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 .
Election/Restrictions
Applicant’s election of Group I (claims 1-8) in the reply filed on 12/16/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 9-10 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-8 are pending and have been considered on the merits.
Claim Objections
Claims 1, 5 and 7-8 are objected to because of the following informalities:
The term “DNT” appears to be an abbreviation of “double negative T”. It would be more appropriate to disclose a full name followed by the abbreviation in the parentheses.
Claim 5 discloses “1 x 106 to 4 x 106”. It would be more appropriate to use a superscript for “6”, i.e. 1 x 106 to 4 x 106.
Claim 7 contains the term “wherein” in duplicate.
Claim 8 discloses “1x108”. It would be more appropriate to use a superscript for “8”, i.e. 1 x 108.
Appropriate correction is required.
Applicant is advised that should claim 6 be found allowable, claim 7 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 1-8 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 discloses the term “DNT cell”. It is not clear what the term “DNT” intend to point out. It appears that the abbreviation is for double negative T cells, however, it is not clear what are double negative in these T cells. Clarification is required.
Claim 1 discloses the step (ii) removing CD4+ and CD8+ T cells from the starting sample, thereby obtaining a sample II. It is not clear if the sample II refers to the CD4+ and CD8+ T cells removed from the sample I or the remaining cell population comprising CD4- and CD8- T cells. While it appears that the sample II would be DNT cells, however, the steps of claim 1 are not clear if sample II comprises CD4- and CD8- T cells.
Claim 1 discloses “(preferably 40-60 ng/mL, more preferably 50 ng/mL)” in the step (iv). It is not clear if the limitation in the parenthesis is required for the step. Furthermore, even if it is considered a part of the limitation, however, the limitations contain broad range and narrower range together. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the limitation of step (iv) recites the broad recitation 30-80 ng/mL, and the claim also recites 40-60 ng/ml and 50 ng/mL, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 1, step (v), discloses “the medium contains soluble T-cell mitogen at a concentration of 15-40 ng/mL (preferably 20-30 ng/mL, more preferably 25 ng/mL, more preferably soluble T-cell mitogen in an amount 1/2 of the added amount of the T-cell mitogen as described in sub-step (va)”. There is an open parenthesis right after the term “15-40 ng/mL”, however, there is no close parenthesis. As discussed above, it is not clear if the limitation in the parentheses is a part of the step required for the claimed method. In addition, this limitation discloses both broader and narrower ranges together and thus, render them indefinite. Still further, the step (v) discloses the term “sub-step (va)”. It is not clear what this limitation is intended to point out. There is no disclosure of “sub-step (va)” prior to this disclosure, and thus, it is not clear what the sub-step is referred to.
The wherein clause of claim 1 at the end of the claim discloses “all contain 200-1000 IU/mL (preferably 300- 700 IU/mL, more preferably 500 IU/mL) of recombinant human interleukin 2”. It is not clear if the limitation in the parentheses is a part of the step required for the claimed method. In addition, this limitation discloses both broader and narrower ranges together and thus, render them indefinite.
Claim 2 discloses that the sample II is a solution of recovered cell after cryopreservation. It is not clear what subject matter this limitation intends to point out. Claim 1 discloses that the sample II is obtained from the sample of peripheral blood from a donor after removing CD4+ and CD8+ T cells, and it is vague how a solution of recovered cell after cryopreservation can be the sample II. Is this intended to mean that the sample I is a solution of recovered cell after cryopreservation or the sample I was cryopreserved prior to the step (ii)? Clarification is required.
Claim 8 discloses the term “(or “solvent”)” in lines 4-6. It is not clear if the limitation in the parentheses is a part of the step required for the claimed method. In addition, if this limitation is required by the claim, it discloses both broader (solvent) and narrower (saline) scope together and thus, render them indefinite.
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.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US2009/0098095; Zhang2009 hereinafter) in view of Zhang et al. (US2020/0046768; published on 2/13/2020; Zhang2020 hereinafter; IDS ref.), Lee et al. (2019, Clin. Cancer Res.; IDS ref.)
Regarding the steps (i)-(iii) of claim 1, Zhang2009 teach that peripheral blood samples were collected from healthy individuals. Erythrocytes and CD4, CD8 T cells were depleted using the Human CD4/CD8 depletion cocktail kit (Stem Cell Technologies). The residual DNT cell enriched population was then cultured in anti-CD3 mAb pre-coated 24-well plates for 3 days in the presence of recombinant human interleukin-2 (rhIL-2, 50 U/mL) and rhIL-4 (30 U/mL) (para. 71). The anti-CD3 mAb coated on the plates reads on the immobilized T cell mitogen of step (iii).
Regarding the step (iv) of claim 1, Zhang2009 teach that on day 7, viable cells were split and cultured in fresh media supplemented with rhIL-2, rhIL-4 and soluble anti-CD3 mAb for another 3 days (para. 71). The soluble anti-CD3 mAb (clone OKT3) reads on the soluble T-cell mitogen of step (iv).
Regarding the concentration of the soluble T-cell mitogen of steps (iv) and (v), Zhang2009 teach 0.1 mg/ml (100 ng/ml) of soluble anti-CD3 antibody for day 7 (para. 72), and 50 ng/ml of anti-CD3 for 10 days to 3 weeks (para. 73). However, Zhang2009 do not teach 30-80 ng/ml (step (iv)) or 15-40 ng/ml (step (v)).
Zhang2020 teach the use of soluble anti-CD3 antibody at the concentration of 0.01-1 mg/ml (i.e. 10-1000 ng/ml) for culturing DNT cells (para. 73).
It would have been obvious to a person skilled in the art to modify the concentration of the anti-CD3 for the method of Zhang2009 to arrive the claimed concentration with a reasonable expectation of success as the concentration of the soluble anti-CD3 antibody can be 10-1000 ng/ml for restimulation as taught by Zhang2020.
Regarding the concentration of rhIL-2 in claim 1, Zhang2009 do not teach the claimed concentration of 200-1000 IU/ml as they teach 50 IU/ml (para. 73). However, Zhang2020 teach the concentration of IL-2 for the same purpose can be 250 IU/ml (para. 73).
It would have been obvious to a person skilled in the art to use the concentration of the IL-2 taught by Zhang2020 for the method of Zhang2009 to arrive the claimed concentration with a reasonable expectation of success as the concentration of IL-2 taught by Zhang2020 is for the same purpose as the method of Zhang2009.
Claim 1 requires that the culture system of steps (iii)-(vi) does not contain recombinant human interleukin 4 (rhIL-4) or AB serum. Zhang2009 teach that the cytokine utilized in the culturing DN T cell comprises IL-2, IL-4, IL-7, IL-15, IL-12 or mixtures of two or more (para. 40). This teaching would meet the using IL-2 only as the cytokine utilized for the culturing the DN T cell can be one cytokine from the above list. Zhang et al. teach that the culture medium can be serum free (para. 42).
Furthermore, Zhang2020 teach a method of culturing DNT cells without using IL-4 or AB serum as they do not disclose any IL-4 or AB serum (though they teach the use of FBS) in the method of culturing DNT cells (see para. 73). Still further, Lee et al. teach a method of culture expanding DNTs in a serum-free media without using IL-4 as Lee et al.’s method utilizes IL-2 and anti-CD3 (see p.2242, Materials and Methods).
Thus, it would have been obvious to a person skilled in the art to modify the method of Zhang2009 to omit the use of IL-4 or any serum as it is known in the art that the culturing of DNT cells can be carried out without IL-4 and AB serum with a reasonable expectation of success.
Regarding claim 2, the limitation is interpreted as there is a step of cryopreservation after the step (ii) of claim 1. While Zhang2009 do not particularly disclose that the DNT cells after removing non-DNT cells from the source are cryopreserved prior to the culturing, however, it is extremely well known in the art that the isolated cells can be cryopreserved for storage at any point of in vitro manipulation. In fact, Zhang2009 teach that the frozen cells as starting population for ex vivo expansion (para. 74), and this teaching would meet the limitation of claim 2.
Regarding claim 3, as discussed above, Zhang2009 teach the use of other cytokine including IL-7, IL-15 (para. 40).
Regarding claim 4 directed to the T cell mitogen being an antibody binding CD3, this limitation has been addressed as Zhang2009 teach anti-CD3 antibody (para. 38).
Regarding claim 5 directed to the concentration of DNT cells in the culture being 1x106 to 4x106 cells/ml, Zhang2009 teach that the cells were then cultured with the concentration of 0.5-1.0E+06 (0.5-1x106) cells per ml in each well of 24-well plate (para. 72), and this teaching would meet the claimed range.
Regarding claims 6-7 directed to the step of detecting DNT cell phenotype and viability, Zhang2009 teach that the phenotype and percentage of DN T cells before and after ex vivo expansion are analyzed (para. 20; Fig. 4), and this teaching would meet the limitation.
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(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang2009 in view of Zhang2020 and Lee et al. as applied to claims 1-7 above, and further in view of Dudley et al. (2003, J. Immunother.).
Regarding claim 8 directed to the step (vi) further comprising the steps of collecting DNT cells by centrifugation and washing with saline containing 2.5% human albumin and adjusting the concentration to 1x108 cells/ml, Zhang2009 in view of Zhang2020 and Lee et al. do not teach the limitation.
Dudley et al. teach a method of culturing T lymphocytes for use in a therapy, and the method includes the step of harvesting the culture T cells after expansion in culture by using centrifugation, and then wash the harvested cells in 0.9% sodium chloride (saline) and resuspended in 0.9% sodium chloride with 2.5% human albumin (p.4, Rapid Expansion Protocol and Preparation of Cells for infusion).
It would have been obvious to a person skilled in the art that the DNT cells expanded in culture in vitro would be harvested, washed and adjusted for the desired concentration for a therapeutic purpose of the DNT cells. Zhang2009 teach the use of DNT cells for a method of treating a tumor, and thus, the culture expanded DNT cells are needed to be harvested, washed and resuspended in a suitable medium for a desired therapeutic application. As Dudley et al. teach the method of harvesting T cells after culture expansion using saline solution and utilizing human album at 2.5% for preparing a cell composition for infusion, one skilled in the art would utilize the same harvesting, washing and resuspending method taught by Dudley et al. for the DNT cells of Zhang2009 in view of Zhang2020 and Lee et al. with a reasonable expectation of success. It is noted that the washing step taught by Dudley et al. is using saline per se and Dudley et al. do not disclose the washing step carried out with saline with 2.5% human albumin. However, as the resuspending step is carried out with saline comprising 2.5% human albumin, it would have been obvious to a person skilled in the art to use saline with 2.5% human albumin for washing and resuspending the cells for preparing a therapeutic composition with a reasonable expectation of success.
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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/TAEYOON KIM/ Primary Examiner, Art Unit 1631