The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-3, 7, 13, 16, 19-30 and 36 are rejected under 35 U.S.C. 112(a), as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Independent claims 1 and 2 require obtaining a first blood sample from a transplant recipient patient pre-tolerization, pre-transplant, and pre-initiation of transient immunotherapy and a second blood sample from the transplant patient post-tolerization, post-transplant, and post-initiation of administration of a transient immunotherapy to the transplant recipient patient. The first and second blood samples are assayed to detect levels of target Tr1 cells is before and after tolerization, transplantation, and initiation of the administration of the transient immunotherapy to the transplant recipient patient. A transplant recipient patient is identified as having (long term) transplantation tolerance when the post- procedure frequency of Tr1 cells in the second blood sample is at least 2-fold greater than the baseline frequency of Tr1 cells in the first blood sample wherein the frequency of the Tr1 cells is a percentage of the Tr1 cells in a blood sample, and wherein the target cells are T regulatory Type 1 (Tr1) cells having markers express the markers CD49b+, LAG-3+, and CD4+. The long-term transplantation tolerance induced by one or more donor antigens administered under cover of transient immunotherapy in which claim 3 requires the one or more donor antigens to be apoptotic donor leukocytes (ADLs), donor-specific transfusion (DST) nanoparticles conjugated with donor peptides or encapsulating donor peptides, and/or apoptotic recipient leukocytes conjugated with donor peptides. Claim 1 sets the period for long-term transplantation tolerance as greater than one year. As such, the independent claims do not set forth a specific time for obtaining the second blood sample or establish a specific treatment regime. Thus the instant claims cover any method in which donor antigens are administered under cover of transient immunotherapy and the second blood sample is obtained at any point after initiation of administration of a transient immunotherapy to the transplant recipient patient.
Examiner notes that the paragraph bridging pages 18-19 describes other NPH studies in which one or more donor antigens (i.e. donor bone marrow or donor specific transfusions) were administered to the transplant recipient patients with varied results. The varied results included those that resulted in a portion of the transplant recipient patients in at least one study having induced long term transplant tolerance. That paragraph also makes a comparison/distinction between the treatment of applicant and the other cell-based tolerance strategies relative to the need for adoptive transfer of regulatory cells and/or the safety of the treatment. However, the instant independent claims are of a scope that they would cover the other treatment strategies if the respective blood samples were obtained and assayed for the target cells and the target cells in the second blood sample met the at least 2-fold increase requirement of the independent claims. Examiner notes that the instant disclosure does not show that these other types of treatments would result in the required increase of the instantly claimed target cells when long term tolerance was induced. Thus there is no evidence that that other treatments would result in the required increase in the target cells other than the instantly disclosed treatment resulting in the induced long term tolerance in 5 of 5 nonsensitized, 1 MHC-II DRB allele-matched monkeys described in the first paragraph of example 1 on page 18 of the instant specification. Thus in looking at the Wands factors, the variability in the response to the different treatments points to a lack of general predictability in the response to the treatment.
In support of this, examiner next points applicant to the second full paragraph on page 33 looking at loss of the tolerance biomarker prior to loss of graft function. In that paragraph an experiment is described in which ADL+TIS was administered to completely mismatched islet allograft recipients in the posttransplant treatment process. Based on instant claim 3, the ADL+TIS constitutes one or more donor antigens being administered as a part of the treatment process. This treatment reportedly resulted in the loss of graft function at −300 days post-transplant whereas transplantation in one-DRB matched recipients resulted in indefinite survival and function of the transplanted islets (365 days). Since the independent claims don’t specify the type of treatment or specifics of the transplant, the transplant and treatment process are within the scope of the instant claims. The paragraph teaches that similar to the one-DRB matched group, administration of ADL+TIS resulted in a significant increase in the fold change in the frequency of Tr1 cells on day 90 (3.98±0.98), followed by a reduction at day 180 (1.98±0.75) and reached the levels observed in the naïve status on day 300 (1.19±0.1). In other words, applicant obtained blood samples from the transplant recipient patient pre-tolerization, pre-transplant, and pre-initiation of transient immunotherapy (the naïve status) and subsequent to post-tolerization, post-transplant, and post-initiation of administration of a transient immunotherapy on days 90, 180 and 300. When looking comparing the frequency/level of the target Tr1 cells in the blood sample pre-tolerization, pre-transplant, and pre-initiation of transient immunotherapy (the naïve status, 1.19±0.1) and to the blood samples subsequent to post-tolerization, post-transplant, and post-initiation of administration of a transient immunotherapy, the blood sample at 90 days shows a frequency that is greater than the claimed 2-fold increase, the blood samples a 180 and 300 days do not meet the requirement of the independent claims. In other words, applicant’s own disclosure supports the lack of enablement of the independent claims since a process was described that was fully within the scope of the independent claims including treatment with the donor antigens described/disclosed by applicant that resulted in a more than 2 fold increase in the target Tr1 cells in the second blood sample that did not result in long term tolerance.
Examiner further notes that the newly cited Chen paper applied a transplant procedure that included administration of donor antigens (donor ECDI-SP) under the cover of transient immunotherapy (with a short course of rapamycin) that provided indefinite cardiac allograft survival in 100% of the recipients (see at least the abstract). The paragraph bridging pages 2927-2928 of the paper teaches a heightened presence of intragraft Foxp3+ cells and IL-10 production in ECDI-SPs treated recipients (Figures 4D and 5B). One possible mechanism of IDO-dependent induction of Foxp3+ cells is by activation of the aryl hydrocarbon receptor (AhR), a receptor shown to be important in the balance of regulatory T cell and Th17 differentiation. Kynurenine, the first breakdown product of IDO-mediated tryptophan degradation, could activate AhR leading to AhR dependent regulatory T cell induction. Moreover, in an islet transplantation model, activation of AhR using a low molecular weight AhR agonist leads to direct induction of Foxp3+ cells, as well as indirect induction of these cells by tolerogenic DCs, concomitant with islet allograft protection. Similarly, IL-10 producing Tr1 cells have also been shown to be induced by AhR signaling in mouse and in man. This could also be accomplished directly or indirectly via DCs with altered immunogenicity. Their findings of heightened intragraft Foxp3+ cells and IL-10 production seen in the context of induction of CD11b+IDO+ cells are consistent with these previous studies. The newly cited Gandhi paper is the paper referenced with respect to inducement of IL-10 producing Tr1 cells. Neither reference identifies the IL-10 producing Tr1 cells as Tr1 cells expressing the markers CD49b+, LAG-3+, and CD4+.
Based on the above observations, there is ample evidence that the claims are not enabled and/or that one of ordinary skill in the art would expect the instant claims to be applicable to transplants having long-term transplantation tolerance induced by one or more donor antigens administered under cover of transient immunotherapy generally.
Claims 1-3, 7, 13, 16, 19-30 and 36 are 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. Each of claims 1 and 2 in some form requires the step of identifying the transplant recipient patient as having transplantation tolerance induced by one or more donor antigens administered under cover of transient immunotherapy when the frequency of Tr1 cells in the second blood sample is at least 2-fold greater than the frequency of Tr1 cells in the first blood sample, wherein the frequency of the Tr1 cells is a percentage of the Tr1 cells in a blood sample. The claims also require that the T regulatory Type 1 (Tr1) cells express the markers CD49b+, LAG-3+, CD4+. The requirement that wherein the frequency of the Tr1 cells is a percentage of the Tr1 cells in a blood sample is not clear in that there is nothing to distinguish the Tr1 cells that are a percentage of the Tr1 cells in a blood sample from any other Tr1 cells in the blood sample that are not part of the percentage. For examination purposes, examiner will treat the Tr1 cells that the frequency is a percentage as a target Tr1 cell as a percentage of all the Tr1 cells in the blood sample, wherein the target T regulatory Type 1 (Tr1) cells express the markers CD49b+, LAG-3+, CD4+. It is not clear whether the target cells are required to have all three of the markers on each cell or only at least one marker selected from the group consisting of CD49b+, LAG-3+ and CD4+. For examining purposes, the latter scope will be used as the minimum scope required to meet the limitation. All claims depend from these claims and fail to remedy the issue. With respect to claim 13, it is not clear if the required properties are inherent if the Tr1 cells have the required markers or if the claim needs a step to determine if any or all of the three properties are present in the Tr1 cells. Put another way, is an assay required to identify any or all of the stated properties or are they inherent based on the Tr1 cells expressing the required markers? For examination purposes, examiner will treat the presence of one or more of the CD49b+, LAG-3+ and CD4+ markers as evidence that the Tr1 cells meet the limitation of claim 13.
Applicant's arguments filed August 5, 2025 have been fully considered but they are not persuasive. In response to the amendments the rejection under 35 U.S.C. 112(b) was modified, the obviousness rejection was withdrawn by examiner and a new rejection under 35 U.S.C. 112(a) was applied to the claims. The modification of the rejection under 35 U.S.C. 112(b) addresses new clarity issues with claims 1-2 and provides additional explanation relative the previous issues of claim 13 that applicant’s changes did not overcome. With respect to the new rejection under 35 U.S.C. 112(a), the withdrawn obviousness rejections and the new clarity issues, applicant’s arguments are moot. With respect to claim 13, it is still not clear if the presence of the required markers on the Tr1 cells are inherently indicative of (having indirect specificity for) the stated properties or if the method is attempting to require some assay to determine if Tr1 cells actually have the stated properties. Examiner notes that applicant has added the phrase “as determined by an assay” at the end of the claim after the listing of properties. However, it is not clear if the added language is only relevant to the final property or all three stated properties. Alternatively, it is not clear if the added language is still referring to an inherent property that an assay would have shown to exist. As such the changes to claim 13 failed to overcome the previous problem and the argument that it has been overcome is not persuasive.
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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to transplantation tolerance including references such as the Chan paper noted above in which donor antigens were administered under the cover of transient immunotherapy leading to long-term transplant survival (transplant tolerance).
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/ARLEN SODERQUIST/ Primary Examiner, Art Unit 1797