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 .
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract contains more than 150 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the term “CTS”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: the first instance of “ISR” should be spelled out.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-18 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "harvesting CAR-T cells" in fourth step of the claim. There is insufficient antecedent basis for this limitation in the claim.
Claim 6 contains the trademark/trade name “Xuri”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
In the present case, the trademark/trade name is used to identify/describe a specific type of bioreactor and, accordingly, the identification/description is indefinite.
The dependent claims are included in the rejection because they depend from an indefinite claim and do not remedy the issue.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4-6 and 12-14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 requires a limitation regarding the cell density being greater than or equal to a preset value, however, claim 1 step 4 already requires the cell density of 0.5-1.1 x 106 cells/mL, a preset value. Therefore, claim 4 fails to further limit claim 1 from which it depends.
Claim 12 requires a limitation regarding the preset value being 0.3-1.2x106 cells/mL, which is broader than the preset value recited in claim 1 step 4, from which it ultimately depends.
The dependent claims are included in the rejection because they depend from a rejected claim and do not remedy the issue.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
The second and third stages of the perfusion culture method of claim 1 read as optional limitations as they are listed in the alternative. Therefore, claim 1 is interpreted as only requiring the first stage.
The third step of claim 1, infecting the activated T cells with a lentiviral vector, does not limit what the vector comprises. As an example, a lentiviral vector encoding GFP reads on the limitation of claim 1 step 3.
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 (i.e., changing from AIA to pre-AIA ) 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 8-9, 11-13, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Ou et al. (Journal of Biological Engineering, 2019) in view of Costariol et al. (Biotechnology Journal, 2020) and Smith et al. (Clinical & Translational Immunology, 2015, IDS ref.) and evidenced by Tao et al. (Biotechnol. Prog., 2011).
Regarding claims 1-2, 4, and 11-13, Ou et al. teach WAVE system generated 100-700 folds of T cell expansion from an 18-day perfusion culture (p. 1, Introduction). Ou et al. teach the advantages of a stirred bioreactor compared to the WAVE system, which at the time was the current large-scale T cell biomanufacturing system (p. 9, New human T cell biomanufacturing). Ou et al. teach human PBMCs were used to isolate T cells with magnetic beads followed by anti-CD3 and anti-CD28 mAbs to prepare the seed culture for processing in the stirred-tank bioreactor (p. 2, Results). Ou et al. teach maintenance and expansion of T cells is highly dependent on culture media and other factors, as such, to reduce risk of disease transmission and cellular product variability caused by animal derived components, AIM-V medium was utilized as the basal medium (p. 3, Basal media and supplements). Ou et al. teach IL-2 is critical to healthy T cell grown due to its important regulatory role in cell survival, proliferation, and differentiation (p. 3, 2, column). Ou et al. teach their T cell biomanufacturing process can be applied to CAR-T cells production (p. 10, Application and consideration in CAR-T biomanufacturing).
Ou et al. teach perfusion bioreactors were the preferred method of expanding T-cells, yet does not specifically teach the stirred bioreactor is a perfusion system.
However, Costariol et al. teach perfusion mode in a stirred bioreactor for CAR-T cell manufacture could provide improved performance when compared to fed-batch (p. 11, section 3.6). Costariol et al. also teach the continuous perfusion conditions in a rocking motion platform system, such as the WAVE system, was the standard for T-cell expansion (p. 10, section 3.6).
Ou et al. in view of Costariol et al. do not teach that the composition of the serum-free culture medium is supplemented with 3-9% ISR.
However, Smith et al. teach xeno-free serum replacement that can be reproducibly used for the production of clinical grade T-cell therapies in combination with several different cell culture media (Abstract). Smith et al. teach Dynabeads CD3/CD28 cell therapy system (CTS)-activated or antigen-specific T cells expanded using CTS Immune Cell SR, showed comparable growth kinetics observed with cell culture media supplemented with HS or FBS (Abstract). Smith et al. teach T cells expanded using xeno-free SR medium were highly amenable to lentivirus-mediated gene transduction for potential application for gene-modified T cells (Abstract).
Smith et al. teach ex vivo expansion of T cells isolated and activated from PMBC (claim 1, step 1) with CTS Dynabeads (magnetic beads) CD3/CD28 (claim 1, step 2) is a commonly used protocol for production of T cell products for cell therapy (p. 2, Results and Fig. 1). Smith et al. teach T cells were cultured in CTS OpTmizer T-cell Expansion SFM supplemented titrated amounts of CTS Immune Cell SR, at a range of 0, 2, 5 or 10% (p. 2, Results). Smith et al. teach T cells supplemented with 5% SR displayed the highest average fold expansion (Fig. 1). Smith et al. teach polyclonal T cells were activated according to the rapid expansion protocol and cultured in XVIVO15, OpTmizer or CTS AIM-V supplemented with SR (p. 2, Results, 2nd column). Smith et al. teach the different culture medium formulations supplemented with CTS Immune Cell SR consistently expanded polyclonal and virus-specific T cells (p. 7, Discussion) which suggests XVIVO15, OpTmizer, and AIM-V are equivalent culture mediums. Smith et al. teach polyclonal activation of T cells is commonly used in the generation of gene-modified T cells encoding tumor-specific chimeric antigen receptors (CAR) (p. 2, Results, 2nd column). Smith et al. teach polyclonal T cells activated with CTS Dynabeads CD3/CD28 were transduced with a GFP-expressing lentiviral vector (claim 1, step 3) (p. 2, Results, 2nd column). Smith et al. teach the activated T cells isolated from PBMCs were seeded at 1 x 106 cells/mL (claim 1, first stage; claim 4; and claims 12-13) (p. 8, Methods).
Thus, Smith et al. teach the method of culturing CAR T-cells by isolating and activating PBMCs with CD3/CD28 magnetic beads, infecting activated T cells with a lentiviral vector in a serum-free culture medium wherein the medium is AIM-V supplemented with 5% Immune Cell SR (claims 2 and 11) and suggest culturing CAR-T cells.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the perfusion culture method for CAR-T cells of Ou et al. in view of Costariol et al. and Smith et al. with a reasonable expectation of success because Ou et al. and Costariol et al. teach perfusion culture methods for CAR-T cell activation and expansion and Smith et al. teach the same methods with the addition of the Immune Cell SR to improve upon the standard method of expansion of CAR-T cells. One would be motivated to include the 5% ISR of Smith et al. because Smith et al. teach T cells supplemented with 5% SR displayed the highest average fold expansion. Additionally, Smith et al. teach polyclonal activation of T cells is commonly used in the generation of gene-modified T cells encoding tumor-specific chimeric antigen receptors (CAR).
Ou et al. in view of Costariol et al. and Smith et al. are silent to the rate of perfusion.
However, the rate of perfusion is recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to find the appropriate perfusion rate as a matter of routine optimization as evidenced by Tao et al.
Tao et al. teach the culture perfusion rate (volume of fresh medium/working volume of reactor/day, vvd) was increased daily according to the integral cell growth (ICG) of the culture and a cell specific perfusion rate (CSPR) using the following equation; Perfusion rate (vvd) = CSPR x ICG where CSPR (nL/cell/day) represents the volume of the medium provided to one cell in one day and ICG (106 cells/mL x day) is determined from the area under the viable cell curve of current viable cell density and predicted viable cell density in 24h interval, which is estimated by the specific cell growth of the cell line (p. 825, 1st column). A person of ordinary skill would have been motivated to optimize the perfusion rate because Tao et al. teach and suggest the beneficial optimization of media perfusion rate to support exponential growth of cells (p. 827, 1st column).
Regarding claim 3, as discussed above, Tao et al. teach perfusion rate is an optimizable result-effective variable (p. 827, 1st column and Fig. 5). Therefore, the optimization of the perfusion rates to arrive at those recited in claim 3 would have been a matter of routine experimentation motivated by the cell numbers and viability.
Regarding claim 8, Smith et al. teach activation of polyclonal T cells using CTS Dynabeads CD3/CD28, wherein the bead to T cell ratio is 3:1 and the T cells were seeded at 1 x 106 T cell/mL and cultured for 2 weeks (p. 8). Smith et al. does not discuss the ratio of beads to cells in terms of volume, however, the volume of beads would be considered a result-effective variable. A person of ordinary skill in the art would have been motivated to find the volume of beads in order to effectively activate the T cells as a matter of routine optimization and experimentation. Smith et al. is silent to the culturing conditions, such as 37°C and 5% CO2, however, these variables are recognized in the art as standard cell culture conditions.
Regarding claims 9 and 17-18, Smith et al. teach T cells were cultured in CTS OpTmizer T-cell Expansion SFM supplemented titrated amounts of CTS Immune Cell SR, at a range of 0, 2, 5 or 10% (p. 2, Results). Smith et al. teach T cells supplemented with 5% SR displayed the highest average fold expansion (Fig. 1). Smith et al. teach polyclonal T cells were activated according to the rapid expansion protocol and cultured in XVIVO15, OpTmizer or CTS AIM-V supplemented with SR (p. 2, Results, 2nd column). Smith et al. teach the different culture medium formulations supplemented with CTS Immune Cell SR consistently expanded polyclonal and virus-specific T cells (p. 7, Discussion) which suggests XVIVO15, OpTmizer, and AIM-V are equivalent culture mediums. Thus, Smith et al. teach the method of culturing CAR T-cells by isolating and activating PBMCs with CD3/CD28 magnetic beads, infecting activated T cells with a lentiviral vector in a serum-free culture medium wherein the medium is AIM-V supplemented with 5% Immune Cell SR (claims 17-18) (serum-free media that lacks animal-derived components) and suggest culturing CAR-T cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 5-7 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ou et al. (Journal of Biological Engineering, 2019) in view of Costariol et al. (Biotechnology Journal, 2020) and Smith et al. (Clinical & Translational Immunology, 2015, IDS ref.) and evidenced by Tao et al. (Biotechnol. Prog., 2011) as applied to claims 1-4, 8-9, 11-13, and 17-18 above, and further in view of T. Smith (Methods in Molecular Biology, Chapter 11, published 10 November 2019) and evidenced by Sartorius (Biostat RM Bioreactor product datasheet, 2026).
Regarding claims 5 and 6, Ou et al. in view of Costariol et al. and Smith et al. are silent to the cell culture methods before the perfusion culture steps.
However, T. Smith teaches Xuri cell expansion system (claim 6) setup for expanding CAR-T cells (p. 151, Introduction). T. Smith teaches the initial minimum culture volume of 300 mL and initial minimum viable cell density of 0.5 x 106 cells/mL (p. 161). T. Smith teaches culturing conditions will vary from workflow to workflow, however, typical settings include 10 rocks per minute (RPM) and 5% CO2 for T lymphocyte culture (p. 162). T. Smith does not specifically label the process of fed-batch culture, however, cells would require fed-batch process since T. Smith does not initiate perfusion culture until the cells reach 2 x 106 cells/mL (Table 1). T. Smith does not specifically identify ventilation volume, however, Sartorius lists the aeration rate of rocking motion bioreactors is 50 – 1,000 mL/min (p. 4). MPEP 2144.05(I) states, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Therefore, the claimed ventilation volume of 0.1-1 L/min overlap with the standard range for rocking motion bioreactors. T. Smith teaches maintaining the culture at a cell density of 1 x 106 viable cells/mL until minimum volume of 300 mL is reached, 15 x 107 total viable cells (claim 6) (p. 155).
Regarding claims 7 and 15-16, T. Smith teaches culturing conditions will vary from workflow to workflow, however, typical settings include 10 rocks per minute (RPM) and 5% CO2 for T lymphocyte culture (p. 162). T. Smith does not specifically identify ventilation volume, however, Sartorius lists the aeration rate of rocking motion bioreactors is 50 – 1,000 mL/min (p. 4). MPEP 2144.05(I) states, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Therefore, the claimed ventilation volume of 0.3-0.8 L/min (claim 7), 0.4-0.6 L/min (claim 15), and 0.5 L/min (claim 16) overlap with the standard range for rocking motion bioreactors.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ou et al. (Journal of Biological Engineering, 2019) in view of Costariol et al. (Biotechnology Journal, 2020) and Smith et al. (Clinical & Translational Immunology, 2015, IDS ref.) and evidenced by Tao et al. (Biotechnol. Prog., 2011) as applied to claims 1-4, 8-9, 11-13, and 17-18 above, and further in view of Wenzheng et al. (CN112301060A, published 02 February 2021) and Elegheert et al. (Nat Protoc. 2018).
A machine translation of the specification was used for CN112301060A, as the original was published in Chinese.
Regarding claim 10, Ou et al. in view of Costariol et al. and Smith et al. teach culturing CAR-T cells at 37°C and 5% CO2 for at least 24 hours, but are silent to the use of polybrene.
However, Wenzheng et al. teach separating PBMCs from human peripheral blood, activated with CD3 and CD28 antibodies, plating the activated T cells at 1 x 106 cells/well in a 24-well plate, adding virus at MOI=10:1, and 10µg/mL polybrene was added to promote infection (p. 6, section 4, 1st para.). Wenzheng et al. teach after 24 hours, the cells were collected, centrifuged at 1800 rpm for 60 minutes, the medium discarded, and fresh medium was added (p. 6, section 4, 1st para.). Wenzheng et al. teach the cells were collected 48 hours after infection with lentivirus and showed a near 100% infection efficiency (p. 6, section 4, 2nd para.).
Elegheert et al. teach polybrene is a cationic polymer that reduces charge repulsion between viral particles and the cell membrane which will promote virus-host cell fusion, leading to higher transduction efficiencies (p. 19, step 14). Elegheert et al. teach lentiviral transduction at MOI rates of 0, 1, 4, and 10 at 37°C for 24 hours (p. 26). Elegheert et al. teach a MOI of approximately 3.2 has a theoretical efficiency of approximately 95% (Box 2).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize polybrene in the method of culturing CAR-T cells of Ou et al. in view of Costariol et al. and Smith et al. with a reasonable expectation of success because Elegheert et al. teach polybrene is known in the art to enhance transduction efficiency in T cells. One would be motivated to utilize polybrene in the method of culturing CAR-T cells of Ou et al. in view of Costariol et al. and Smith et al. because polybrene is shown to increase infection efficiency, thus, a lower MOI can be utilized while still maintaining a high efficiency of infection.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Ou et al. (Journal of Biological Engineering, 2019) in view of Costariol et al. (Biotechnology Journal, 2020) and Smith et al. (Clinical & Translational Immunology, 2015, IDS ref.) and evidenced by Tao et al. (Biotechnol. Prog., 2011), as applied to claims 1-4, 8-9, 11-13, and 17-18 above, and further in view of Lee et al. (WO 2020/123524, published 18 June 2020).
Regarding claim 14, Ou et al. in view of Costariol et al. and Smith et al. are silent to the cell density being 0.5 x 106 cells/mL.
However, Lee et al. teach methods of manufacturing cell based products using small volume perfusion processes (Abstract). Lee et al. teach cell therapy point of use may be associated with CAR-T therapy, the method comprising activating the cells with a magnetic bead loaded with human CD3 and CD28 antibodies (p. 16, lines 1-3). Lee et al. teach the method may comprise transducing the cells with lentivirus (p. 16, lines 2-3). Lee et al. teach the method may comprise introducing a media comprising at least about 0.5 x 106 cells/mL into a perfusion chamber having a volume of 50 mL or less (p. 2, lines 21-23).
Therefore, it would have been obvious to one or ordinary skill in the art to start with a cell density of 0.5 x 106 cells/mL in a perfusion chamber with a reasonable expectation of success because Lee et al. teach the lower cell density of 0.5 x 106 cells/mL is suitable for perfusion chambers of 50 mL or less. One would be motivated to start with a cell density of 0.5 x 106 cells/mL in a perfusion chamber because a lower starting cell density in perfusion culture could improve viability, control nutrient dynamics, reduce variability, and ensure a stable, predictable process. Additionally, the cell density would be a considered a readily optimizable variable based on cell type and desired outcome.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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