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 .
Status of Claims
Claims 1-18, 20 and 21 are pending
Claims 1-18, 20 and 21 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 09/13/2022 based on the provisional application 63/406,082 (filed 09/13/2022).
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 appears to have a typographical error where the word “is” is missing in line 3 in the phrase “each dose of TBI between about 15 and about 75 cGy”. The claim should be amended to recite “each dose of TBI is between about 15 and about 75 cGy”.
Claim 1 appears to have a second typographical error where the word “and” is missing in line 4 before the phrase “infusing the recipient with a donor-derived hematopoietic stem cell product”. The claim should be amended to recite “and infusing the recipient with a donor-derived hematopoietic stem cell product”.
Appropriate correction is required.
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.
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.
Claim(s) 1-18, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Lowsky et al. (WO2022072320A1 Date Published 2022-04-07) in view of Ikehara et al. (US6383481B1 Date Published 2002-05-07).
Lowsky et al. teaches compositions and methods for the achievement of organ and tissue transplantation and autoimmune tolerance using the infusion of living and/or deceased donor hematopoietic cells (Abstract). They teach a method for achieving immune tolerance in a recipient, the method comprising: conditioning the recipient with a plurality of total lymphoid irradiation (TLI) doses, and a single dose of very low total body irradiation (svIdTBI) of from 40 to 140 cGy; infusing the recipient with a donor, in vitro engineered, hematopoietic stem cell product; wherein the recipient achieves stable, high level mixed-chimerism with the donor hematopoietic cells (claim 1).
Lowsky et al. teaches a novel method of recipient conditioning wherein TLI is fractionated over a plurality of doses, e.g. at least about 5, 6, 7, 8, 9, 10 or more doses administered, and combined with a single, very low dose of total body irradiation (svIdTBI), where said conditioning is referred to as “TLI-svIdTBI” and wherein the svIdTBI is typically the final dose of radiation before transplantation (paragraph [0007]). They teach that the TLI doses can be combined with anti-thymocyte globulin (ATG), to which said protocol is referred to as TLI-svIdTBI-ATG” (paragraph [007]). They also specifically teach a modification and improvement to conventional host conditioning wherein 9 doses of TLI at 80-120 cGy/dose was administered followed by a single very low dose of TBI (svldTBI) at a dose of 40-140 cGy (paragraph [00229]).
Lowsky et al. teaches methods that apply to both HLA-matched and HLA-mismatched transplantation conditions that include the steps of: obtaining a solid organ and hematopoietic cells from a donor; isolating hematopoietic cells of the appropriate type and dose; transplanting the solid organ; performing a conditioning regimen on the recipient following transplantation of the solid organ and prior to infusion of the engineered hematopoietic cells; and monitoring the recipient for mixed chimerism of the hematopoietic system (paragraph [0086]).
Lowsky et al. teaches that the HLA mismatched kidney donor to the recipient undergoes blood apheresis and the obtained cellular product is manipulated to give a unique non-physiologic ratio of CD34+ and CD3+ T cells and in some cases, donor CD8+ T memory cells are also added in a unique non-physiologic ratio to the CD34+, CD3+ T cell product (paragraph [0021]). They teach that the CD34+ enriched product can have a value of from about 4 to about 20 x 106 CD34+ cells/kg recipient weight (paragraph [0011]), and the non-CD34+ cell fraction following a CD34+ enrichment step is used to obtain a defined dose of CD3+ T cells of from about 25 to about 100 x 106 CD3+/kg recipient weight (paragraph [0012]). They also teach enriched populations of donor derived CD8+ memory T cells can be at a dose of 1-12 million cells/kg (equivalent to 1 to 12 x 106 cells/kg; paragraph [00200]).
Lowsky et al. does not specifically teach a method for transplantation wherein the TBI is at least two doses. They do not specifically teach wherein two doses of TBI are provided to the recipient or wherein three or more doses are provided to the recipient. They also do not specifically teach the method wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy.
However, these deficiencies are made up in the teachings of Ikehara et al.
Ikehara et al. teaches a method of transplanting hemopoietic stem cells which comprises subjecting a recipient to a radiation treatment using an effective exposure dose for hemopoietic stem cell transplantation (Abstract). They teach a transplantation method wherein the radiation treatment is carried out by total body irradiation (TBI) using two divided doses, particularly two fractional doses of 500-600 cGy each (Column 2 lines 5-6, Column 3 lines 51-52 and Column 5 lines 33-62).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for a method for transplantation, the method comprising: conditioning a recipient of an organ transplant with a plurality of total lymphoid irradiation (TLI) doses, and a single dose of very low total body irradiation (svIdTBI) of from 40 to 140 cGy; infusing the recipient with a donor-derived hematopoietic stem cell product; wherein the recipient achieves stable, high level mixed-chimerism with the donor hematopoietic cells as taught by Lowsky et al. and substituting the single dose of TBI of from 40 to 140 cGy taught by Lowsky et al. with two doses of TBI as taught by Ikehara et al. because Ikehara et al. teaches that graft failure or rejection of donor cells can be avoided with said hemopoietic stem cells transplant method comprising two doses of TBI, thereby maintaining the transplant in satisfactory condition (Column 2 lines 5-6 and Abstract) and Lowsky et al. teaches that the combination of low dose TBI and TLI-ATG induces recipient immune cell depletion by specifically targeting non-lymphoid-tissue memory immune cells which does not induce toxicities such as marrow hypoaplasia with severe cytopenias, mucositis, and other Gl toxicities, thus resulting in improved rates of persistent mixed donor hematopoietic cell chimerism and avoids risks of graft-versus-host disease (GVHD) (paragraphs [0008] and [0078]). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding claims 1-3, wherein the method comprises at least two doses of TBI, each dose of TBI is between about 15 and about 75 cGy, since Lowsky et al. teaches a single very low dose of TBI from 40 to 140 cGy and Ikehara et al. teaches TBI administration that is fractionated in two doses, it would be conventional and routine for one to perform a combined method comprising administering a TBI in two fractionated doses as taught by Ikehara et al. at doses of 40 to 140 cGy as taught by Lowsky et al. and at various doses and at various dosing frequencies to a recipient, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, it is noted that the TBI dose taught by Lowsky et al. of 40 cGy could be administered as two separate doses each of 20 cGy, or the dose of 140 cGy could be administered as two separate doses each of 70 cGy, which would meet the limitations of instant claims 1 and 2, such that “the method comprises two doses of TBI, each dose of TBI is between about 15 and about 75 cGy” are fulfilled. In addition, given the known TBI doses and dosing frequencies taught by Lowsky et al. and Ikehara et al., it is well within the level of the ordinary skilled artisan to adjust the dosages of administration for optimal therapeutic efficacy and safety, and to arrive at the doses of administration as instantly claimed, wherein the at least two doses of TBI (instant claims 1 and 2), or wherein the three or more doses of TBI (instant claim 3), is expected to provide an optimal method for transplantation. Further, varying dose amounts and dosage frequencies or schedules of the TBI of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered TBI and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding claim 5, the method wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, Lowsky et al. teaches 9 doses of TLI at 80-120 cGy/dose (paragraph [00229]) which is a total dose of 720 to 1080 cGy which is just outside the total dose recited in the instant claims. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. See Titanium Metals Corp. of Amer.v.Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In addition, Lowsky et al. teaches that the TLI can be fractionated over a plurality of doses including 10 or more doses (paragraph [0007]), which potentially can be a total dose of at least 1200 cGy (when the TLI is 120 cGy/dose x 10 doses), thus meeting the limitation of instant claim 5. Further, it would be conventional and routine for one to perform a combined method wherein the plurality of TLI doses comprise a total dose as encompassed by the claim, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Even further, varying TLI total doses of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying doses of the administered irradiation and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding claim 14, the method wherein the hematopoietic cellular product comprises at least 1 x 105 CD34+ cells/kg recipient weight and at least 1x105 CD3+ cells/kg recipient weight; and claim 15, the method wherein the hematopoietic cellular product comprises at least 1 x 106 CD34+ cells/kg recipient weight and at least 1 x 106 CD3+ cells/kg recipient weight, since Lowsky et al. teaches CD34+ enriched product comprising from about 4 to about 20 x 106 CD34+ cells/kg recipient weight (paragraph [0011]), and CD3+ T cells comprising from about 25 to about 100 x 106 CD3+/kg recipient weight (paragraph [0012]), it would be conventional and routine for one to perform a combined method of infusing the recipient with hematopoietic stem cell product comprising CD34+ and CD3+ cells at various doses, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, given the known CD34+ and CD3+ cells/kg recipient weight taught by Lowsky et al., it is well within the level of the ordinary skilled artisan to adjust the dosages of administration for optimal therapeutic efficacy and safety, and to arrive at the doses of administration as instantly claimed. Further, varying dose amounts of the CD34+ and CD3+ cells of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered irradiation and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
First NSDP: U.S. Patent No. 11819521 B2
Claims 1-18, 20, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 8, 9, 14 and 15 of U.S. Patent No. 11819521 B2 in view of Lowsky et al. (WO2022072320A1 Date Published 2022-04-07) and Ikehara et al. (US6383481B1 Date Published 2002-05-07).
The patented claims are drawn in part to a method for establishing mixed chimerism in a recipient of a solid organ transplant from a subject, the method comprising administering at least one cellular product for establishing mixed chimerism to a recipient of a solid organ transplant after the recipient has already undergone a solid organ transplant procedure, wherein the at least one cellular product comprises CD34+ cells and CD3+ cells, and wherein the at least one cellular product comprises:
greater than 5×105 CD34+ cells/kg recipient weight; and
greater than 1×105 CD3+ cells/kg recipient weight.
Patented claims do not specifically recite a method for transplantation, wherein stable, high level mixed-chimerism with donor hematopoietic cells is achieved, the method comprising: conditioning a recipient of an organ transplant with a plurality of total lymphoid irradiation (TLI) doses, and at least two doses of total body irradiation (TBI), each dose of TBI is between about 15 and about 75 cGy; infusing the recipient with a donor-derived hematopoietic stem cell product. Patented claims also do not specifically recite the method, wherein two doses of TBI are provided to the recipient, or wherein three or more doses of TBI are provided to the recipient, or wherein the plurality of TLI doses consists of between 1and 11 doses, or wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, or wherein each individual TLI dose comprises a dose of between about 130 cGy and about 150 cGy.
Patented claims further do not specifically recite the method further comprising administering one or more doses of anti-thymocyte globulin (ATG) to the recipient or wherein a final dose of irradiation is one or more of the TBI doses, or wherein the donor donates the solid organ, or wherein the hematopoietic cellular product further comprises at least 1x106 CD8+ memory T cells, or wherein the donor is deceased.
However, these deficiencies are made up in the teachings of Lowsky et al and Ikehara et al. The teachings of Lowsky et al and Ikehara et al. are as discussed above in the 103 rejection.
Therefore, it would be obvious to perform a combined method for a method for transplantation, the method comprising administering at least one cellular product to a recipient of a solid organ transplant after the recipient has already undergone a solid organ transplant procedure, wherein the at least one cellular product comprises CD34+ cells and CD3+ cells, and wherein the at least one cellular product comprises: greater than 5×105 CD34+ cells/kg recipient weight; and greater than 1×105 CD3+ cells/kg recipient weight as recited by the patent and in combination with the plurality of TLI doses and single TBI dose as taught by Lowsky et al., wherein the TBI dose is substituted by the two doses of TBI as taught by Ikehara et al., the final dose of irradiation is one or more of TBI doses as taught by Lowsky et al., the method further comprising anti-thymocyte globulin as taught by Lowsky et al., the donor donates the solid organ and is deceased as taught by Lowsky et al., and the method further comprises CD8+ memory T cells comprising at least 1 x 106 CD8+ memory T cells/kg recipient weight as taught by Lowsky et al., because Lowsky et al. teaches that the combination of low dose TBI and TLI-ATG induces recipient immune cell depletion by specifically targeting non-lymphoid-tissue memory immune cells which does not induce toxicities such as marrow hypoaplasia with severe cytopenias, mucositis, and other Gl toxicities, thus resulting in improved rates of persistent mixed donor hematopoietic cell chimerism and avoids risks of graft-versus-host disease (GVHD) (paragraph [0008]), and Ikehara et al. teaches that graft failure or rejection of donor cells can be avoided with a transplant method comprising two doses of TBI, thereby maintaining the transplant in satisfactory condition (Column 2 lines 5-6 and Abstract).
Regarding instant claims 1-3, wherein the method comprises at least two doses of TBI, each dose of TBI is between about 15 and about 75 cGy, since Lowsky et al. teaches a single very low dose of TBI from 40 to 140 cGy and Ikehara et al. teaches TBI administration that is fractionated in two doses, it would be conventional and routine for one to perform a combined method comprising administering a TBI in two fractionated doses as taught by Ikehara et al. at doses of 40 to 140 cGy as taught by Lowsky et al. and at various doses and at various dosing frequencies to a recipient, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, it is noted that the TBI dose taught by Lowsky et al. of 40 cGy could be administered as two separate doses each of 20 cGy, or the dose of 140 cGy could be administered as two separate doses each of 70 cGy, which would meet the limitations of instant claims 1 and 2, such that “the method comprises two doses of TBI, each dose of TBI is between about 15 and about 75 cGy” are fulfilled. In addition, given the known TBI doses and dosing frequencies taught by Lowsky et al. and Ikehara et al., it is well within the level of the ordinary skilled artisan to adjust the dosages of administration for optimal therapeutic efficacy and safety, and to arrive at the doses of administration as instantly claimed, wherein the at least two doses of TBI (instant claims 1 and 2), or wherein the three or more doses of TBI (instant claim 3), is expected to provide an optimal method for transplantation. Further, varying dose amounts and dosage frequencies or schedules of the TBI of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered TBI and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding instant claim 5, the method wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, Lowsky et al. teaches 9 doses of TLI at 80-120 cGy/dose (paragraph [00229]) which is a total dose of 720 to 1080 cGy which is just outside the total dose recited in the instant claims. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. See Titanium Metals Corp. of Amer.v.Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In addition, Lowsky et al. teaches that the TLI can be fractionated over a plurality of doses including 10 or more doses (paragraph [0007]), which potentially can be a total dose of at least 1200 cGy (when the TLI is 120 cGy/dose x 10 doses), thus meeting the limitation of instant claim 5. Further, it would be conventional and routine for one to perform a combined method wherein the plurality of TLI doses comprise a total dose as encompassed by the claim, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Even further, varying TLI total doses of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying doses of the administered irradiation and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Second NSDP: Copending Application No. 18/378,963
Claims 1-18, 20, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 and 16 of copending Application No. 18/378,963 in view of Lowsky et al. (WO2022072320A1 Date Published 2022-04-07) and Ikehara et al. (US6383481B1 Date Published 2002-05-07).
The copending claims are drawn to a method for establishing mixed chimerism in a solid organ transplant recipient, the method comprising providing to a subject that has received a solid organ transplant a product comprising: greater than 5×105 CD34+ cells/kg recipient weight derived from bone marrow of a deceased donor; and greater than 1×105 CD3+ cells/kg recipient weight derived from bone marrow of a deceased donor (claim 1). Copending claims are also drawn to the method wherein the CD34+ cells and the CD3+ cells are HLA-mismatched to the solid organ transplant recipient.
Copending claims do not specifically recite a method for transplantation, wherein stable, high level mixed-chimerism with donor hematopoietic cells is achieved, the method comprising: conditioning a recipient of an organ transplant with a plurality of total lymphoid irradiation (TLI) doses, and at least two doses of total body irradiation (TBI), each dose of TBI is between about 15 and about 75 cGy; infusing the recipient with a donor-derived hematopoietic stem cell product. Copending claims also do not specifically recite the method, wherein two doses of TBI are provided to the recipient, or wherein three or more doses of TBI are provided to the recipient, or wherein the plurality of TLI doses consists of between 1and 11 doses, or wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, or wherein each individual TLI dose comprises a dose of between about 130 cGy and about 150 cGy.
Copending claims further do not specifically recite the method further comprising administering one or more doses of anti-thymocyte globulin (ATG) to the recipient or wherein a final dose of irradiation is one or more of the TBI doses, or wherein the donor donates the solid organ, or wherein the hematopoietic cellular product further comprises at least 1x106 CD8+ memory T cells.
However, these deficiencies are made up in the teachings of Lowsky et al and Ikehara et al. The teachings of Lowsky et al and Ikehara et al. are as discussed above in the 103 rejection.
Therefore, it would be obvious to perform a combined method for a method for transplantation, the method comprising providing to a subject that has received a solid organ transplant a product comprising: greater than 5×105 CD34+ cells/kg recipient weight derived from bone marrow of a deceased donor; and greater than 1×105 CD3+ cells/kg recipient weight derived from bone marrow of a deceased donor as recited by the copending method and in combination with the plurality of TLI doses and single TBI dose as taught by Lowsky et al., wherein the TBI dose is substitute by the two doses of TBI as taught by Ikehara et al., the final dose of irradiation is one or more of TBI doses as taught by Lowsky et al., the method further comprising anti-thymocyte globulin as taught by Lowsky et al., the donor donates the solid organ and is deceased as taught by Lowsky et al., and the method further comprises CD8+ memory T cells comprising at least 1 x 106 CD8+ memory T cells/kg recipient weight as taught by Lowsky et al., because Lowsky et al. teaches that the combination of low dose TBI and TLI-ATG induces recipient immune cell depletion by specifically targeting non-lymphoid-tissue memory immune cells which does not induce toxicities such as marrow hypoaplasia with severe cytopenias, mucositis, and other Gl toxicities, thus resulting in improved rates of persistent mixed donor hematopoietic cell chimerism and avoids risks of graft-versus-host disease (GVHD) (paragraph [0008]), and Ikehara et al. teaches that graft failure or rejection of donor cells can be avoided with a transplant method comprising two doses of TBI, thereby maintaining the transplant in satisfactory condition (Column 2 lines 5-6 and Abstract).
Regarding instant claims 1-3, wherein the method comprises at least two doses of TBI, each dose of TBI is between about 15 and about 75 cGy, since Lowsky et al. teaches a single very low dose of TBI from 40 to 140 cGy and Ikehara et al. teaches TBI administration that is fractionated in two doses, it would be conventional and routine for one to perform a combined method comprising administering a TBI in two fractionated doses as taught by Ikehara et al. at doses of 40 to 140 cGy as taught by Lowsky et al. and at various doses and at various dosing frequencies to a recipient, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, it is noted that the TBI dose taught by Lowsky et al. of 40 cGy could be administered as two separate doses each of 20 cGy, or the dose of 140 cGy could be administered as two separate doses each of 70 cGy, which would meet the limitations of instant claims 1 and 2, such that “the method comprises two doses of TBI, each dose of TBI is between about 15 and about 75 cGy” are fulfilled. In addition, given the known TBI doses and dosing frequencies taught by Lowsky et al. and Ikehara et al., it is well within the level of the ordinary skilled artisan to adjust the dosages of administration for optimal therapeutic efficacy and safety, and to arrive at the doses of administration as instantly claimed, wherein the at least two doses of TBI (instant claims 1 and 2), or wherein the three or more doses of TBI (instant claim 3), is expected to provide an optimal method for transplantation. Further, varying dose amounts and dosage frequencies or schedules of the TBI of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered TBI and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding instant claim 5, the method wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, Lowsky et al. teaches 9 doses of TLI at 80-120 cGy/dose (paragraph [00229]) which is a total dose of 720 to 1080 cGy which is just outside the total dose recited in the instant claims. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. See Titanium Metals Corp. of Amer.v.Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In addition, Lowsky et al. teaches that the TLI can be fractionated over a plurality of doses including 10 or more doses (paragraph [0007]), which potentially can be a total dose of at least 1200 cGy (when the TLI is 120 cGy/dose x 10 doses), thus meeting the limitation of instant claim 5. Further, it would be conventional and routine for one to perform a combined method wherein the plurality of TLI doses comprise a total dose as encompassed by the claim, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Even further, varying TLI total doses of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying doses of the administered irradiation and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Third NSDP: Copending Application No. 18/381,418
Claims 1-18, 20, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 19 and 21 of copending Application No. 18/381,418 in view of Lowsky et al. (WO2022072320A1 Date Published 2022-04-07) and Ikehara et al. (US6383481B1 Date Published 2002-05-07).
The copending claims are drawn in part to a method for establishing mixed chimerism in a recipient of a solid organ transplant from a donor, the method comprising administering a cellular product for establishing mixed chimerism to a recipient of a solid organ transplant after the recipient has already undergone a solid organ transplant procedure (claim 18), wherein the cellular product comprises: greater than 5×105 CD34+ cells/kg recipient weight; and greater than 1×105 CD3+ cells/kg recipient weight (claim 19), and wherein the solid organ is a kidney (claim 21).
Copending claims do not specifically recite a method for transplantation, wherein stable, high level mixed-chimerism with donor hematopoietic cells is achieved, the method comprising: conditioning a recipient of an organ transplant with a plurality of total lymphoid irradiation (TLI) doses, and at least two doses of total body irradiation (TBI), each dose of TBI is between about 15 and about 75 cGy; infusing the recipient with a donor-derived hematopoietic stem cell product. Patented claims also do not specifically recite the method, wherein two doses of TBI are provided to the recipient, or wherein three or more doses of TBI are provided to the recipient, or wherein the plurality of TLI doses consists of between 1and 11 doses, or wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, or wherein each individual TLI dose comprises a dose of between about 130 cGy and about 150 cGy, or wherein the donor and recipient are MHC- mismatched.
Copending claims further do not specifically recite the method further comprising administering one or more doses of anti-thymocyte globulin (ATG) to the recipient or wherein a final dose of irradiation is one or more of the TBI doses, or wherein the donor donates the solid organ, or wherein the hematopoietic cellular product further comprises at least 1x106 CD8+ memory T cells, or wherein the donor is deceased.
However, these deficiencies are made up in the teachings of Lowsky et al and Ikehara et al. The teachings of Lowsky et al and Ikehara et al. are as discussed above in the 103 rejection.
Therefore, it would be obvious to perform a combined method for a method for transplantation, the method comprising administering a cellular product comprising greater than 5×105 CD34+ cells/kg recipient weight; and greater than 1×105 CD3+ cells/kg recipient weight for establishing mixed chimerism to a recipient of a solid organ transplant after the recipient has already undergone a solid organ transplant procedure as recited by copending method and in combination with the plurality of TLI doses and single TBI dose as taught by Lowsky et al., wherein the TBI dose is substitute by the two doses of TBI as taught by Ikehara et al., the final dose of irradiation is one or more of TBI doses as taught by Lowsky et al., the method further comprising anti-thymocyte globulin as taught by Lowsky et al., the donor donates the solid organ and is deceased as taught by Lowsky et al., and the method further comprises CD8+ memory T cells comprising at least 1 x 106 CD8+ memory T cells/kg recipient weight as taught by Lowsky et al., because Lowsky et al. teaches that the combination of low dose TBI and TLI-ATG induces recipient immune cell depletion by specifically targeting non-lymphoid-tissue memory immune cells which does not induce toxicities such as marrow hypoaplasia with severe cytopenias, mucositis, and other Gl toxicities, thus resulting in improved rates of persistent mixed donor hematopoietic cell chimerism and avoids risks of graft-versus-host disease (GVHD) (paragraph [0008]), and Ikehara et al. teaches that graft failure or rejection of donor cells can be avoided with a transplant method comprising two doses of TBI, thereby maintaining the transplant in satisfactory condition (Column 2 lines 5-6 and Abstract).
Regarding instant claims 1-3, wherein the method comprises at least two doses of TBI, each dose of TBI is between about 15 and about 75 cGy, since Lowsky et al. teaches a single very low dose of TBI from 40 to 140 cGy and Ikehara et al. teaches TBI administration that is fractionated in two doses, it would be conventional and routine for one to perform a combined method comprising administering a TBI in two fractionated doses as taught by Ikehara et al. at doses of 40 to 140 cGy as taught by Lowsky et al. and at various doses and at various dosing frequencies to a recipient, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” In the instant case, it is noted that the TBI dose taught by Lowsky et al. of 40 cGy could be administered as two separate doses each of 20 cGy, or the dose of 140 cGy could be administered as two separate doses each of 70 cGy, which would meet the limitations of instant claims 1 and 2, such that “the method comprises two doses of TBI, each dose of TBI is between about 15 and about 75 cGy” are fulfilled. In addition, given the known TBI doses and dosing frequencies taught by Lowsky et al. and Ikehara et al., it is well within the level of the ordinary skilled artisan to adjust the dosages of administration for optimal therapeutic efficacy and safety, and to arrive at the doses of administration as instantly claimed, wherein the at least two doses of TBI (instant claims 1 and 2), or wherein the three or more doses of TBI (instant claim 3), is expected to provide an optimal method for transplantation. Further, varying dose amounts and dosage frequencies or schedules of the TBI of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered TBI and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Regarding instant claim 5, the method wherein the plurality of TLI doses comprise a total dose of between about 1100 cGy and about 1300 cGy, Lowsky et al. teaches 9 doses of TLI at 80-120 cGy/dose (paragraph [00229]) which is a total dose of 720 to 1080 cGy which is just outside the total dose recited in the instant claims. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. See Titanium Metals Corp. of Amer.v.Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In addition, Lowsky et al. teaches that the TLI can be fractionated over a plurality of doses including 10 or more doses (paragraph [0007]), which potentially can be a total dose of at least 1200 cGy (when the TLI is 120 cGy/dose x 10 doses), thus meeting the limitation of instant claim 5. Further, it would be conventional and routine for one to perform a combined method wherein the plurality of TLI doses comprise a total dose as encompassed by the claim, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Even further, varying TLI total doses of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying doses of the administered irradiation and hematopoietic stem cell products. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642