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 .
Election/Restrictions
Applicant’s election without traverse of the invention of group I, drawn to a method of inducing immune cell tolerance in a transplant recipient comprising administering to the recipient an anti-CD154 antibody, hematopoietic stem cells, and a donor organ, in the reply filed on 05/05/2026 is acknowledged.
Applicant further elects a) central tolerance, b) T cell depleting antibodies particularly anti-CD20 antibodies, c) human recipient, d) xenogenic transplant, and d) an Fc species of SEQ ID NO: 23 or 42.
Upon further consideration, the species election requirement for the Fc region/heavy chain constant domain/heavy chain of the anti-CD154 antibody is withdrawn. The Fc region of SEQ ID NOs: 23 or 42; the heavy chain constant domain of SEQ ID NO: 95 or 109; the heavy chain of SEQ ID NO: 151 or 165 are examined on the merits in the present office action.
Claims 4, 5, 53, 54, 56-59, and 63-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/05/2026.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The nature of the invention relates to methods of inducing immune tolerance during transplantation by administering to a transplant recipient anti-CD154 antibodies with reduced effector functions.
Claim 9, which depends on claim 1, recites that the T cell depleting antibodies used to deplete T cells in the thymus and/or bone marrow includes anti-CD20 antibodies.
It is known in the art that anti-CD20 antibodies target the B-cell specific marker CD20, leading to depletion of B cells (not T cells) (Crickx et al, see Abstract, left column on Page 886, and Figure 1). Since CD20 is a B-cell specific marker, an antibody that binds to CD20 does not predictably target and deplete T cells. The specification does not provide any evidence or guidance for the use of anti-CD20 antibodies in the depletion of T cells in the thymus and/or bone marrow. A person of ordinary skill in the art at the time of filing would have had experience in immunology, cell biology, and pharmacology with emphasis of mechanisms to mitigate graft intolerance. Even at this high level of skill, however, artisans would not be able to use anti-CD20 antibodies to deplete T cells in the thymus and/or bone marrow, especially given the fact that CD20 is a B-cell specific marker. It would require artisans to engage in undue trial and error experimentation to determine how an anti-CD20 antibody can be used to deplete T cells in the thymus and/or bone marrow commensurate in scope of the claims.
Therefore, the specification is not enabling over the full scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 31, 41, and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 31 recites the limitation "the heavy chain" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 41 recites the limitation "the heavy chain" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 42 recites the limitation "the light chain" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Specifically, claims 31, 41, and 42 each depends on claim 1 which recites “the isolated anti-CD154 antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL)”. Thus, claim 1 recites that the anti-CD154 antibody comprises a VH and VL chain, but not heavy and light chains which would include both the variable and constant domains of the antibody.
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.
Claims 1, 2, 3, 8-13, 30-33, 41-42, 49, 52, 55, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Sykes (US6514513B1) in view of Burkly et al (US20100104573A1), hereinafter Burkly, and Wang et al (WO2019001417A1), hereinafter Wang as evidenced by Al-Adra et al (Al-Adra, David P, and Colin C Anderson. “Mixed chimerism and split tolerance: mechanisms and clinical correlations.” Chimerism vol. 2,4 (2011): 89-101. doi:10.4161/chim.2.4.19017), hereinafter Al-Adra.
Sykes teaches method of inducing tolerance to a donor graft in a recipient, comprising administering to the recipient an inhibitor of a costimulatory pathway, introducing into the recipient hematopoietic stem cells, and transplanting a graft from a donor into the recipient, wherein the number of hematopoietic stem cells is sufficient to induce mixed chimerism without whole body irradiation or entirely replacing the recipient's stem cells with donor cells (Col. 1, Ln. 31-32, Ln. 37-52; Col. 2, Ln. 51-55; Col. 2, Ln. 60-62; Col. 16, Ln. 37-40; Claims 1, 4, 29, and 32; Col. 38, Ln. 15-19). Mixed chimerism involves both central and peripheral tolerance mechanisms as evidenced by Al-Adra, with central tolerance as the dominant mechanism (see “Tolerance mechanisms in mixed chimeras” and “Central tolerance” sections). In particular embodiments, the recipient is human and the donor is a different species such as miniature swine such that the graft is a xenograft (Col. 2, Ln. 9-16 and Claims 1, 9, 10, 11, 37, 38, and 39). The term “graft” includes organs (e.g. liver, kidney, heart, or lung) (Col. 14, Ln. 63-67 and Claims 1, 9, 10, and 11). Bone marrow preparations can be used to provide hematopoietic stem cells (Col. 15, Ln. 1-8). The inhibitor of a costimulatory pathway can be an antibody that binds to CD40L and blocks the CD40L/CD40 interaction (note: CD40L is also known as CD154) (Col. 1, Ln. 53-60 and Example 2: Col. 27, Ln. 64-65). In some embodiments, the method is practiced with T cell depletion or inactivation, for example, via the thymic irradiation or T-cell depleting antibodies such as anti-CD4 or anti-CD8 antibodies (Col. 2, Ln. 23-25; Col. 5, Ln. 8-9; Col. 8, Ln. 18-35; and Col. 9, Ln. 37-39). The CD40L/CD40 blockers (e.g. anti-CD154 antibodies) can be administered one or more times prior to and/or after donor bone marrow transplantation (i.e. stem cell transplantation) (Col. 38, Ln. 19-41). Accordingly, the anti-CD154 antibodies can be administered prior to or transplantation of hematopoietic stem cells.
Sykes does not teach the anti-CD154 antibody of the instant claims having a VH chain comprising the CDRs of SEQ ID NOs: 57-59 and a VL chain comprising the CDRs of SEQ ID NOs: 60-62, wherein the VH chain is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid mutations.
However, Burkly teaches an anti-CD154 antibodies capable of inhibiting rejection by the subject of a transplanted organ (e.g. heart, kidney, liver, skin, etc.), including the clone hu5c8, wherein the antibody comprises the heavy chain of SEQ ID NO: 66 and the light chain of SEQ ID NO: 63 (Abstract, Para. 0036, and Para. 0326-0327). The heavy chain of SEQ ID NO: 66 fully comprises the VH chain of SEQ ID NO: 64 of the instant claims and thus the CDRs of SEQ ID NOs: 57-59. The light chain of SEQ ID NO: 63 corresponds to the light chain of SEQ ID NO: 196 of the instant claims and thus fully comprises the VL chain of SEQ ID NO: 66 as well as the CDRs of SEQ ID NOs: 60-62 of the instant claims (see sequence alignments below). The anti-CD154 antibodies can be humanized and can be antigen fragments such as Fab fragments (Para. 0068). Fab fragments can be modified by the addition to the C-terminal end of its heavy chain of one or more amino acids allow attachment of a functional moiety, such as polypeptides, proteins, antibody derivatives or fragments. The anti-CD154 antibodies can further comprise an Fc region of or derived from IgG4 (Para. 0051). Since an Fc region of an antibody is a fragment of the antibody, it can be considered a functional moiety. As such, anti-CD154 Fab fragments can be operably linked to an IgG4 Fc region. In some embodiments, the Fc region is engineered to elicit reduced effector functions compared to an anti-CD154 antibody having a native, parental, or unmodified Fc region (Para. 0048-0051). For example, the anti-CD154 antibody can comprise an IgG4 Fc region having one or more substitutions that reduce or eliminate effector function such a leucine to alanine substitution at position 235 (L235A) (Para. 0214 and 0216). Modifications in the hinge region are also contemplated (Para. 0123) and disclosed such as serine to proline substitution at position 228 (S228P), which also plays a role in reduced effector function (Para. 0216, Para. 0226, Para. 0393-0394). Anti-CD154 antibodies with diminished effector function reduce the risk of thromboembolic events (Para. 0196, Para. 0208-0208, Para. 0231, and Para. 0345). The anti-CD154 antibodies can be administered to a subject at any dose per body weight and any dosage frequency that is medically acceptable, wherein an acceptable dosage includes a range of between about 0.01 and 200 mg/kg subject body weight (Para. 0372). The dosage range fully encompasses the range of 5-50 mg/kg recited in the instant claims. Lastly, the anti-CD154 antibodies can be administered to a subject intravenously, subcutaneously, or by enteral, intrapulmonary, transmucosal, or sublingual routes (Para. 0364).
VH chains: SEQ ID NO: 64 (instant claims) vs SEQ ID NO: 66 (prior art)
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364
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VL chains: SEQ ID NO: 66 (instant claims) vs SEQ ID NO: 63 (prior art)
Wang further teaches that a human IgG4 Fc variant of SEQ ID NO: 93, comprising S228P and L235A mutations, can be used in therapeutic antibodies to reduce effector functions (see Table 5). The amino acid sequence of SEQ ID NO: 93 is identical to the heavy chain constant region of SEQ ID NO: 109 recited by the instant claims. The heavy chain constant region of SEQ ID NO: 109 (with a C-terminal lysine) also fully comprises SEQ ID NO: 95 (without a C-terminal lysine) as well as the Fc regions of SEQ ID NOs: 23 and 42 recited in the instant claims. The VH chain at positions 1-118 of SEQ ID NO: 66 disclosed by Burkly, when fused to the human IgG4 Fc variant of SEQ ID NO: 93, yields a full-length heavy chain identical to SEQ ID NOs: 165 (with a C-terminal lysine) of the instant claims, and fully encompasses the heavy chain of SEQ ID NO: 151 (without C-terminal lysine) of the instant claims. In particular, the VH chain of SEQ ID NO: 66 disclosed by Burkly is present at positions 1-118 of SEQ ID NOs: 151 (or SEQ ID NO: 165) and the human IgG4 Fc variant of SEQ ID NO: 93 is present at positions 119-445 of SEQ ID NO: 151.
HC constant domain: SEQ ID NO: 109 (instant claims) vs SEQ ID NO: 93 (prior art)
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750
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HC constant domain: SEQ ID NO: 95 (instant claims) vs SEQ ID NO: 93 (prior art)
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Fc region: SEQ ID NO: 23 (instant claims) vs SEQ ID NO: 93 (prior art)
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500
777
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Fc region: SEQ ID NO: 42 (instant claims) vs SEQ ID NO: 93 (prior art)
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513
786
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Heavy Chain of SEQ ID NO: 165 (instant claims) comprises VH chain present in SEQ ID NO: 66 of Burkly (top alignment) at positions 1-118 and human IgG4 Fc variant of SEQ ID NO: 93 (bottom alignment) at positions 119-445.
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236
726
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It would have been obvious to one of ordinary skill in the art to modify the method of inducing donor graft tolerance disclosed by Sykes by utilizing the anti-CD154 antibody of Burkly as the CD40L/CD40 blocker and further engineering said to incorporate the human IgG4 Fc variant of SEQ ID NO: 93 possessing S228P and L235A mutations as disclosed by Wang. One of ordinary skill in the art would have been motivated to do so since the anti-CD154 antibody disclosed by Burkly is capable of inhibiting organ transplant rejection in a recipient. Further, anti-CD154 antibodies engineered to have reduced effector functions—such as via S228P and L235A mutations—significantly mitigate thromboembolic risk as highlighted by Burkly. In particular, Wang exemplifies a human IgG4 Fc variant of SEQ ID NO: 93 having S228P and L235A mutations that can be used in therapeutic antibodies to reduce effector functions. The wherein clause of instant claim 60 is a statement of intended result that does not carry patentable weight. Nevertheless, the method of inducing tolerance in transplant recipient taught by the combined teachings of the prior art including the minimally required steps and components of the instantly claimed method and thus is expected to promote long-term survival of the donor organ at least 6 months to 5 years post-transplant. Therefore, one of ordinary skill in the art would reasonably expect that the administration of anti-CD154 antibodies having IgG4 Fc region with L235A and S228P mutations in combination with hematopoietic stem cells can effectively promote tolerance to a donor graft in a recipient, while concurrently mitigating thromboembolic events.
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.
Claims 1-2, 30-33, 41-42, 49, 55, and 60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 19-21, 28-29, 46, 49, 59, 65, 67, 99, 109, 116, and 135-142 of copending Application No. 17623710.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite methods of inducing central tolerance in a transplant recipient comprising administering to the recipient one or more doses of the recited anti-CD154 antibody, transplanting into the recipient hematopoietic stem cells, and transplanting a donor tissue into the recipient, wherein the hematopoietic stem cells produce immune cells that are tolerant of the donor tissue, thereby inducing central tolerance in the recipient (co-pending claims 1 and 109). Further recited are a) methods of inhibiting an immune response in a subject that has or will receive an organ transplant comprising administering an effective amount recited anti-CD154 antibody, wherein the transplant is a xenotransplant thus the recipient and donor are different species (co-pending claims 49, 59, 67) and b) methods of inducing hematopoietic chimerism in a transplant recipient comprising administering one or more doses of the recited anti-CD154 antibody and hematopoietic stem cells to the transplant recipient (co-pending claim 99). The anti-CD154 antibody comprises a VH chain having the CDRs of SEQ ID NOs: 57-59 and a VL chain having the CDRs of SEQ ID NOs: 60-62, wherein the VH chain is operably linked to a human IgG4 Fc region consisting essentially of S228P and L235A mutations (co-pending claim 1). The anti-human Fc region comprises the amino acid sequence of SEQ ID NOs: 23 or 42, corresponding to SEQ ID NOs: 23 and 42, respectively of the instant claims (co-pending claim 17). The VH chain comprises the amino acid sequence of SEQ ID NO: 64, and the VL chain comprises the amino acid sequences of SEQ ID NO: 66, corresponding to SEQ ID NOs: 64 and 66, respectively of the instant claims (co-pending claims 19 and 20). The anti-CD154 antibody can also be defined by a heavy chain of SEQ ID NO: 151 or 165 (corresponding to SEQ ID NOs: 151 and 165 of the instant claims) and a light chain of SEQ ID NO: 196 (corresponding to SEQ ID NO: 196 of the instant claims). The heavy chains of SEQ ID NOs: 151 and 165 fully comprise the heavy chain constant domains of SEQ ID NOs: 95 and 109 respectively of the instant claims. Both the instant and co-pending claims recite the amino acid sequences of the anti-CD154 antibody TNX05 having a human IgG4 Fc variant with S228P and L235A mutations (see Table 6 of the co-pending specification and Table 1 of the instant specification). Therefore, the amino acid sequences recited in the co-pending claims are identical to those recited in the instant claims. The co-pending claims teach that administration of anti-CD154 antibodies inhibit an immune response in an organ transplant recipient. Since administration of anti-CD154 in combination with hematopoietic stems cells can induce central tolerance in a recipient transplanted with a donor tissue, artisans would have reasonably expected that the combination can be used to induce central tolerance to a donor organ. The wherein clause of instant claim 60 is a statement of intended result that does not carry patentable weight. Nevertheless, the method of inducing tolerance in transplant recipient taught by the combined teachings of the prior art including the minimally required steps and components of the instantly claimed method and thus is expected to promote long-term survival of the donor organ at least 6 months to 5 years post-transplant.
Thus, the co-pending claims anticipate or render obvious the limitations of the instant claims.
Claims 3 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 19-21, 28-29, 46, 49, 59, 65, 67, 99, 109, 116, and 135-142 of copending Application No. 17623710, as applied to claims 1-2, 30-33, 41-42, 49, 55, and 60 above, and further in view of Sykes (US6514513B1).
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically recited that the method of inducing central tolerance in a transplant recipient further comprises depleting T cell in the thymus and/or bone marrow using T-cell depleting antibodies such as anti-CD4 and anti-CD8 antibodies. In addition, it is not specifically taught that the transplant recipient is human or that the anti-CD154 antibody is administered prior to, subsequently to, or simultaneously with transplantation of hematopoietic stem cells. Lastly, it is not specifically taught that the method results in mixed chimerism.
However, Sykes teaches a method of inducing tolerance to a donor graft in a recipient, comprising administering to the recipient an inhibitor of a costimulatory pathway, introducing into the recipient hematopoietic stem cells, and transplanting a graft from a donor into the recipient, wherein the number of hematopoietic stem cells is sufficient to induce mixed chimerism without whole body irradiation or entirely replacing the recipient's stem cells with donor cells (Col. 1, Ln. 31-32, Ln. 37-52; Col. 2, Ln. 51-55; Col. 2, Ln. 60-62; Col. 16, Ln. 37-40; Claims 1, 4, 29, and 32; Col. 38, Ln. 15-19). In particular embodiments, the recipient is human and the donor is a different species such as miniature swine such that the graft is a xenograft (Col. 2, Ln. 9-16 and Claims 1, 9, 10, 11, 37, 38, and 39). Bone marrow preparations can be used to provide hematopoietic stem cells (Col. 15, Ln. 1-8). The inhibitor of a costimulatory pathway can be an antibody that binds to CD40L and blocks the CD40L/CD40 interaction (note: CD40L is also known as CD154) (Col. 1, Ln. 53-60 and Example 2: Col. 27, Ln. 64-65). In some embodiments, the method is optionally practiced with T cell depletion or inactivation, for example, via the thymic irradiation or T-cell depleting antibodies such as anti-CD4 or anti-CD8 antibodies (Col. 2, Ln. 23-25; Col. 5, Ln. 8-9; Col. 8, Ln. 18-35; and Col. 9, Ln. 37-39). The CD40L/CD40 blockers (e.g. anti-CD154 antibodies) can be administered one or more times prior to and/or after donor bone marrow transplantation (i.e. stem cell transplantation) (Col. 38, Ln. 19-41). Accordingly, the anti-CD154 antibodies can be administered prior to or transplantation of hematopoietic stem cells.
It would have been obvious to one of ordinary skill in the art to modify the method of inducing central tolerance in a transplant recipient taught by the co-pending claims such that (i) hematopoietic stem cells are administered in an amount sufficient to induce mixed tolerance, (ii_ the method optionally comprises T cell-depletion and/or inactivation by thymic irradiation or T cell-depleting antibodies; and (iii) anti-CD154 antibodies are administered before or after administration of the hematopoietic stem cells. One of ordinary skill in the art would have been motivated to do so because administration of a sufficient number of hematopoietic stem cells can induce mixed chimerism without requiring whole-body irradiation or complete replacement of the recipient’s stem cells with donor cells as taught by Sykes. Nevertheless, T cell depletion or inactivation, including by thymic irradiation or administration of T-cell depleting antibodies, is still an optional step to facilitate induction of tolerance. Moreover, artisans would have been motivated to administer anti-CD154 antibodies before or after hematopoietic stem cell transplantation in the method of inducing tolerance in a transplant recipient because Sykes teaches that either sequence of administration can be utilized in a such a method. Therefore, one of ordinary skill in the art would reasonably expect that that (i) administration of a sufficient amount of hematopoietic stem cells can induce mixed tolerance, (ii) optional T cell-depletion and/or inactivation by thymic irradiation or T cell-depleting antibodies can further help promote tolerance induction; and (iii) anti-CD154 antibodies can be administered before or after administration of the hematopoietic stem cells in order to induce tolerance in transplant recipient.
Claims 12 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 19-21, 28-29, 46, 49, 59, 65, 67, 99, 109, 116, and 135-142 of copending Application No. 17623710, as applied to claims 1-2, 30-33, 41-42, 49, 55, and 60 above, and further in view of Burkly et al (US20100104573A1), hereinafter Burkly.
The teachings of the co-pending claims have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-CD154 antibody is administered at a dose of 5-50 mg/kg nor that the antibody is administered via the routes recited in instant claim 12.
However, Burkly teaches an anti-CD154 antibodies capable of inhibiting rejection by the subject of a transplanted organ (e.g. heart, kidney, liver, skin, etc.) (Abstract, Para. 0036, and Para. 0326-0327). The anti-CD154 antibodies can be administered to a subject at any dose per body weight and any dosage frequency that is medically acceptable, wherein an acceptable dosage includes a range of between about 0.01 and 200 mg/kg subject body weight (Para. 0372). The range of 0.01 and 200 mg/kg encompasses the instantly claimed range of 5 -50 mg/kg. Lastly, the anti-CD154 antibodies can be administered to a subject intravenously, subcutaneously, or by enteral, intrapulmonary, transmucosal, or sublingual routes (Para. 0364).
It would have been obvious to one of ordinary skill in the art to modify the method of inducing central tolerance in a transplant recipient recited by the co-pending claims such that the anti-CD154 antibodies are administered in a range of about 0.01 and 200 mg/kg via intravenous or subcutaneous routes. One of ordinary skill in the art would have been motivated to do so since Burkly teaches that these are medically acceptable dosage amounts and administration routes of anti-CD154 antibodies that can be used to treat or prevent various conditions, including transplant rejection in a recipient. Therefore, one of ordinary skill in the art would reasonably expect that the anti-CD154 antibody can be administered in a range of about 0.01 and 200 mg/kg via intravenous or subcutaneous routes in order to effectively induce central tolerance in a transplant recipient according to the methods of the co-pending claims.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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