DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 25 July 2025 have been entered. Claims 1-7, 12, 14-15, 17-18, 20-21, 24, 29-30, 32, 34, 36, 38, 42, 44-46, 48, 50-54, and 57 were previously pending in the application. Claims 7 and 53 have been cancelled, and new claims 61-63 have been added by Applicant. Claims 1-6, 12, 14-15, 17-18, 20-21, 24, 29-30, 32, 34, 36, 38, 42, 44-46, 48, 50-52, 54, 57, and 61-63 are currently pending in the application. Claims 1, 2, 3, 45 are independent claims. The following election of species remains in effect in the instant application:
1)a.i. Inhibitors of an anti-apoptotic Bcl-2 family member: Bcl-2 inhibitor: Venetoclax, and
2)b.v. Inhibitors of an anti-apoptotic Bcl-2 family member: Mcl-2 inhibitor: S63845.
Claims 51-52 and 54 remain withdrawn from consideration as being directed to a nonelected species. Claims 1-6, 12, 14-15, 17-18, 20-21, 24, 29-30, 32, 34, 36, 38, 42, 44-46, 48, 50, 57, and 61-63 are currently pending and under examination in the instant application to which the following grounds of rejection are applicable.. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US20/32144, filed 08 May 2020, which claims priority to U.S. provisional Application No. 62/845,680, filed 09 May 2019.
Thus, the earliest possible priority for the instant application is 09 May 2019.
Claim Objections
*The following new objection is necessitated by amendments to the claim.
Amended and new claims 45 and 62-63 is newly objected to because of the following informalities: amended claim 45 and new claims 62-63 each recites the abbreviation “TBI” without first writing out the term for which it is an abbreviation. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claim 12 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting, "the dose" in line 1 and “wherein the dose of TBI is 0.5 Gy, 0.75 Gy, 1.0 Gy, 1.25 Gy, 1.50 Gy, 1.75 Gy, 2.0 Gy, 2.25 Gy, 2.50 Gy, or 3 Gy” is withdrawn in view of Applicant’s amendments to the claims such that claim 1 now recites, “administering a total dose of up to 1.5 Gy of total body irradiation to the patient” and claim 12 now recites, “wherein the total dose of TBI is 0.5 Gy, 0.75 Gy, 1.0 Gy, 1.25 Gy, or 1.5 Gy”.
The rejection of amended claim 17 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting, "the inhibitor of an anti-apoptotic BCL-2 family member" in lines 1-2” is withdrawn in view of Applicant’s amendments to the claims such that claim 17 now recites, “wherein an inhibitor of Mcl-1 and an inhibitor of Bcl-2 are administered”.
The rejection of amended claim 29 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting, “the Bcl-2 inhibitor” in lines 1-2 is withdrawn in view of Applicant’s amendments to the claims such that claim 29 now recites, “wherein the inhibitor of an anti-apoptotic Bcl-2 family member “.
The rejection of amended claim 38 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting a list of daily doses in lines 5-7 which does not include any “and”, “or”, or “and/or” notation, is withdrawn in view of Applicant’s amendments to the claims such that the list now ends with “or about 50 mg/kg”.
The rejection of amended claim 44 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “wherein the organ is HLA mismatched” is withdrawn in view of Applicant’s amendments to the claims such that claim 44 now recites, “wherein the kidney is HLA mismatched to the patient”.
The rejection of cancelled claim 53 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting "wherein the initial administration of the first anti-apoptotic BCL-2 family member" in lines 1-2, “the initial administration of the second anti-apoptotic BCL-2 family member”, and “the initial administration of the first anti-apoptotic BCL-2 family member to the patient occurs at the same time as the initial administration of the second anti-apoptotic BCL-2 family member to the patient” in lines 1-4, is withdrawn.
Claim Interpretation
Amended claim 45 recites, “the method comprises administering to the recipient of the bone marrow transplant an inhibitor of Mcl-1, optionally with a specific inhibitor of Bcl-2, and wherein the method further comprises administering a total dose of up to 1.5 Gy of TBI”, which has been interpreted such that the term “optionally” refers to “with a specific inhibitor of Bcl-2” and NOT to “wherein the method further comprises administering a total dose of up to 1.5 Gy of TBI”. As such, the new limitation of “wherein the method further comprises administering a total dose of up to 1.5 Gy of TBI” is considered to be a required limitation of the claim, whereas the limitation “with a specific inhibitor of Bcl-2” is not a required limitation of the claim.
Claim Rejections - 35 USC § 102
The rejection of amended, previously presented, original, and cancelled claims 1-4, 6-7, 12, 14-15, 21, 24, 29-30, 34, 36, 38, and 57 under 35 U.S.C. 102(a)(1) as being anticipated by Oura et al. (2018, Transplantation, 10(7S), abstract: 503.5, published online July 2018), is withdrawn over cancelled claim 7 , maintained over amended, previously presented, and original claims 1-4, 6, 12, 14-15, 21, 24, 29-30, 34, 36, 38, and 57, and newly applied to new claims 61-63. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended claim 1 to recite a total dose of up to 1.5 Gy of total body irradiation and transplanting both bone marrow and a kidney from a donor to the patient. Applicant amended claims 2 and 3 to also recite transplanting bone marrow and a kidney. New claim 61 recites wherein the total dose of TBI is 1.5 Gy. However, both of these limitations were addressed in the prior office action on page 9 lines 5-7:
“Regarding claim 7, Oura teaches that the method further comprises transplanting a kidney from a donor to the patient [lines 8-9].
Regarding claim 12, Oura teaches that the dose of TBI is 1.5 Gy [lines 9-10].”
Applicant added new claims 62 and 63, which each recite the method of claim 2 or 3, respectively, does not comprise administering TBI. However, Oura teaches two recipients received the same regimen without TBI [lines 12-13].
Therefore, Applicant’s amendments do not overcome the finding of anticipation by Oura under 35 USC 102(a)(1).
Applicant argues that Oura is the inventor’s own work, was published less than one year before the effective filing date of the instant application, and thus Oura is not available as prior art under 35 USC 102(a)(1). However, this is not agreed.
Note that although this reference includes the inventor of the instant application, it does not qualify for a grace period exception, and therefore qualifies as prior art under 35 U.S.C. 102(a)(1), because it lists authors who are not listed as inventors on the instant application, namely, Tetsu Oura, Abbas Dehnadi, Hajime Sasaki, Ivy Rosales, A. Benedict Cosimi, Pietro Cippa, and Thomas Fehr. See MPEP 2152.05.
As set forth in MPEP 2153.01(a), if the application names fewer joint inventors than a publication (e.g., the application names as joint inventions A and B, and the publication names as authors A, B, and C), it would not be readily apparent form the publication that it is by the inventor (i.e., the inventive entity) or a joint inventor and the publication would be treated as prior art under AIA 35 U.S.C. 102(a)(1).
If applicant wishes to invoke the exception under AIA 35 U.S.C. 102(b)(1)(A) for a grace perioddisclosure, the Office has provided a mechanism for filing an affidavit or declaration (under 37 CFR 1.130) to establish that a disclosure is not prior art under AIA 35 U.S.C. 102(a) due to an exception in AIA 35 U.S.C. 102(b). See MPEP § 717. In the situations in which it is not apparent from the prior disclosureor the patent application specification that the prior disclosure is by the inventor or a joint inventor, theapplicant may establish by way of an affidavit or declaration that a grace period disclosure is not priorart under AIA 35 U.S.C. 102(a)(1) because the prior disclosure was by the inventor or a joint inventor.MPEP 2155.01 discusses the use of affidavits or declarations to show that the prior disclosure was madeby the inventor or a joint inventor under the exception of AIA 35 U.S.C. 102(b)(1)(A) for a grace periodinventor disclosure.
Therefore, Applicant’s arguments do not overcome the finding of anticipation by Oura under 35 USC 102(a)(1), and the rejection is maintained.
The rejection of amended, previously presented, original, and cancelled claims 1-2, 6-7, 12, 14-15, 34, 36, 38, and 57 under 35 U.S.C. 102(a)(1) as being anticipated by Kawai et al. (2019, J Immunol., 202, Supplement 1: 6938, published online 1 May 2019), is withdrawn over cancelled claim 7, maintained over amended, previously presented, and original claims 1-2, 6, 12, 14-15, 34, 36, 38, and 57, and newly applied to new claims 61-63. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended claim 1 to recite a total dose of up to 1.5 Gy of total body irradiation and transplanting both bone marrow and a kidney from a donor to the patient. Applicant amended claims 2 and 3 to also recite transplanting bone marrow and a kidney. New claim 61 recites wherein the total dose of TBI is 1.5 Gy. However, as discussed in the prior action, Kawai teaches administering one dose of 1.5 Gy of TBI to the patient [lines 7-8] and transplanting an organ (e.g., kidney) from a donor to the patient [lines 3-4, 6, 13, 15, 21].
Applicant added new claims 62 and 63, which each recite the method of claim 2 or 3, respectively, does not comprise administering TBI. However, Kawai teaches Group D recipients received the same regimen without TBI [line 7].
Therefore, Applicant’s amendments do not overcome the finding of anticipation by Kawai under 35 USC 102(a)(1).
Applicant argues that Kawai is the inventor’s own work, was published less than one year before the effective filing date of the instant application, and thus Kawai is not available as prior art under 35 USC 102(a)(1). However, this is not agreed.
Note that although this reference includes the inventor of the instant application, it does not qualify for a grace period exception, and therefore qualifies as prior art under 35 U.S.C. 102(a)(1), because it lists authors who are not listed as inventors on the instant application, namely, Hajime Sasaki, David Ma, Abbas Dehnadi, A. Benedict Cosimi, Pietro Cippa, and Thomas Fehr. See MPEP 2152.05.
As set forth in MPEP 2153.01(a), if the application names fewer joint inventors than a publication (e.g., the application names as joint inventions A and B, and the publication names as authors A, B, and C), it would not be readily apparent form the publication that it is by the inventor (i.e., the inventive entity) or a joint inventor and the publication would be treated as prior art under AIA 35 U.S.C. 102(a)(1).
If applicant wishes to invoke the exception under AIA 35 U.S.C. 102(b)(1)(A) for a grace perioddisclosure, the Office has provided a mechanism for filing an affidavit or declaration (under 37 CFR 1.130) to establish that a disclosure is not prior art under AIA 35 U.S.C. 102(a) due to an exception in AIA 35 U.S.C. 102(b). See MPEP § 717. In the situations in which it is not apparent from the prior disclosureor the patent application specification that the prior disclosure is by the inventor or a joint inventor, theapplicant may establish by way of an affidavit or declaration that a grace period disclosure is not priorart under AIA 35 U.S.C. 102(a)(1) because the prior disclosure was by the inventor or a joint inventor.MPEP 2155.01 discusses the use of affidavits or declarations to show that the prior disclosure was madeby the inventor or a joint inventor under the exception of AIA 35 U.S.C. 102(b)(1)(A) for a grace periodinventor disclosure.
Therefore, Applicant’s arguments do not overcome the finding of anticipation by Kawai under 35 USC 102(a)(1), and the rejection is maintained.
The rejection of amended, previously presented, and original claims 1-6, 14-15, 17-18, 21, 24, 32, 45-46, 48, and 57 under 35 U.S.C. 102(a)(1) as being anticipated by Jiao et al. (2019, Cell Death & Differentiation, 26, 1516-1530, published online 12 November 2018), is withdrawn over claims 1-6, 14-15, 17-18, 21, 24, 32, and 57 and maintained over claims 45-46 and 48 in view of Applicant’s claims which now recite transplanting bone marrow and a kidney in independent claims 1-3 and administering a total dose of up to 1.5 Gy of total body irradiation in independent claims 1 and 45.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1-7, 12, 14-15, 17-18, 20-21, 24, 32, 34, 36, 38, 42, 44-46, 48, 50, and 57 under 35 U.S.C. 103 as being unpatentable over Jiao et al. [2019, Cell Death & Differentiation, 26, 1516-1530, published online 12 November 2018]; in view of Cippa et al. [2013, Blood, 122(9), 1669-1677]; Husky et al. [2018, Transplantation, 102, 1994-2001]; and Ito et al. [2004, Blood, 103(5), 1949-1954], is withdrawn over cancelled claim 7, maintained over amended, previously presented, and original claims 1-6, 12, 14-15, 17-18, 20-21, 24, 32, 34, 36, 38, 42, 44-46, 48, 50, and 57, and newly applied to new claims 61-63. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended claim 1 to recite a total dose of up to 1.5 Gy of total body irradiation and transplanting both bone marrow and a kidney from a donor to the patient. Applicant amended claims 2 and 3 to also recite transplanting bone marrow and a kidney. Applicant additionally amended independent claim 45 to recite administering a total dose of up to 1.5 Gy of total body irradiation. Further, new claim 61 recites wherein the total dose of TBI is 1.5 Gy.
Regarding the total irradiation dose of up to 1.5 Gy or of specifically 1.5 Gy, as discussed in the prior action, Jiao does not teach wherein the dose of TBI is any of the options listed in amended claim 12, which now range from 0.5 Gy to 1.5 Gy, nor specifically 1.5 Gy as recited in new claim 61.
However, Cippa teaches that they tested different conditioning protocols, wherein recipient mice received 1.5 or 3 Gy total body irradiation (TBI) on day -1 with respect to bone marrow transplantation [column 3 ¶ 4]. Cippa further teaches that the effect of Bcl-2 inhibitors on BM engraftment and tolerance induction was assessed by adding a short course of ABT-737 (50 mg/kg/day, from day -3 to day 12 after BMT) to a reduced conditioning protocol comprising low-dose TBI (1.5 Gy) on the day before BMT [column 4 ¶ 6- column 5 ¶ 1]. Cippa further teaches that the Bcl-2 inhibitor increased the percentage of chimeric mice and induced a higher level of chimerism in all hematopoietic cell lineages, wherein all chimeric animals accepted donor-type skin grafts for more than 100 days and promptly rejected third-party grafts [column 5 ¶ 1, Figure 1A]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a low dose TBI of 1.5 Gy in a method of inducing hematopoietic chimerism combined with administration of a Bcl-2 inhibitor to induce higher levels of chimerism.
Regarding the co-transplantation of bone marrow and kidneys, as discussed in the prior action, Jiao does not teach that the method for inducing hematopoietic chimerism in a patient in need thereof further comprises transplanting a kidney from a donor to the patient.
However, Cippa was cited for teaching a combination of Bcl1-2 inhibition, bone marrow transplantation, and transplantation of an organ (e.g., skin) [abstract, column 3 ¶ 4-column 4 ¶ 2, column 5 ¶ 1]. Cippa teaches that all chimeric animals accepted donor-type skin grafts for more than 100 days [column 5 ¶ 1]. Cippa additionally teaches that Bcl-2 inhibition is a novel option to induce donor-specific tolerance in the context of mixed chimerism protocols, that Bcl-2 inhibition promotes tolerance by supporting the deletion of donor reactive T cells in combination with costimulation blockade, and that by targeting the intrinsic apoptosis pathway, their protocol achieves complete deletion of donor-reactive T cells with a minimal toxicity and induces robust systemic tolerance without myelosuppression [column 3 ¶ 2]. Cippa also teaches that a short conditioning protocol with the Bcl-2 inhibitor ABT-737 in combination with costimulation blockade and low-dose cyclosporine A (CsA) resulted in a complete deletion of peripheral donor-reactive lymphocytes and was sufficient to induce mixed chimerism and robust systemic tolerance across full major histocompatibility complex barriers, without myelosuppression, and by using moderate doses of bone marrow cells [abstract]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to combine a method for inducing hematopoietic chimerism in a patient with a step of transplanting a donor organ, such that the hematopoietic chimerism induces tolerance of the donor organ in the patient.
Further, Husky teaches that chronic kidney disease is common in patients with multiple myeloma (MM), and that recent literature has suggested that certain patients with MM can successfully undergo renal transplantation after stem transplantation [abstract]. Husky also teaches that one strategy includes non-marrow ablative therapy with the transplant of HLA identical stem cell and kidney transplant from the same donor for patients with end stage renal disease (ESRD) and MM [column 5 ¶ 3- column 6 ¶ 1], and that 9 of 16 patients treated with this protocol achieved complete remission and 10 achieved operational tolerance allowing for the complete withdrawal of immunosuppression [column 6 ¶ 1, Table 2]. Additionally, Husky teaches that individuals who achieved tolerance after HSCT and kidney transplant had better renal function compared to standard living donor transplantation over a period of 250 patient years with no episodes of allograft loss [column 6 ¶ 1]. Husky further teaches that another strategy is to treat with chemotherapy and stem cell transplant (SCT) to obtain remission of MM followed by kidney transplantation [column 6 ¶ 2, Table 3], and that of 14 patients with monoclonal Ig kidney deposition disease (MIDD) treated with the strategy of SCT followed by kidney transplantation, one had a relapse of MIDD, 2 had a partial response, and 11 appear to have obtained complete response of the MM [column 7 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to combine a method of inducing hematopoietic chimerism (including transplanting bone morrow from a donor) with a method of transplanting a kidney to address to replace a damaged kidney and promote tolerance for the transplanted donor kidney.
Accordingly, the amendments to the claims and the limitations of new claim 61 were addressed in the prior action.
Applicant additionally added new claims 62-63, which depend on independent claims 2-3, respectively, and recite wherein the method does not comprise administering TBI.
Although Jiao does not teach a method lacking TBI administration, Ito was cited for teaching local thymic irradiation at a dose of 7 Gy prior to bone marrow transplantation for induction of allograft tolerance, such that local thymic irradiation facilitates systemic repopulation by donor marrow cells and enhances donor pluripotent hematopoietic stem cell engraftment [title, column 2 ¶ 3, column 4 ¶ 1]. Ito also teaches inducing hematopoietic chimerism in the absence of TBI, such that the level of donor repopulation of all hematopoietic lineages increased in all hematopoietic tissues when 7 Gy of thymic irradiation was given, and that both early and late after BMT, the level of donor chimerism and number of PHSCs were higher in nonirradiated bones of mice that received local irradiation at the time of original transplantation than in the bones of animals that had received no irradiation [column 6 ¶ 1-2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to administer thymic irradiation in the absence of TBI in a method to induce hematopoietic chimerism to achieve increased levels of donor chimerism. As such, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to perform the methods of claims 2 or 3, as taught by Jiao, Cippa, Husky, and Ito, in the absence of TBI.
Accordingly, Applicant’s amendments to the claims do not overcome a finding of obviousness under 35 USC 103 over Jiao, Cippa, Husky, and Ito.
Applicant argues that none of the cited references discloses or suggests a method for inducing hematopoietic chimerism in a kidney transplant recipient such that one skilled in the art would have no expectation that administering such a low dose of TBI along with administering an inhibitor of Mcl-1 and/or an inhibitor of Bcl-2 was sufficient to support bone marrow transplantation, specifically that:
Jiao is only concerned with a method for inducing hematopoietic chimerism in allo-bone marrow transplantation for patients with acute myeloid leukemia;
Cippa at most suggests method for inducing hematopoietic chimerism in a skin transplant;
Ito is only concerned with a method for pluripotent hematopoietic stem cell engraftment and shows no teaching on a method for kidney transplantation; and
Huskey is concerned with kidney transplantation for multiple myeloma, but shows no teaching on a method for inducing hematopoietic chimerism.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, note that the claims as recited do not require that the method steps claimed are sufficient to support bone marrow transplantation beyond an initial inducing of hematopoietic chimerism within the patient, such that no maintenance of the chimerism or sustained allograft tolerance is required by the claims as written.
Additionally, note that Jiao was not cited for teaching every limitation of the claimed invention. As discussed in the prior action, Jiao was cited for teaching a method for inducing hematopoietic chimerism in a patient in need thereof [column 13 ¶ 2], wherein the method comprises administering an inhibitor of an anti-apoptotic Bcl-2 family member (e.g., the BCL-2 inhibitor ABT-199/venetoclax) to the patient [column 5 ¶ 3, column 6 ¶ 2, column 13 ¶ 2]; and transplanting bone marrow from a donor to the patient [column 5 ¶ 3, column 13 ¶ 2]; such that hematopoietic chimerism is induced in the patient [column 13 ¶ 2]. Jiao was not relied on for teaching the specific doses of TBI nor the combination of bone marrow and kidney transplantation.
However, Cippa was cited for teaching that the effect of Bcl-2 inhibitors on BM engraftment and tolerance induction was assessed by adding a short course of ABT-737 (50 mg/kg/day, from day -3 to day 12 after BMT) to a reduced conditioning protocol comprising low-dose TBI (1.5 Gy) on the day before BMT [column 4 ¶ 6- column 5 ¶ 1]. Cippa further teaches that the Bcl-2 inhibitor increased the percentage of chimeric mice and induced a higher level of chimerism in all hematopoietic cell lineages, wherein all chimeric animals accepted donor-type skin grafts for more than 100 days and promptly rejected third-party grafts [column 5 ¶ 1, Figure 1A]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a low dose TBI of 1.5 Gy combined with administration of a Bcl-2 inhibitor to induce higher levels of chimerism in a method comprising the transplantation of both bone marrow and an organ.
Further, Husky was cited for teaching the combined transplantation of bone marrow-derived stem cells and a kidney. Husky specifically teaches that one strategy includes non-marrow ablative therapy with the transplant of HLA identical stem cell and kidney transplant from the same donor for patients with end stage renal disease (ESRD) and MM [column 5 ¶ 3- column 6 ¶ 1], and that 9 of 16 patients treated with this protocol achieved complete remission and 10 achieved operational tolerance allowing for the complete withdrawal of immunosuppression, such that those who achieved tolerance had better renal function compared to standard living donor transplantation over a period of 250 patient years with no episodes of allograft loss [column 6 ¶ 1, Table 2], thereby teaching the combination of HSC cell transplant with a kidney transplant promotes immune tolerance of the grafted kidney. Further, the method of Husky teaches the induction of hematopoietic chimerism in that patients received an allogenic HSC transplant in a non-marrow ablative therapy, teaching that the patient had both endogenous hematopoietic cells and allogenic HSCs and cells derived therefrom. Therefore, Husky teaches the motivation to combine a method of promoting immune tolerance through transplantation of bone marrow cells (e.g., HSCs) and a kidney to promote immune tolerance and graft survival.
Accordingly, the combined teachings of Jiao, Cippa, Husky, and Ito provide the teachings and motivation to combine a bone marrow transplantation (which comprises HSCs) with a kidney transplantation to promote immune tolerance and graft survival.
Regarding the low dose TBI, Cippa teaches that they tested different conditioning protocols, wherein recipient mice received 1.5 or 3 Gy total body irradiation (TBI) on day -1 with respect to bone marrow transplantation [column 3 ¶ 4]. Cippa further teaches that the effect of Bcl-2 inhibitors on BM engraftment and tolerance induction was assessed by adding a short course of ABT-737 (50 mg/kg/day, from day -3 to day 12 after BMT) to a reduced conditioning protocol comprising low-dose TBI (1.5 Gy) on the day before BMT [column 4 ¶ 6- column 5 ¶ 1]. Cippa further teaches that the Bcl-2 inhibitor increased the percentage of chimeric mice and induced a higher level of chimerism in all hematopoietic cell lineages, wherein all chimeric animals accepted donor-type skin grafts for more than 100 days and promptly rejected third-party grafts [column 5 ¶ 1, Figure 1A].
Ito also teaches that a dose of 1.5 to 3 Gy if TBI had previously been shown to be required to reliably permit PHSC engraftment [column 8 ¶ 1].
As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a low dose TBI of 1.5 Gy in a method of inducing hematopoietic chimerism combined with administration of a Bcl-2 inhibitor to induce higher levels of chimerism.
Therefore, the combined teachings of Jiao, Cippa, Husky, and Ito provide the teachings and motivation to use a low dose TBI of 1.5 Gy in a such a method.
As such, Applicant’s arguments do not overcome a finding of obviousness over Jiao, Cippa, Husky, and Ito under 35 USC 103, and the rejection is maintained.
The rejection of amended and previously presented claims 29-30 under 35 U.S.C. 103 as being unpatentable over Jiao et al. [2019, Cell Death & Differentiation, 26, 1516-1530, published online 12 November 2018]; in view of Cippa et al. [2013, Blood, 122(9), 1669-1677]; Husky et al. [2018, Transplantation, 102, 1994-2001]; and Ito et al. [2004, Blood, 103(5), 1949-1954]; as applied to claim(s) 1 above, and further in view of Oura et al. [2018, Transplantation, 10(7S), abstract: 503.5, published online July 2018], is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
As discussed above, Jiao, Cippa, Husky, and Ito teach all of the limitations of claim 1.
Claim 29 has been amended to clarify that the inhibitor of an anti-apoptotic Bcl-2 family member is what is administered at the recited doses, which is consistent with Examiner’s interpretation of the claim in the prior action. As such, the amendment to claim 29 does not add any new limitations nor further narrow the claims sufficiently to overcome the rejection of record.
Additionally, Applicant has provided no arguments for this rejection beyond those addressed above for the base reference. As such, Applicant’s arguments do not overcome a finding of obviousness over Jiao, Cippa, Husky, Ito, and Oura under 35 USC 103, and the rejection is maintained.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634