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 .
Notes
All the objections and rejections in the previous Office Action not reiterated herein have been withdrawn.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1 and 3-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ling et al. (US 2017/0321178; hereinafter “Ling”) in view of Zhen et al. (CN 108866013-A; with English machine translation) (hereinafter “Zhen”) and Jones et al. (US 2018/0142199; hereinafter “Jones”).
Regarding claim 1, Ling discloses a method for expansion of viral vector producing cells comprising: supplying a three-dimensional bioreactor comprising a plurality of voids having a surface area for cell expansion (Ling discloses a method of providing a bioreactor comprising a plurality of voids (FIG. 1: voids 14) having a culture surface areas (12); [0012] and [0053]; Claims 1 and 19), said plurality of voids having a diameter (D) ([0012], claims 1 and 19), a plurality of pore openings between said voids having a diameter (d) ([0012], claims 1 and 19), such that D>d ([0012], claims 1 and 19), and wherein: (a) 90% or more of said voids have a selected void volume (V) that does not vary by more than +/- 10.0% ([0013], claims 1 and 19); and (b) 90% or more of said pore openings between said voids have a value of d that does not vary by more than +/- 10.0% ([0013], claims 1 and 19); seeding said three-dimensional bioreactor with adherent cells that attach to the three-dimensional bioreactor surface (cells are seeded in the three-dimensional bioreactor, [0072], [0076]); flowing a perfusion medium into and out of said three-dimensional bioreactor and promoting cell expansion (perfusion system is utilized with the three-dimensional bioreactor for cell proliferation; [0027], [0062], [0073], [0075], [0083], [0094]; FIGS. 2-3 and 9). Ling does not explicitly disclose the process of seeding said three-dimensional bioreactor with adherent viral vector producing cells that attach to the three-dimensional bioreactor surface; and flowing a perfusion medium containing transfection reagent into and out of said three-dimensional bioreactor and promoting said viral vector cell expansion and transfecting said viral vector cells on said three-dimensional bioreactor surface and producing viral vectors and collecting said viral vectors. However, Ling discloses that the three-dimensional bioreactor is suitable for the proliferation of stem cells, primary cells, and other adherent or non-adherent cells under appropriate surface coating of the three-dimensional bioreactor (Ling at [0002]).
Zhen discloses a method for expansion of viral vector producing cells and viral vector production comprising seeding a three-dimensional bioreactor (cell culture bag; [0013]) with adherent viral vector producing cells that attach to the three-dimensional bioreactor surface (see [0013], [0028]-[0033] and [0037] of the English machine translation), and flowing a perfusion medium containing transfection reagent into and out of said three-dimensional bioreactor and promoting said viral vector cell expansion and transfecting said viral vector cells on said three-dimensional bioreactor surface and producing viral vectors and collecting said viral vectors ([0007], [0013]-[0017], [0039], [0115]). In view of Zhen, it would have been prima facie obvious to one of ordinary skill in the art to have modified the method of Ling such that the culture cells are adherent viral vector producing cells that attach to the three-dimensional bioreactor, and the media flowing through the three-dimensional bioreactor contain transfection reagent into and out of said three-dimensional bioreactor and promoting said viral vector cell expansion and transfecting said viral vector cells on said three-dimensional bioreactor surface and producing viral vectors, as disclosed by Zhen. One of ordinary skill in the art would have made said modification since Ling explicitly indicates that the three-dimensional bioreactor can be employed to culture various types of cells including adherent and non-adherent cells (Ling at [0002], [0072], [0076]). One of ordinary skill in the art would have made said modification with the expectation of producing desired cell culture product, since Ling explicitly indicates that the three-dimensional bioreactor can be employed to produce desired cell culture product (i.e., culturing desired cell type according to need; Ling at [0002]). Further, one of ordinary skill in the art would have made said modification because said modification would have been the simple substitution of one type of cell and perfusion medium for another for the predictable result of culturing desired cells, as suggested by Ling ([0002]). Modified Ling does not explicitly disclose the process of flushing said three-dimensional bioreactor. Jones discloses a method including the process of flushing non-attached cells from a bioreactor ([0081]). In view of Jones, it would have been prima facie obvious to one of ordinary skill in the art to have modified the method of modified Ling with the method of Jones to arrive at the claimed invention. One of ordinary skill in the art would have made said modification for the purpose of removing unwanted materials from the bioreactor as suggested by Jones ([0081]), and thereby enhancing the cell culture process. Modified Ling does not explicitly disclose wherein said surface of said three-dimensional bioreactor is exposed to plasma treatment. However, Ling further discloses that it is well-known in the art to treat surfaces for cell culture with plasma to enhance cell attachment ([0006]). It would therefore have been prima facie obvious to one of ordinary skill in the art to have treated the cell culture surface of the bioreactor of modified Ling to arrive at the claimed invention. One of ordinary skill in the art would have made said modification for the purpose of enhancing the cell attachment to the cell culture surface and thereby enhance cell culture process.
Regarding claim 3, modified Ling further discloses wherein said viral vector producing cells comprises HEK 293T cells and said viral vector comprises a lentiviral vector (Ling at [0026], [0038]).
Regarding claim 4, modified Ling further discloses wherein said diameter (D) of said voids is 0.4 mm to 100.0 (Ling at [0013] and claims 2-3).
Regarding claim 5, modified Ling further discloses wherein said diameter (D) of said voids is in the range of 0.4 mm to 50.0 mm (Ling at [0013] and claims 2-3).
Regarding claim 6, modified Ling further discloses wherein said diameter (d) of said pore openings is in the range of 0.2 mm to 10.0 mm (Ling at [0013], Claim 4).
Regarding claim 7, modified Ling further discloses wherein 95.0 % or more of said voids indicate a void volume (V) that does not vary by more than +/- 10.0% (Ling at [0012]-[0013], claim 5).
Regarding claim 8, modified Ling further discloses wherein 99.0% to 100% of said voids indicate a void volume 25 (V) that does not vary by more than +/- 10.0% (Ling at [0012]-[0013], claims 5-6).
Regarding claim 9, modified Ling further discloses wherein 95.0 % or more of said pore openings between said voids have a value of d that does not vary by more than +/- 10.0% (Ling at [0012]-[0013], claim 7).
Regarding claim 10, modified Ling further discloses wherein 99.0 to 100 % or more of said pore openings between said voids have a value of d that does not vary by more than +/- 10.0% (Ling at [0012]-[0013], claim 8).
Regarding claim 11, modified Ling further discloses wherein at least 90.0% of the voids present have 2 pore openings per void (Ling at [0062], claim 9).
Regarding claim 12, modified Ling further discloses wherein at least 90.0% of the voids present have 8 to 12 pore openings per void (Ling at [0062], claim 10).
Regarding claim 13, modified Ling further discloses wherein said voids have an internal concave surface (Ling at FIG. 1, claim 11).
Regarding claim 14, modified Ling further discloses wherein said voids comprise spherical voids (Ling at [0026], claim 12).
Regarding claim 15, modified Ling further discloses wherein said spherical voids have a packing efficiency of greater than 64.0 % in a 3D cylindrical space (Ling at claim 13).
Regarding claim 16, modified Ling further discloses wherein said three-dimensional (3D) bioreactor is formed from a material that has a Tensile Modulus of at least 0.01 GPa (Ling at claim 14).
Regarding claim 17, modified Ling further discloses wherein said three-dimensional (3D) bioreactor is formed from a material that is biocompatible (Ling at [0056] and claim 15).
Regarding claim 18, modified Ling further discloses wherein said 3D three-dimensional (3D) bioreactor is formed from a material not susceptible to hydrolysis during cell expansion such that the amount of hydrolysis does not exceed 5.0 % by weight of the material present (Ling at [0056] and claim 16).
Regarding claim 19, modified Ling further discloses the three-dimensional (3D) bioreactor of claim 1 (see discussion of claim above) wherein said bioreactor has a diameter (Φ) and a height (H) and the ratio Ф:H has a value in the range of greater than 1:1 to 100:1 (Ling at [0056] and claim 17).
Response to Arguments
Applicant's arguments filed on September 4, 2025 have been fully considered but they are not persuasive.
Applicant argues that it would not have been prima facie obvious to one of ordinary skill in the art to have modified the method of Ling, as disclosed by Zhen et al. In particular, Applicant argues that such modification would alter the purpose and principle of operation of Ling. See Remarks at pages 9-11.
Examiner respectfully disagrees. Ling is the primary reference and discloses the structure of the claimed three-dimensional bioreactor. As discussed in the rejection, Ling discloses the process of seeding cells in the voids of the structure of the bioreactor and the process of flowing medium into the bioreactor. Zhen was relied upon for disclosing the process of culturing the type of the claimed cells in a bioreactor. Contrary to the Applicant’s assertion, modifying the cells and medium disclosed by Ling with the cells and medium disclosed by Zhen would not alter the purpose and principle of operation of Ling. Further, in response to applicant's arguments that “taking the 3D bioreactor of Ling and placing it on a shaking table at 10-20 rpm and rocking at 7-9° would be clearly incompatible with the intended purpose of Ling” and “application respectfully notes that this appears as an extrapolation from Zhen et al of the teaching of introducing adherent cells into a bag and overlooking what Zhen traches after such cells are adhered, which therefore fails to consider Zhen et al in its entirety,” the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In that, all the steps of culturing cells in Zhen do not need to be incorporated or taught by the primary reference of Ling. Further, the modification of Ling with Zhen merely replaces the type of cells and medium disclosed by Ling with the cells and medium disclosed by Zhen. As such, Applicant’s argument is not persuasive.
Applicant further argues that it is not believed reasonable to conclude that a person of ordinary skill in the art would therefore conclude that paragraph 00081] of Jones would lead one to believe that transfected viral vector cells on the three-dimensional bioreactor surface of claim 1, containing the specifically recited voids and pores where the diameter of the voids D exceed the diameter d of the interconnecting pores, could be expected to reliably and conveniently flush after viral cell expansion and transfection, and allow for efficient perfusion collection of viral vectors. See Remarks at page 11.
In response, it is to be noted that the claims merely require the process of flushing the three-dimensional bioreactor. No specifics about the flushing process is provided by the claims. Further, Jones is relied upon for disclosing that cells are adherent into the lumen of the hollow fibers and cells that did not adhere are simply flushed. As such, it is respectfully submitted that Jones meets the flushing process limitation.
In response to the Applicant’s argument regarding unexpected results (Remarks at page 12), Applicant’s argument is not persuasive. The closest prior art to the claimed invention is Ling and not Zhen et al. Further, none of the applied prior art that discusses the use of T-25 Flask which is used to show the unexpected results.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 LIBAN M HASSAN whose telephone number is (571)270-7636. The examiner can normally be reached on 8:30 AM - 5:00 PM.
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/LIBAN M HASSAN/Primary Examiner, Art Unit 1799