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 .
Applicant’s amendments and remarks filed 4-28-26 are acknowledged.
Claims 1, 6, 8-11, 18, 26, 27, 29, 32, 34-36, 38-40, 43-45 and 48 are pending and under examination as they read on:
the species of a method of manufacturing isolation technique of claim 1(a) which comprises “antibody conjugated magnetic beads”;
the species of method of manufacturing that involves contacting the target cells with an activating molecule;
the species of method of manufacturing which is performed with an enhancing reagent as recited in claims 29 /45;
the species of method of manufacturing wherein the transfection step (d) follows the activation step (b) as recited in claim 34;
the species of method of manufacturing wherein the target cells are expanded after transfection using expansion feeding as in claim 40; and
the species of method of manufacturing wherein the activating of step (b) is as recited in claim 49.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
As preliminary matter, applicant’s amendment of claim 1 to recite “an anti-CD3 antibody coated culture vessel” given its broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art would be understood to encompass in its breadth coating, e.g., a bag, a plate, a flask or the “stationary phase” matrix contained within a chromatography column. With respect to the latter in particular, note that coating / immobilizing an anti-CD3 antibody onto a “stationary phase” matrix contained within a chromatography column would be considered by the ordinarily skilled artisan to be a type of culture vessel wherein the column walls enclose a solid phase, i.e., the “stationary phase” matrix which is coated with / upon which is immobilized an anti-CD3 antibody.
Claim(s) 1, 6, 8-11, 18, 26, 27, 29, 34, 35, 40, 43-45 and 48 stand rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (J Immunother Cancer. 2019 Nov 14;7(1):304) in view of Germeroth et al. (WO2020089343), Kotz et al. (20190085280) and Moore et al. (Sci Rep. 2019 Oct 22;9(1):15101), as evidenced by He et al. (20210369779)(all of record) and as further evidenced by ThermoFisher (“T Cell Activation via Anti-CD3 and Anti-CD28,” internet published December 9, 2020, pages 1-5, cited herewith in direct response to applicant’s claim amendments / arguments).
Claim(s) 36, 38 and 39 stand rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (J Immunother Cancer. 2019 Nov 14;7(1):304) in view of Germeroth et al. (WO2020089343), Kotz et al. (20190085280) and Moore et al. (Sci Rep. 2019 Oct 22;9(1):15101), as evidenced by He et al. (20210369779)(all of record) and as evidenced by ThermoFisher (“T Cell Activation via Anti-CD3 and Anti-CD28,” internet published December 9, 2020, pages 1-5, cited herewith) as applied to claims 1, 6, 8-11, 18, 26, 27, 29, 34, 35, 40, 43-45 and 48 as described further below, and further in view of Wiesinger et al., Cancers (Basel). 2019 Aug 16;11(8):1198 (of record).
Applicant argues “…examination of Germeroth reveals, however, that (A) it stresses that both
antibodies are not immobilized, and (B) at least does not even hint at separating them between an
immobilized phase and a soluble one, as the instant claims recite,” and further points to certain teachings of Germeroth paragraphs [0082]-[0083] reproduced below with applicant’s emphasis shown:
[0082] …In general, such reagents may employ beads, e.g., magnetic beads, of greater than 1 μm in diameter to which various binding agents (e.g. anti-CD3 antibody and/or anti-CD28 antibody) are immobilized. However, in some cases, such magnetic beads are, for example, difficult to integrate into methods for stimulating cells under conditions required for clinical trials or therapeutic purposes since it has to be made sure that these magnetic beads are substantially or completely removed before administering the engineered T cells to a subject. In some aspects, such removal, such as by exposing the cells to a magnetic field, may decrease the yield of viable cells available for the cell therapy. In certain cases, such reagents, e.g., stimulatory reagents containing magnetic beads, must be incubated with the cells for a minimal amount of time to allow a sufficient amount of detachment of the T cells from the stimulatory reagent. Furthermore, reagents such as beads are not readily compatible with column chromatography due to physical constraints.
[0083] The provided methods utilizing oligomeric stimulatory reagents (e.g. streptavidin mutein oligomer conjugated to anti-CD3 and anti-CD28 antibodies, such as Fabs) overcome such potential limitations. For example, in some embodiments, the provided methods include addition of a soluble oligomeric reagent not bound to a solid support (e.g., bead) to the stationary phase to initiate stimulation.
(applicant’s emphasis)
Applicant further asserts, “As explained by Germeroth, immobilization of the anti-CD3/anti-CD28 antibodies presents a challenge for integration of the activation step under conditions required for clinical trials or therapeutic purposes, and results in decrease of yield and longer processing time. From these passages, Germeroth clearly stresses the importance of keeping both antibodies soluble, which is contrary to the conventional technology, in which both antibodies are immobilized. In either case, there is not even a hint that the anti-CD3 antibody and the anti-CD28 antibody should be separated into different (immobilized/soluble) phases. It necessarily follows that Germeroth teaches away from the claimed invention.“
Applicant’s argument has been considered but is not found convincing for the reasons set forth below.
One reason applicant’s argument is not found convincing is because, as set forth in the prior office action, paragraph 132 of Germeroth teaches selection steps wherein a stationary phase / column based CD3 binding agent is used as part of a sequential process to select, e.g., CD3+CD8+ T-cells.
For example, as described at page 8, 1st paragraph of the prior Office Action:
“Alternatively, paragraph 132 the teachings of Germeroth further encompass in their breadth methods wherein cell selection is performed via chromatography columns employing a step of anti-CD3 selection, consistent with claim 25, noting that an anti-CD3 antibody will inherently activate target cells to some extent.”
See also the prior Office Action at page 7, 1st – 2nd full paragraphs (emphasis in the original):
“[a]t paragraph 150, Germeroth describes a selection agent based on ‘Magnetically attractable particles’ (emphasis added):
‘[0151] A chromatography matrix employed in the present invention may also include magnetically attractable matter such as one or more magnetically attractable particles or a ferrofluid. A respective magnetically attractable particle may comprise a selection reagent with a binding site (e.g., selection agent) that is capable of binding to and immobilizing the target cell on the chromatography matrix. Magnetically attractable particles may contain diamagnetic, ferromagnetic, paramagnetic or superparamagnetic material. Superparamagnetic material responds to a magnetic field with an induced magnetic field without a resulting permanent magnetization. Magnetic particles based on iron oxide are for example commercially available as Dynabeads® from Dynal Biotech, as magnetic MicroBeads from Miltenyi Biotec….,’ and as to the particular selection agent capable of binding CD4+ or CD8+ expressing T-cells, paragraphs 164-165 describe the use of anti-CD4 and anti-CD8 antibodies as selections agents.”
Note further in this regard as set forth in paragraph 166 of Germeroth, a Fab fragment from the OKT3 anti-CD3 antibody is one type of CD3 selection agent, and this is exemplified in working example 3 at paragraph 775 of Germeroth. Consistent with the prima facie case set forth in the prior office action, and the quotes therefrom reproduced above, as described by “ThermoFisher,” when a surface is coated with an OKT3-based anti-CD3 antibody Fab, and T-cells and soluble anti-CD28 antibodies are added to said surface comprising immobilized anti-CD3, T-cell activation and expansion occurs (see pages 1-2).
Thus, for the reasons set forth in the prior office action, even after consideration of applicant’s claim amendment the teachings of Choi in view of Germeroth, Kotz and Moore as evidenced by He still demonstrate the prima facie obviousness of the claimed invention prior to applicant’s first filed application.
Indeed, as described in the prima facie case set forth in the prior Office Action, the “challenges” associated with the use of anti-CD3/anti-CD28 conjugated magnetic beads as T-cell stimulatory agents were addressed by Germeroth’s use of soluble oligomeric stimulatory reagents bound to anti-CD3/anti-CD28 antibodies; moreover, the use of an anti-CD3-bound column chromatography matrix for selection of T-cells was also described by Germeroth in the context of on-column cell selection and stimulation leading to collection of the activated T-cells within 24 hours of initiating the stimulation step.
Finally, at page 9, 1st full paragraph applicant asserts that “the claimed invention has achieved unexpected successes, as demonstrated in the experimental examples. For instance, in Example 1, the "Improved method #1" and "Improved method #2" both used immobilized anti-CD3 antibody and soluble anti-CD28 antibody for T cell activation. As compared to the conventional method, Table 1 shows that both Improved Method #1 and Improved Method #2 took substantially less time (24 hours of activation vs. 73 hours of activation) and resulted in substantially higher transduction efficiency (35% to 64% vs. 25% ).”
Applicant’s assertion is acknowledged but it would not have been surprising to the ordinarily skilled artisan given that the on-column selection and stimulation method of Germeroth allowed for activation within 24 hours as stated in the prior Office Action at page 8-9 bridging paragraph (emphasis added):
“With respect to claim 43 which recites ‘activating of step (b) for up to 96 hours at about 37 C and 5% CO2--,’ paragraphs 61, 75 and 78 (for example) of Germeroth shows / teaches cell stimulation occurs within 24 hours; paragraph 191 of Germeroth teaches cells bound to a stimulatory reagent including stimulatory agents is incubated at 37°C; and paragraph 336 of Germeroth teaches cells incubated or cultivated at around 5% CO2--, the latter two of which are conditions consistent with the temperature and carbon dioxide parameters of human blood.”
Likewise, as further set forth at page 10, final full paragraph through page 10-11 bridging paragraph of the prior Office Action, yet more rapid stimulation, i.e., within 4.5 hours, was taught by Germeroth:
“Concluding paragraph 805 of Germeroth states (emphasis added):
[0993] Together, these data indicate that on-column selection and stimulation can be used in a process for producing engineered T cells (e.g. CAR+ T cells), including in a process in which selected T cells are collected from the column within 4.5 hours after initiation of stimulation with anti-CD3/anti-CD28 oligomeric reagent for use in subsequent steps of the process including transduction. The results demonstrate that the on-column selection and stimulation process results in an engineered (e.g. CAR+ cells) cell composition that exhibits phenotypic and functional features that are comparable to the alternative process, yet can be carried out more efficiently and in a shorter time due to the ability to combine the selection and stimulation in a single step.”
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. §§ 716.01(d) and 2142.
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 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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
Prosecution Insights