMC in Nexell culture bags in Mix-Med medium.
Step 2: Perform two transduction cycles at days 2 and 3 post T lymphocyte activation using:
Fibronectin fragment CH-296 coated to
Nexell LifeCell®X-fold® culture bags at
0.5 x 106 lymphocytes per
0.3 mL of RTVsup per cm2 of culture bag per transduction. (0.3 is rounded up from 0.25 mL, see Pg 618, col. 1 “RTVsup volume and lymphocyte density per surface….”, which says “The minimum volume of RTVsup and the maximum number of T lymphocytes that can be used per square centimeter without lowering gene transduction efficiencies… are 0.25 mL of RTVsup and 0.5 x 106 T lymphocytes/cm2…”).
Step 3: Between the two transduction cycles, maintain the T lymphocytes in RPMI 1640 medium supplemented with human serum.
Step 4: Expand the transduced T lymphocytes in the Nexell culture bags in Mix-Med medium for greater than 12 days.
The optimized protocol is comparable to the claim as follows:
Regarding claim 1: Lamers et al is transducing and culturing T cells. Step 2 is comparable to the first claimed step (adding a first volume…). Specifically, the RTVsup medium (a first volume of medium as well as a genetic modification agent) and activated T lymphocytes (a quantity of T cells) are added to the X-fold culture bag (a device). The T cells are provided at a concentration of 4 x 106 cells/mL (0.5 x 106 cells/cm2 in 0.25 mL of RTVsup/cm2 = 4.0 x 106 cells/mL) (T cells are at a cell concentration beyond 2 million cells per milliliter of media).
The period of time between Steps 2 and 4 reads on the second claimed step (allowing a period of time whereby said genetic modification agents act to transduce at least a portion of said T cells).
The expansion of Step 4 is comparable to the third and fourth claimed steps. From the detailed method section, it is noted that the expansion step involved reseeding of the transduced T cells at a density of 0.5 x 106 cells/mL (See Pg. 615, col. 2).
The protocol of Lamers et al differs from the instant claims in that Lamers et al perform the transduction and cell expansion in X-fold culture bags, which, while they do include a gas permeable, liquid impermeable material, they are different than the device used in the instant claims. Specifically, the transduction and expansion is not performed in a single bag, but rather the transduced cells appear to be transferred to a different bag for expansion. Furthermore, even if a single X-fold bag were used throughout the process, the X-fold culture bags cannot accommodate addition of media to achieve a second medium height of over 2 cm, thus Lamers does not teach the third claimed step of adding a second volume of medium to the device to raise the medium height to beyond 2 cm.
Wilson et al teaches a cell culture device that permits for large scale expansion of cells and provides specific benefits over cell culture bags. Wilson et al specifically teaches their cell culture devices are beneficial over Lifecell®X-Fold® culture bags (See Wilson et al, ¶0020, 0026, 0028, 0071-0072). The cell culture device of Wilson et al comprises a cell culture chamber defined by a lower gas permeable material and walls that define an area that accommodates a high volume of culture medium. The devices provide for a reduced ratio of gas permeable surface area to medium volume. Wilson et al reports this configuration unexpectedly increases culture efficacy (See Wilson et al, ¶0113). Fig. 16 is representative of the device.
In Example 1, Wilson utilize a device having the configuration of Fig. 16. The lower surface was of gas permeable material and had a surface area of 5.06 cm2. Cells were provided at 0.76 x 106 cells/cm2 (3.85 x 106 cells total). Culture medium was added at different ‘medium heights’, the following heights were tested: 1.6 (representative of standard conditions in a cell culture bag), 3.20, 5.09, 10.20, 15.31 and 20.39 cm (See Wilson et al, ¶0154). Wilson et al reports the maximum number of cells achieved in culture was directly related to the medium height, meaning the greater the medium height, the greater the number of cells the culture could support (See Wilson et al, Table 2). The device of Wilson et al thus permits for generation of greater cell numbers for a smaller device footprint, particularly compared to cell culture bags (See Wilson et al, ¶0157).
It would have been prima facie obvious to have modified the method of Lamers et al to perform Steps 2-4 in the cell culture device of Wilson et al instead of the X-fold culture bags used by Lamers et al. This conclusion of obviousness is based off teachings in Wilson et al that their cell culture device are improvements over cell-culture bags, specifically the Lifecell® X-Fold® bag used by Lamers et al, in terms of the quantity of cells which can be produced/footprint of the device. The reduced footprint of the device permits for greater cell expansion while taking up less lab space. Saved lab space equates to saved cost. It is emphasized that Lamers et al state a goal is to achieve scale up of T lymphocyte production.
Modifying the method of Lamers et al to utilize the cell culture device of Wilson et al instead of the X-fold culture bags would involve performing Steps 2-4 in a single cell culture device of Wilson et al. Specifically, the Step 2 transduction step would be carried out by coating the Fibronectin fragment CH-296 to the gas permeable material of the lower surface of the cell culture device, and adding 0.5 x 106 lymphocytes per 0.25 mL RTVsup per cm2 of gas permeable material of the lower surface of the cell culture device (this reads on adding a first volume of media, a quantity of T cells and a genetic modification agent into a device that includes a horizonal cell growth surface comprised of gas permeable, liquid impermeable material). The RTVsup medium will necessarily be at a first media height. The cells are provided at 4 x 106 cells/mL, which is a first cell concentration beyond 2 million cells per milliliter of media.
The cells would remain in the cell culture device where at least a portion would necessarily gravitate to said cell growth surface which is in a horizontal position. The period of time during Step 2 and Step 3 reads on the second claimed step (allowing a period of time whereby said genetic modification agents act to transduce at least a portion of said T cells).
After transduction is complete, instead of needing to transfer the cells to a different X-fold bag, the Med-Mix media can be added directly to the cell culture device and expansion can proceed for Step 4. Addition of the Med-Mix media will read on adding a second volume of media into the device, the combination of the first volume of media and the second volume of media thereby elevating the first media height to a second media height. Wilson et al teaches medium heights of over 20 cm, and teaches that the greater the medium height, the greater number of total cells that can be grown. Thus, given that the goal of Step 4 is to expand T lymphocytes, it would have been prima facie obvious to add sufficient Med-Mix medium to achieve a medium height of up to or greater than 20 cm (which is beyond 2 cm), to achieve maximum T cell expansion.
The period of time during which the T cells are permitted to grow in the culture medium reads on allowing a period of time for the transduced T cells to be cultured without adding media whereby the transduced T cells increase in quantity when the device is oriented in a position such that at least a portion of said transduced T cells reside upon said cell growth surface and ambient gas suitable for cell culture is in contact with the opposite side of said cell growth surface.
One would have had a reasonable expectation of successfully modifying the method of Lamers et al to be carried out in the single cell culture device of Wilson et al because Wilson et al teach the device, and teach the device is suitable for generation and expansion of lymphocytes (the hybridomas of Example 1 are lymphocytes). Furthermore, it is noted that Wilson et al teach cells can be seeded at an initial density of 0.76 x 106/cm2, which is slightly above the cell density at which the T lymphocytes are transduced at (0.5 x 106 cells/cm2), thus, even accounting for some cell expansion during the transduction steps, the surface density of the transduced cells is within the parameters for the device of Wilson et al. As such, there is a reasonable expectation that all of Steps 2-4 of Lamers et al can be carried out in a single cell culture device as described by Wilson et al.
Regarding claim 4: Following the discussion of claim 1 above, Lamers et al teach the T cells are provided at a concentration of 4.0 x 106 cells/mL for transduction (in the first medium).
Regarding claim 7: Following the discussion of claim 1 above, neither Lamers et al nor Wilson et al specifically teach swirling or moving the cell bag or cell culture device during the transduction step. However, official notice is taken that gentle swirling or mixing was routine to facilitate interaction between the viral particles and the T cells. As such, it would have been prima facie obvious to have gently swirled the cell culture device of Wilson et al during Step 2 of the modified method described above. This conclusion of obviousness based on a motivation to increase interaction of the RTVsup and the cells to improve transduction efficiency.
Regarding claim 8: Following the discussion of claim 1 above, Lamers et al describe using the STITCH retroviral system, not a lentivirus. However, official notice is taken that lentivirus is an alternative retrovirus system that is capable of transducing T cells. Given that both the STITCH retroviral system and lentiviral systems were known as effective to transduce T cells, it would have been prima facie obvious to have substituted a lentiviral system for the STITCH system with a reasonable expectation of success.
Regarding claim 9: Following the discussion of claim 1 above, the device of Wilson et al illustrated in Fig. 16 comprises the liquid impermeable, gas permeable lower material (30A) which is supported by and in contact with gas permeable material support (80) (See Wilson et al, ¶0137).
Allowable Subject Matter
Claims 5, 6 and 10 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Lamers et al is considered the closest prior art. Lamers et al teach an optimized protocol for T lymphocyte transduction and expansion.
Regarding claims 5 and 6: Lamers et al teaches performing transduction using a T lymphocyte concentration of 4 million cells/mL. Because Lamers et al is already considered optimized, it would have required impermissible hindsight to further modify the method of Lamers et al to utilize as many as 5 million cells/mL or 6 million cells/mL.
Regarding claim 10: Lamers et al teaches providing 0.5 x 106 T lymphocytes/cm2 in 0.25 mL of RTVsup/cm2. The number of genetic modification units in RTVsup medium cannot be calculated off information provided in Lamers et al. Thus the ration of genetic modification units to cell cannot be calculated. As above, because Lamers et al is already an optimized protocol, further modification/optimization would have required impermissible hindsight.
Conclusion
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/ALLISON M FOX/Primary Examiner, Art Unit 1633