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 .
DETAILED ACTION
Claims 1-20 are pending and under examination.
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.
Claim(s) 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Strober et al. (US20180221410) in view of Veale et al. (20210189344) and Mathew et al. (Transplantation, Volume 65(7), 15 April 1998, pp 947-955), as evidenced by Kawalk (Biol Blood Marrow Transplant 16: 1388-1401 (2010) (all cited herewith).
Claim 1 of Strober is drawn to “[a] cellular product for establishing mixed chimerism in a solid organ transplant recipient, the product comprising: greater than lxl05 CD34+ cells/kg recipient weight derived from a deceased donor; and greater than 1x105 CD3 + cells/kg recipient weight derived from the deceased donor.”
Claims 3 and 4 specify that the cellular product of claim 1 can have CD34+ and CD3+ cells that are either HLA-matched to the solid organ transplant recipient or are HLA-mismatched to the solid organ transplant recipient.
Claims 5 and 6 specify that the cellular product of claim 1 can comprise the CD34+ and CD3+ cells in separate containers or in a common container.
Claim 8 specifies that the cellular product of claim 1 can comprise a cryopreservation medium, e.g., a polymeric carbohydrate as recited in claim 9. At paragraph 0053, Strober teaches “Hematopoietic cells can be frozen (e.g., cryopreserved) for prolonged periods without damaging a significant number of cells. To cryopreserve HSC, a preservative, DMSO, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic cellular injury during ice crystal formation.”
Claim 10 recites “[t]he cellular product of claim 1, wherein the CD34+ cells and the CD3+ cells are derived from the same donor,” which, by the principal of claim differentiation, would be understood by the ordinarily skilled artisan to imply that the CD34+ cells and the CD3+ cells can also be derived from different deceased donors.
Consistent with claim 10, at paragraph 0120 Strober teaches: “In some cases, specific types of cells may be isolated and purified from the hematopoietic stem cells. In some cases, the cells that may be isolated and purified from the hematopoietic stem cells are CD34+ cells and CD3+ cells. In some cases, the CD34+ and CD3+ cells are isolated from the same fraction of hematopoietic stem cells. In some cases, the CD34+ and CD3+ cells are isolated from a different fraction of hematopoietic stem cells. In some cases, the CD34+ cells are progenitor cells. In some cases, the CD3+ cells are T cells.”
Claims 11 and dependent claims thereof of Strober is drawn to “[a] method for manufacturing a cellular product for establishing mixed chimerism in a solid organ transplant recipient, the method comprising: receiving a sample comprising CD34+ cells and CD3+ cells from a deceased organ transplant donor; purifying a first portion of the sample to obtain an enriched amount of CD34+ cells; and retaining a second portion of the sample comprising CD3+ cells, thereby manufacturing the cellular product.”
Paragraph 0005-0010 summarize how said cellular products of Strober can be used to promote tolerance of a tissue allograft in an HLA-mismatched subject, e.g., in a recipient of a kidney allograft:
“[0005] Generally transplant recipients will take immunosuppressive anti-rejection drugs for as long as the transplanted kidney functions. Even for a mixture of widely used immunosuppressives the cost can be high.
[0006] Preclinical studies have shown that conditioning with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) is advantageous for inducing tolerance after combined organ and bone marrow transplantation because the conditioning regimen prevents graft versus host disease (GVHD) as compared to total body irradiation (TBI). For a review, see Strober et al. (2011) Seminars in Immunology 23:273-281.
[0007] It is therefore of great clinical interest to develop therapeutic regimens that achieve tolerance and complete withdrawal of immunosuppressive drugs in adult transplant patients and without induction of GVHD.
[0008] Methods and compositions are provided herein for the combined transplantation of a solid organ and hematopoietic cells to a recipient, where tolerance to the graft is established through development of a stable mixed chimera. Preferably, the solid organ is a kidney. An individual with stable mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.
[0009] Disclosed herein are methods for organ transplantation. The methods provided herein describe, in some cases, following transplantation of an HLA-matched or HLA-mismatched solid organ, administration of donor-derived hematopoietic stem cells to a recipient. In some cases, the donor-derived hematopoietic stem cells may be prepared to be at least 70% pure prior to formulation as an engineered hematopoietic cell composition.
[0010] In some cases, a method for transplantation of an HLA-mismatched solid organ from a donor comprising implanting the HLA-mismatched solid human organ from the donor in a recipient human body, treating the recipient with non-myeloablative conditioning, infusing the recipient with an engineered hematopoietic cell composition comprising at least 1×106 CD34+ cells/kg and at least 1.0×107 CD3+ cells/kg, and maintaining the recipient on an immunosuppressive regimen for a period of time sufficient to develop mixed chimerism for at least six months is disclosed.”
At paragraph 0092, Strober teaches “…In cases of a deceased donor, hematopoietic cells may be
obtained from bone marrow. For example, the cells may be obtained from the bone marrow in vertebrae, pelvic bone…”
At paragraphs 0088-0092, Strober describes the combination of transplantation of a solid organ from a deceased donor with hematopoietic stem cell transplantation from a deceased donor.
At paragraphs 0014, 0032 and 0126-0129, Strober teaches the isolation of CD3+ T-cells from apheresis product.
However, Strober does not explicitly teach a cellular product for establishing mixed chimerism in a solid organ transplant recipient, the product comprising: greater than lxl05 CD34+ cells/kg recipient weight derived from bone marrow of a deceased donor; and greater than lxl05 CD3+ cells/kg recipient weight derived from non-bone marrow of the deceased donor.
Likwewise, Strober does not explicitly teach a method for establishing mixed chimerism in a solid organ transplant recipient, the method comprising providing to a subject that has received or will receive a solid organ transplant a product comprising: greater than 1 x 105 CD34+ cells/kg recipient weight derived from bone marrow of a deceased donor; and greater than 1 x 105 CD3+ cells/kg recipient weight derived from non-bone marrow of the deceased donor.
Veale teaches methods “…for the mobilization and collection of peripheral blood cells such as HSC's from deceased donors can produce quantities of viable HSC's useful in a multitude of applications without harming the ability to recover the donor's organs for transplantation…. In these methods, cells collected from the peripheral blood can include, but are not limited to,
CD34+ stem/progenitor cells, mesenchymal stem cells, CD133+ stem/progenitor cells, CD3+ pan T cells…. Embodiments of the invention can further comprise isolating one or more subsets of cell types from the apheresis product such as CD34+ cells, T cells (e.g. CD3+)….” (see paragraphs 0008-0010, emphasis added).
With respect to the steps taken to perform their method, paragraph 0010 of Veale further teaches one embodiment that includes “…the collection of HSC's from the donor's bone marrow after apheresis by aspirating bone marrow from a donor hip bone(s) and/or vertebrae into a syringe. Certain embodiments of the invention are combined with other medical procedures, for example removing an organ ( e.g. a kidney, liver, heart, lung or vascularized composite allograft) from the donor for transplantation into a recipient patient.” (emphasis added). Similar teachings also appear at paragraph 0033.
The teachings of Veale described above are further summarized in claims 1, 7 and 11.
Mathew teaches cadaver donor bone marrow cells (DBMC) differ from donor peripheral blood cells isolated from donor spleen.
For example, at page 14, 1st paragraph, Mathew teaches:
“…human cadaver DBMC proliferated in response to mitogens and in MLC (Table 3)
but with stimulation indices significantly lower than comparable numbers of PBL or spleen cells…”
“The number of CD3 molecules were significantly lower on the T cells in the DBMC than in the peripheral blood and may, therefore, have been unable to transduce adequate activation signals for an optimal alloreactive response.”
“…vertebral DBMC… T cells consisted of predominantly nonclassical, alternative, or “intermediate type” CD3 dimly staining T cells (Table 2).”
Given the reference teachings it would have been obvious to the ordinarily skilled artisan contemplating the preparation of a cellular product for establishing mixed chimerism in a solid organ transplant recipient that (i) CD34+ HSCs can be obtained from the deceased donor bone marrow as taught by both Strober and Veale, and (ii) CD3+ T cells can be obtained from the deceased donor blood using the methods taught by Veale. One reason the skilled artisan would have been motivated to combine HSCs obtained from the deceased donor bone marrow as taught by both Strober and Veale, with CD3+ T cells obtained from the deceased donor blood as taught be Veale, was because as taught by Mathew, cadaveric donor DBMC were known to have a number of differences relative to cadaveric peripheral blood T-cells, e.g., diminished CD3 expression and diminished ability to be stimulated by mitogens or MLC, that would be expected by the ordinarily skilled artisan to compromise their ability to mediate the “graft-versus-malignancy effect” by Kawalk at page 1389, left col., 2nd full paragraph.
Moreover, given the teachings of Strober that the combined transplantation of a solid organ, e.g., a kidney, and hematopoietic cells to a recipient (where tolerance to the graft is established through development of a stable mixed chimera) allows the solid organ recipient to withdraw from the use of immunosuppressive drugs, the skilled artisan would have been motivated use said obvious cellular product comprising (i) CD34+ HSCs obtained from the deceased donor bone marrow as taught by both Strober and Veale, and (ii) CD3+ T cells obtained from the deceased donor blood using the methods taught by Veale to inhibit and/or prevent, e.g., donor kidney rejection.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11813376 (cited herewith). Although the claims at issue are not identical, they are not patentably distinct from each other because the cellular product for establishing mixed chimerism in a solid organ transplant recipient of reference claims 1-11 anticipate instant claims 1-10.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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