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 .
Priority
The instant application, filed on 28 August 2023, claims domestic benefit to US provisional application no. 63/152,787, filed on 02/23/2021 and PCT/US2022/017526 filed on 02/23/2022.
Information Disclosure Agreement
The information disclosure statements (IDS) submitted on 20, October, 2025 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 07, February, 2025 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 17, April, 2024 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 26, February, 2026 has been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 25 July, 2025 has been entered in full. These are the amended claims of the original claim set received on 23 August, 2023. In the amendment, claims 2, 3, 5, 7, 15, 24, 27, 29, 30, 31, 33, 40, 41, 42, 44, 48, 49, and 51 are amended and claims 4, 6, 8, 9, 11-14, 16-23, 25, 26, 28, 32, 34-39, 43, 45-47, 50, and 52-54 are cancelled. Therefore, claims 1-3, 5, 7, 10, 15, 24, 27, 29-31, 33, 40-42, 44, 48, 49, and 51 are pending and are the subject of this Office Action.
Specification
The use of the term DSORTTM, which is mark used in commerce and further does not seem to registered as a trade name, has been noted in this application.
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 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.
Claim 30 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 30 recites claim to “the method of claim 2 wherein the population of Tregs is cultured in the presence of a stimulatory agent for about 1 to about 5 days, then cultured in the absence of a stimulatory agent for about 1 to about 5 days, then cultured in the presence of a stimulatory agent for about 1 to about 5 days, and then genetically engineered; and/or wherein the population of Tregs is cultured in the presence of a stimulatory agent for about 3 to about 4 days, then cultured in the absence of a stimulatory agent for about 3 to about 4 days, then cultured in the presence of a stimulatory agent for about 1 to about 4 days, and then genetically engineered.” This the does not mention the second rest step which is claimed in claim 2. It is unclear if the rest step recited in claim 2 is required for the method claimed in claim 30.
Claim 31 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 31 recites “the population of Tregs is cultured in the presence and/or absence of a stimulatory agent according to Table A.” Table A is not present in claim 31 or claims 1 and 2 from which it depends. Claims by be complete in themselves and incorporation by reference is “permitted only in exceptional circumstances where there is no practical way to define the invention in words” (See MPEP 2173.05(s)). Thus, the claim is not complete within itself and is unclear.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 7, 10, 48 and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Safinia et al. (2016) (Of Record, IDS 04/12/2024).
In regards to claims 1 and 48 Safinia anticipates a method for producing an expanded Treg cell population with a first stimulating step of anti-CD3/CD28 coated beads. Safinia further anticipates a resting step of 4 days before fresh beads are added to the culture again (pg.7573, col 2, lines 7-23).
In regards to claims 2 and 10 Safinia anticipates a method for expanding T reg cells which further comprises a restimulation step 12 days after an initial stimulation step and a 4-day rest period after which new anti-CD3/CD28 beads were added to the culture (pg.7573, col 2, lines 7-23).
In regards to claim 3 Safinia anticipates a method for expanding T reg cells which further comprises a third stimulation step 24 days after the first restimulation step and 12 days after a second stimulation step preceded by a 4-day rest period after which new anti-CD3/CD28 beads were added to the culture. Further after the stimulation the cells were harvested and anti-CD3/CD28 beads were removed from the cells (third resting step) for further processing (pg.7573, col 2, lines 7-23).
In regards to claim 7 Safinia anticipates a two-step stimulation method as outlined above for claim 2 and further anticipates the method of removal of the anti-CD3/CD28 beads by a magnet and washing the cells in PBS multiple times to ensure bead removal (pg.7573, col 2, lines 1-4).
In regards to claim 49 Safinia anticipates the expended Treg population as outlined above for claim 1, further Safinia anticipates the cryopreservation of the Treg cells (pg.7574, col 2, lines 6-13).
Claim 15 is rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Scott et al. (US2019/0203174, of record IDS 04/17/2024).
Scott anticipates a method of developing an expanded engineered Treg cells in which the cells are (a) genetically modified by transduction with a lentiviral vector, followed by (b) a stimulatory step for expansion with an anti-CD3 antibody in the presence of IL-2 and irradiated DR1 PBMCs. After the stimulation of the Treg cells they were (c) rested in media absent of anti-CD3 antibody, IL-2, and irradiated DR1 PBMCs for 48–72-hours. After resting the cells were further stimulated for a second round and then rested for 48 hours. (paragraph 0040).
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 24, 27, 40, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claim 1-3 above, and further in view of McDonald et al. (2019) (of record, IDS 02/07/2025).
In regards to claims 24, 27, 40, and 51 Safinia teaches the method of expansion of Treg cells using up to three stimulating steps and up to three rest steps as outlined above in the 102 rejection for claims 1-3. Also noted in regards to claim 24 Safinia teaches the use of an antibody complex for stimulating step in the form of anti-CD3/CD28 supermagnetic beads (option C of the claim) (pg.7573, col 2, lines 7-23). Further, in regards to claim 40 Safinia teaches the use of rapamycin (pg.7573, col 2, lines 7-23) and in regards to claim 27 Safinia teaches a method which does not use an artificial antigen presenting cell.
Safinia fails to teach the antibody complex which can specifically bind to a combination of CD3, CD28, CD2 or the antibody or antigen binding fragment of anti-CD3 and/or anti-CD28 of claim 24. Safinia also fails to teach a method which does not use supermagnetic beads of claim 27 or a method which does not use rapamycin of claims 27 and 40. Safinia, further, fails to teach a method of treating an autoimmune or inflammatory disease, treating or preventing graft vs host disease or decreasing an immune response using an effective amount of Tregs of claim 51.
MacDonald, however, in regards to claim 24 teaches the use of a variety of methods to expand Treg cells (Table 1) which including an anti-CD3 monoclonal antibody attached to an artificial presenting cell which is more effective at expanding umbilical cord blood Tregs than supermagnetic beads (pg.56, col 1, lines 9-15). Further MacDonalds teaches that Stemcell Technologies has developed an antibody complex which can specifically bind to a combination of CD3 and CD28 or CD3, CD28, and CD2 to provide an activation reagent which is soluble and make their removal from culture easier (pg.56, col 1, lines 1-2 and col 2, lines 6-10).
In regards to claims 27 MacDonald teaches the success of various methods to Treg expansion which include method which do not use supermagnetic beads due to their need to be removed before infusion (pg.56, col 1, lines 8-11), and methods that do not use artificial antigen presenting cells due to their complication to the cell manufacturing process (pg.56, col 1, lines 26-29).
In regards to claims 27 and 40 MacDonald teaches methods that do use rapamycin to limit T effector cell growth, and to increase the suppressive function of Tregs (pg.58, col 1, 7-22). Further MacDonald teaches methods which do not use rapamycin because it limits Treg proliferation (Table 1).
In regards to claim 51 MacDonald teaches it is commonly accepted and clinical trials have been conducted to prove its safety to use adoptive transfer of regulatory T cells for preventing or treating graft vs host disease and autoimmune conditions (pg.52, col 1, lines 1-17). Further MacDonald teaches adoptive transfer of Treg cells works by shifting the balance of Tregs and T effector cells to favor tolerance induction (decreasing an immune response) (pg.52, col 1, lines 7-10).
Thus, Safinia discloses a method of expanding Treg cells in which the cells are stimulated and rested up to three times using anti-CD3/CD28 supermagnetic beads in the presence of rapamycin, and MacDonald teaches various expansion methods which includes using monoclonal antibody attached to artificial antigen presenting cells or antibody complexes for varying efficiency and post stimulation steps. Further MacDonald teaches rapamycin addition or omission to support effector cell suppression or Treg cell proliferation and the use of expanded Tregs to decrease immune response, treat autoimmune conditions, or treat or prevent graft vs host disease. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Safinia with the teachings of MacDonald because addition or omission of rapamycin to the culture of the Treg cells can be used to balance Treg cell purity or Treg expansion size for better control of the Treg product for administration. Further MacDonald motivates the use of the platform taught in Safinia for the treatment of graft vs host disease and autoimmune conditions. Thus, combining the references would allow, with a reasonable expectation of success, the development a method to expand Treg cells which can have with more control on the purity and amount harvested of the end product for use in treating graft vs host disease and autoimmune conditions.
Claims 5, 30, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claims 1-3 above, and further in view of Yu et al. (2019) "Optimization of human T cell activation and expansion protocols improves efficiency of genetic Modification and overall cell yield." European Journal of Immunology (Vol. 49) (hereafter Yu) and Hippen et al. (2011) Massive ex Vivo Expansion of Human Natural Regulatory T cells (Tregs) with Minimal Loss of in Vivo Functional Activity Sci. Transl. Med. (3) 83ra41-83ra41 (hereafter Hippen).
Safinia fails to teach the genetic engineering of the second rested population or third stimulated population of claim 5, and the 1–5-day stimulations and 1-5 days’ rest before genetic modification of claim 30, and the 1000-fold increase in 11 days of claim 41.
Yu, however teaches a method of expanding Treg cells for 1-3 days, followed by genetic engineering with a lentivirus or CRISPR Cas 9 (Figure 2) for improved knockout efficient (abstract).
Further, in regards to claim 41 Yu teaches a method in which one stimulation step for 3 days followed by significant dilution of the cell culture and maintenance of a low concentration of cells resulted in more than 1000-fold expansion of T-cells over 10-12 days (abstract)
Yu fails to teach the multiple stimulations and rest periods of claims 5 and 30.
Hippen, however teaches that the restimulation of Treg cells after letting them return to a resting condition greatly expanded the Treg expansion (pg.3, col 1, lines 13-37) and further teaches maximizing yield to Treg cells is critical for efficiency and reproducibility in graft vs host disease suppression (pg. 1, col 1, lines 12-14).
Thus, Safinia discloses a method of expanding T reg cells comprising up to 3 stimulation steps and 3 rest steps, and Yu teaches genetic engineering after 1–3-day expansion, and maintaining a low cell concentration for a more than 1000 -fold expansion of the T-cells. Further Hippen teaches that restimulation of resting Treg cells expanded Treg expansion. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Safinia, Yu, and Hippen because keeping cells at low concentrations after stimulation and further restimulation allows for increased Treg cell expansion to yield more modified Treg cells and genetic engineering after stimulation allows for a better knockout efficiency to further yield more therapeutic product for use. Thus, combining the references would allow, with a reasonable expectation of success, the development a method of Treg cell expansion and further genetic modification to yield a larger population of modified Treg cells with higher therapeutic efficacy.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claim 1 above, and further in view of Frost et al. (US20190367876, of record IDS 02/07/2025).
The method taught in Safinia teaches culturing the cells in the presence of IL-2. Safinia fails to teach the culturing of N-Acetyl-L-cysteine (NAC), however, frost teaches the addition of NAC in the culture when expanding immune cells including T-cells (pg.11, col 2, lines 1-3). Frost, further, teaches NAC was found to be beneficial during Treg expansion but detrimental during Treg cell modification (pg.11, col 2, lines 1-3).
Thus, Safinia discloses a method of expanding T reg cells comprising at least 1 stimulation step and 1 rest step, and Frost teaches the addition of NAC as a benefit for the expansion of Treg cells. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Safinia with the teachings of Frost because the addition of NAC to the culture of expanding Treg cells increases expansion to yield a larger number of modified Treg cells. Thus, combining the references would allow, with a reasonable expectation of success, the development of a method for Treg cell expansion comprising a stimulation step and a rest step and wherein the cells are cultured with NAC for increased yield of modified Treg cells for use as a therapeutic.
Claims 31 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claim 1 above, and further in view of Marek et al. (2011) The Time Is Crucial for Ex Vivo Expansion of T Regulatory Cells for Therapy Cell Transplantation (20) 1747-1758 (hereafter Marek).
Safinia fails to teach the Tregs cultured in the presence and/or absence of a stimulatory agent according to Table A of Claim 31. Safinia also fails to teach the method resulting in Tregs with a smaller surface area than Tregs that are cultured in the presence of a stimulating agent for 6 days; and/or wherein the method results in an increased proportion of Helios+Foxp3+ Tregs as compared to Tregs that are cultured in the presence of a stimulating agent for 6 days; and/or wherein the method results in Tregs with an increased ability to suppress proliferation of effector T cells (Teffs) as compared to Tregs that are cultured in the presence of a stimulating agent for 6 days; and/or wherein the method prevents overstimulation of the population of Tregs; and/or wherein the method reduces activation- induced cell death as compared to Tregs that are cultured in the presence of a stimulating agent for 6 days of claim 42.
Marek however teaches that suppressive phenotype and suppressive function decrease with time and that the length of culture was found to be a crucial variable to keep the cells regulatory (pg.1751, col 2, lines 1-6).
Thus, Safinia discloses a method of expanding T reg cells comprising at least 1 stimulation step and 1 rest step, and Marek teaches the importance of minimizing timing in T cell expansion. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the teachings of Safinia informed by the teachings of Marek because longer stimulation times induce cell death and degrades the Treg suppressive function. Thus, combining the references would allow, with a reasonable expectation of success, the development of a method of expanding Treg cells comprising a stimulation step and a rest step in which the time of stimulation steps are shortened to preserve Treg cell suppression function for a more efficacious therapeutic.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claim 1 above, and further in view of Osborn et al. US2021/0213062 (priority date 05/17/2018).
Safinia fails to teach Treg cells expanded about 250-fold change before genetic engineering, however Osborn teaches expanded cells can be multiplied by 200-fold or 300-fold and any and all whole or partial integers there between (pg.33, col 2, lines 16-23). Further, Osborn teaches subsequent electroporation to introduce a nucleic acid encoding an agent (pg.34, col 1, lines 61-65).
Thus, Safinia discloses a method of expanding T reg cells comprising at least 1 stimulation step and 1 rest step, and Osborn teaches a method wherein the Treg cells can be expanded to about 250 before genetic modification. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the combination the teachings of Safinia with the teachings of Osborn because 250-fold expansion of Tregs is sufficient to allow for the genetic modification of Tregs. Thus, combining the references would allow, with a reasonable expectation of success, the development of a method of expanding Treg cells before genetic modification in which the cells are expanded to 250-fold to yield a sufficient number of Treg cells for genetic modification.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Safinia as applied to claim 1 above, and further in view of Marek-Trzonkowska (2017) (of record IDS 04/17/2024).
Safinia fails to teach the method wherein at least 75% of Helios expression in the Tregs is maintained, the Tregs are Helios+ and/or have a fully demethylated Treg-Specific region (TSDR). Marek-Trzonkowska, however, teaches that when Treg cells are expanded at both 33°C and 37°C maintained or increased their IKZF2 (Helios) expression (Figure 4). Further, Marek-Trzonkowska teaches that Treg cells expanded at 33°C showed significantly higher frequencies of demethylated TSDR than Treg expanded at 37°C, with both conditions resulting in close to 100% of cells having demethylated TSDRs (pg.5 lines 14-17 /Figure 3D).
Thus, Safinia discloses a method of expanding T reg cells comprising at least 1 stimulation step and 1 rest step, and Marek-Trzonkowska teaches culture at 37°C and even more so at 33°C maintain Helios expression and have demethylated TSDRs. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Safinia with the teachings to Marek-Trzonkowska because temperatures of 37°C or 33°C maintain Helios expression and demethylate the TSDRs for maintained Treg function. Thus, combining the references would allow, with a reasonable expectation of success, the development of a method of expanding Treg cells comprising a stimulation step and a rest step in which the Treg cells are cultured at 37°C or 33°C for maintenance of Helios expression and a fully demethylated TSDR for Treg function maintenance to maintain their use as a therapeutic .
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday - Thursday from 7am to 4pm and Friday 7am – 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683