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 .
Response to Amendment
Applicant's amendment and argument filed 12/29/2025 in response to the final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 1-18 and 20-27 are being examined on the merits.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 8, 10-11, 15-18, 20-26 are rejected under 35 U.S.C. 103 as being unpatentable over Eric Lagasse (From IDS, US20160058794A1). This rejection is maintained with slight modifications due to the amendments and arguments filed on 12/29/2025.
Regarding claims 1, 15, 20, Lagasse teaches a method of transplanting allograft tissue to a subject comprising introducing non-lymphoid cells in a lymphoid tissue of the subject under conditions such that the cells are able to proliferate, wherein the non-lymphoid cells are thymus cells (see claim 17).
Lagasse teaches “using a similar approach, we asked whether de novo thymus function could be generated in the lymph nodes of athymic mice. We harvested thymuses from newborn C57BL/6 GFP+ transgenic mice and minced and injected them directly into the jejunal lymph nodes or under the kidney capsules of athymic BALB/c nude mice. After 1 month, we analyzed the blood of the recipient mice by flow cytometry for the presence of recipient (GFP−) single-positive CD4+ and CD8+ T cells. Thymic transplant into the lymph node (LN-Tx nude mice) or under the kidney capsule (KC-Tx nude mice) generated circulating recipient single-positive CD4+ and CD8+ T cells (FIG. 3 a and FIG. 7). Ten months after transplantation, single-positive CD4+ and CD8+ T cells were still present in the peripheral blood, indicating long-term thymic engraftment in the lymph nodes (FIG. 8). Notably, transplantation of a thymic single-cell suspension also resulted in the presence of single-positive CD4+ and CD8+ T cells, although to a lesser degree than did transplantation of minced thymic tissues (Table 1=FIG. 9)” (see 0107). This teaching by Lagasse shows that the amount of tissue indeed reflects the outcome of functioning T-cells. Persons having ordinary skill in the art can appreciate that the circulating CD4+ and CD8+ cells would also indicate CD3+ cells and thus if there is an increase in the amount of CD4+ and CD8+ there will intrinsically be an increase of circulating CD3+ cells. It is known to those having ordinary skill in the art that CD3+ counts reflect the absolute number of all T lymphocytes.
Lagasse teaches that “thymic tissue injected into single jejunal lymph nodes of athymic nude mice generates functional ectopic thymuses” (see 0009).
Regarding claim 10, Lagasse teaches wherein the cells may be autologous (see first line, p 6).
Regarding claims 8 and 11, Lagasse teaches wherein cells were minced and delivered to the lymph node through injection (presumably with a needle) (see 0107).
Regarding claim 16, Lagasse teaches that the subject is a human (see 0062).
Lagasse does not specifically teach amount or weight of the thymic tissue to be transplanted however discloses that there are functional ectopic thymuses created after injection of thymic tissue into a lymph node. Thus, the amount and weight of the tissue appears to be an optimizable parameter which would have been prima facie obvious to persons of skill in the art especially given the relied upon prior art and since the art teaches that this method already creates functioning thymuses. Lagasse does teach wherein a dosage of a single-cell suspension also resulted in the presence of single-positive CD4+ and CD8+ T cells, although to a lesser degree than did transplantation of minced thymic tissues (Table 1=FIG. 9, or 0107), when compared to harvested thymuses that were minced and injected. Therefore it is recognized that different amounts of the tissue being delivered will have different outcomes and is considered to those skilled in the art as being an optimizable parameter because Lagasse compares amounts of the tissue being used as creating different effects. For example Lagasse teaches specifically a dosage of a single cell suspension vs minced thymus tissue (which is multiple cells) for increasing the amount of circulating CD4+ and CD8+ T cells. This indeed indicates that the amount being used must be optimized.
It would have also been obvious to deliver the thymic tissue to two lymph nodes to increase the chance of the lymph nodes accepting the thymic tissue and create a successful transplantation. It would have further been obvious to use the method on an adult at least about 40 years of age and one suffering from a thymus condition because the objective of the invention is to restore the condition of the thymus due to thymectomy and this would also include adults and subjects suffering from a thymus condition.
Claims 2-7, 12, 20, 22 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Eric Lagasse (From IDS, US20160058794A1) as applied to claims 1, 8, 10-11, 15-18, 20-26 above, and further in view of Markert et. al. (From IDS, Thymus transplantation, Clinical Immunology, 135(2): 236-246 (2010)). This rejection is maintained due to the arguments filed on 07/16/2025.
Lagasse teaches the method of preserving or restoring a thymic function of a subject in need thereof however is silent on the subject having a congenial heart disease and is silent on the T-cells being naïve T-cells that are increased to 5% before the delivery.
Regarding claims 2-7 and 12, Markert teaches children with congenital athymia are candidates for thymus transplantation (see Introduction, 2nd para.). “Thymus tissue is frequently removed by pediatric cardiac surgeons to access the surgical field in infants with congenital heart disease” (see Methods, Thymus tissue procurement).
Regarding claim 20 and 22, Markert teaches “to confirm normal thymus function in the donor, the donor’s blood is examined by flow cytometry to ensure that the donor has greater than 50% naïve (CD45RA+CD62L+) T cells” (see Thymus donor screening, 2nd para.). Markert also teaches cyclosporine therapy was continued after transplantation until naïve T cells increased to over 10% of the total T cells. (see page 7, first para.).
Regarding claim 27, Markert teaches “subjects with typical complete DiGeorge anomaly do not have T cells or T cell function [1, 6], thus they do not have the cells that can affect graft rejection and no immunosuppression is needed” (see Use of immunosuppression in thymus allograft recipients, p 3-4). Markert also teaches wherein the subject population for thymus transplantation were subjects with complete DiGeorge syndrome (see subject population, p 4).
Therefore it would have been obvious to persons having skill in the art and before the effective filing date to administer the treatment taught by Lagasse to subjects such as infants who have had thymus surgery due to a congenital heart disease and to confirm that the CD45+ T cells in the subject are at a frequency of at least 20% after the transplant, because as Markert explains, this is how they determined normal thymus function. Additionally, it would have been obvious to use this treatment for persons with DiGeorge syndrome because Markert teaches this subject population. It would have also been obvious to administer cyclosporine therapy after transplantation until naïve T cells increase to over 10% of the total T cells because one would want to increase naïve T cell populations so that those cells can engage with new antigens and thus build immune responses. There would have been a reasonable expectation of success in arriving at the instantly claimed invention given the prior art as the art discloses delivering of thymic tissues as a way to increase T-cell populations.
Claims 9 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Eric Lagasse (From IDS, US20160058794A1) as applied to claims 1, 8, 10-11, 15-18, 20-26 above, and further in view of Ross et. al. (Transplanted human thymus slices induce and support T‐cell development in mice after cryopreservation, Eur J Immunol. 2018 Feb 1;48(4):716-719). This rejection is maintained due to the arguments filed on 07/16/2025.
Lagasse teaches the method of preserving or restoring a thymic function of a subject in need thereof however is silent on the thymic tissue being cryopreserved.
Ross teaches “Nude mouse human thymus transplant model: Fresh or cryopreserved and thawed human thymus slices were transplanted subcutaneously into recipient nude mice. Nude mice subsequently produced mouse CD3+CD4+ T‐cells” (see abstract).
Regarding claim 9, Ross teaches “We therefore froze the slices in a large‐scale cryocooler‐based control‐rate freezer that can process the larger volumes of tissue required for transplantation of thymus slices into patients, and which is compliant with good manufacturing process (GMP)‐cryopreservation 7. On thawing, slices were cultured for 24 h before histological analysis. Tissue architecture of the slices appeared similar to control fresh human thymus slices, with most of the slices appearing to be normal viable tissue (Fig. 1A)” (see para. 3, p 716). This would indicate culturing the cells ex vivo as instantly claimed.
Therefore it would have been obvious to persons having skill in the art and before the effective filing date to administer cryopreserved thymic tissue in the invention taught by Lagasse because as Ross teaches nude mice that underwent a thymic tissue transplant from cryopreserved thymic tissue were able to successfully produce CD3+CD4+ T‐cells.
There would have been a reasonable expectation of success in arriving at the instantly claimed invention because thymic tissue transplantation through the lymph node has previously been described in the art.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive. The applicant argues that the Office has not provided any evidence as to why the amount of thymic tissue to be transplanted is a results effective variable. This is however not the case as can be appreciated from the above and previous rejections. The applicant specifically argues that Lagasse merely describes dosage forms of the thymic tissue being delivered and does not teach specific amounts/quantities. Lagasse indeed teaches dosage forms and teaches using different dosage amounts, that of being single cell to minced tissue (more than a single cell). Lagasse teaches where there are different effects with the different amounts being administered, specifically the amount of circulating CD4+ and CD8+ T cells. This is the nexus for optimizing the amount of thymus tissue to deliver to the patient. If the amounts did not differ then it would not appear to be an optimizable parameter. However, this does not appear to be the case and persons having ordinary skill in the art would recognize that this parameter creates different effective results specifically the amount of circulating CD4+ and CD8+ T cells (which are also CD3+) and therefore this parameter would need to be optimized.
The applicant argues that they have discovered that delivering more thymus tissue does not necessarily equate to more circulating CD3+ T cells and that this is unexpected, however given the prior art this parameter, as just discussed, is a known result effective variable and therefore this would not be unexpected as it would have been obvious to optimize.
The applicant argues that independent claim 20 recites in part “wherein the thymic tissue is delivered in an amount effective to increase a frequency of CD3+ peripheral blood cells in the subject that are naïve T cells by at least 5% compared to before the delivering” and that Lagasse does not teach the T-cells to be naïve. The applicant argues that Lagasse’s teachings shows that the population of naïve T-cells are fewer than that of the control groups. Lagasse explains that this is possibly due to the fact that these mice had been previously exposed to skin grafts. Markert teaches one way to help the naïve T-cell population reach 10% greater than the total T-cell population is to continue cyclosporine therapy, therefore it would have been obvious to persons having skill in the art to apply this teaching from Markert to Lagasse’s invention so that naïve T-cells are increased.
Conclusion
Currently 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.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655