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 .
Claim Status
Claims 2, 7-9, 11-12, and 25 have been cancelled; claims 1, 6, 17, 20-21, and 23-24 have been amended; and, claims 26-27 have been newly added, as requested in the amendment filed on 05/21/2026. Following the amendment, claims 1, 3-6, 10, 13-24, and 26-27 are pending in the instant application.
Claims 1, 3-6, 10, 13-24, and 26-27 are under examination in the instant office action.
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.
Claims 1, 3-6, 10, 13-24, and 26-27 have an effective filing date of March 08, 2019 corresponding to PRO 62/815,958.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 25 was rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claim 25 has been cancelled, rendering the rejection moot. As such, the rejection of claim 25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 3, 6, 10, 13-15, 17-18, 21-22, and 25 were rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (previously cited on PTO-892; herein after referred to as “Labotka”).
Claims 4-5 were rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (previously cited on PTO-892; herein after referred to as “Labotka”), as applied to claims 1, 3, 6, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of non-patent literature by Singh et. al. (Transplantation Reviews, 2009, 23, 34-46; previously cited on PTO-892; herein after referred to as "Singh").
Claim 16 was rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (previously cited on PTO-892; herein after referred to as “Labotka”), as applied to claims 1, 3, 6, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of non-patent literature by Sureshkumar et. al. (Expert Opinion on Pharmacotherapy, 2007, 8(7), 913-921; previously cited on PTO-892; herein after referred to as "Sureshkumar").
Claims 19-20 and 23-24 were rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (previously cited on PTO-892; herein after referred to as “Labotka”), as applied to claims 1, 3, 6, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of US 2017/0022280 A1 (previously cited on PTO-892; herein after referred to as "Jordan").
With regard to the above-listed claim rejections, wherein the primary reference is Labotka, Applicant argues the following on Pages 8-9 of Remarks (05/21/2026):
Labotka describes methods for treating "proteasome-mediated disorder" including antibody-mediated diseases such as antibody-mediated rejection in kidney transplantation by administering to a patient a combination of an anti-CD38 antibody (such as daratumumab) and a proteasome inhibitor. Labotka generally discloses the anti-CD38 is administered from various doses within 1-100 mg/kg, at various frequencies from daily, once every two days, ... every four weeks, for various durations from 2 to 24 weeks or more. Labotka does not teach a method without a proteasome inhibitor, and there is simply no guidance in Labotka alone or in combination with other references to select only the specified dosing regimen as claimed.
Singh is a review article on various treatment alternatives for ABMR treatment, Sureshkumar is also a review article on ABMR and general treatment options, silent about anti-CD38, Jordan discloses IL-6 inhibitors for use in treating ABMR. So, Singh, Sureshkumar, and Jordan do not cure the deficiencies of Labotka.
The claimed methods, as amended, administer the anti-CD38 without a proteasome inhibitor, and instead of a broad dosing regimen, recite specific ranges and a short duration for reducing HLA antibodies and treating ABMR response. The effect of a narrow anti-CD38 dosage range and a short duration, without a proteasome inhibitor, is unpredictable from Labotka.
Applicant’s arguments have been fully considered, and in view of the instant claim amendments are deemed persuasive. As such, the above-listed claim rejections, wherein the primary reference is Labotka, are withdrawn.
Claims 1, 3, 10, 13-15, 17-18, 21-22, and 25 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature published by Muro et. al. (Int. J. Transplant Res. Med., 2016, 2, 1-2; previously cited on PTO-892; herein after referred to as "Muro") in view of non-patent literature by Van de Donk et. al. (Immunological Reviews, 2016, 270, 95-112; previously cited on PTO-892; herein after referred to as "Donk") and US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi").
Claims 4-6 were rejected under 35 U.S.C. 103 as being unpatentable over Muro et. al. (Int. J. Transplant Res. Med., 2016, 2, 1-2; previously cited on PTO-892; herein after referred to as "Muro"), Van de Donk et. al. (Immunological Reviews, 2016, 270, 95-112; previously cited on PTO-892; herein after referred to as "Donk") and US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi"), as applied to claims 1, 3, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of non-patent literature by Singh et. al. (Transplantation Reviews, 2009, 23, 34-46; previously cited on PTO-892; herein after referred to as "Singh").
Claim 16 was rejected under 35 U.S.C. 103 as being unpatentable over Muro et. al. (Int. J. Transplant Res. Med., 2016, 2, 1-2; previously cited on PTO-892; herein after referred to as "Muro"), Van de Donk et. al. (Immunological Reviews, 2016, 270, 95-112; previously cited on PTO-892; herein after referred to as "Donk") and US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi"), as applied to claims 1, 3, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of non-patent literature by Sureshkumar et. al. (Expert Opinion on Pharmacotherapy, 2007, 8(7), 913-921; previously cited on PTO-892; herein after referred to as " Sureshkumar").
Claims 19-20 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Muro et. al. (Int. J. Transplant Res. Med., 2016, 2, 1-2; previously cited on PTO-892; herein after referred to as "Muro"), Van de Donk et. al. (Immunological Reviews, 2016, 270, 95-112; previously cited on PTO-892; herein after referred to as "Donk") and US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi"), as applied to claims 1, 3, 10, 13-15, 17-18, 21-22, and 25 above, and in further view of US 2017/0022280 A1 (previously cited on PTO-892; herein after referred to as "Jordan").
With regard to the above-listed claim rejections, wherein the primary reference is Muro, Applicant argues the following on Pages 9-10 of Remarks (05/21/2026):
Muro reviews numerous B-cell markers as possible cellular targets that block alloantibody production, but majority of them are shared by other cells of the immune system or by different tissues carrying out important functions. CD38 is said to appear in B cell ontogeny and among others that are less specific; Muro does not specify a nexus between anti-CD38 and treating antibody-mediated rejection (ABMR) or reducing HLA antibodies. Muro further states the eventual interaction and balance between Tregs and Bregs is “controversial”.
Donk focuses on preclinical uses of CD38-based combination therapies in multiple sclerosis, and mentions one sentence that in transplantation medicine reduction in alloantibody levels with an anti-CD38 antibody during acute rejection may diminish transplant loss. Reading as a whole, one of ordinary skill in the art would understand Donk as depicting acute rejection in hematology transplant, i.e. hematopoietic stem cell transplant, and not solid organ transplant.
Doshi discloses a broad range of daratumumab in treating acute lymphoblastic leukemia, without mention of treating ABMR or reducing HLA antibodies, from 0.005 mg to about 100 mg/kg for 1-20 or more doses and repeated after an interval from 1 day or 6 months or more.
The combination of Muro, Donk, and Doshi does not provide a nexus between anti-CD38 antibodies and treating solid organ transplant rejection or related HLA antibodies. The combination also fails to guide one of ordinary skill in the art to select only the specified dosing regimen as claimed, much less predict the surprisingly advantageous persistent benefits therewith.
Singh is a review article on various treatment alternatives for ABMR treatment, Sureshkumar is also a review article on ABMR and general treatment options, silent about anti-CD38, Jordan discloses IL-6 inhibitors for use in treating ABMR. So, Singh, Sureshkumar, and Jordan do not cure the deficiencies of Muro, Donk, and Doshi.
Applicant’s arguments have been fully considered, and in view of the instant claim amendments are deemed persuasive. As such, the above-listed claim rejections, wherein the primary reference is Muro, are withdrawn.
Claim Rejections - 35 USC § 102 - New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 6, 10, 13, 15, 17-18, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by non-patent literature by Kwun et. al. (Am. J. Transplant., 2017, 17(suppl 3), 1 Page; herein after referred to as “Kwun”), as evidenced by US 2017/0121414 A1 (herein after referred to as “Jansson”).
Kwun teaches that the presence of donor-specific antibodies (DSA) leads to antibody-mediated rejection (AMR) and decreased graft survival; therefore efforts continue to be made to reduce DSA in these patients (Introduction). Kwun studies desensitization through drug therapy using Daratumumab (anti-CD38 mAb) and Mozobil (anti-CXCR4 mAb) through a model of sensitization established in rhesus macaques (Id.). Monkeys were sensitized by two sequential skin grafts between mismatched donor-recipient pairs, and six weeks prior to kidney transplantation, weekly IV doses of Mozobil (0.24 mg/kg) and Daratumumab (16 mg/kg) for desensitization was given (n=4) and results compared to animals without desensitization (n=4) (Methods). Despite early transient changes with therapy, lymphocytes, monocytes, or T and B cells did not change significantly in numbers or percentages. The study demonstrated that (i) plasma cells (PCs) initially declined in the peripheral blood (0.7% vs. 6.7% of total non T/B cells) but returned to baseline levels (10.7%) after desensitization treatment; (ii) the level of DSA significantly declined during desensitization compared to untreated controls (57.9% vs. 13% reduction); (iii) targeting PCs with daratumumab and mozobi1 induced more Ki67+IgD- B cells, suggesting that the B cell/PC repertoire may change from a donor-specific to non-donor-specific population; and (iv) desensitization with Daratumumab and Mozobil resulted in prolonged graft survival compared to controls (28.0d vs. 5.2d: p<0.01) (Result; see also the Figure reproduced below).
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Targeting PCs and memory B cells with Daratumumab and Mozobil significantly reduced OSA and prolonged graft survival; based on the repopulation of PC and B cells daratumumab/mozobil may promote PC and B cell repertoire changes, wherein the treatment prevented AMR, with grafts eventually succumbing to cell-mediated rejection (Conclusion). Thus, Kwun discloses a method of inhibiting/reducing antibody-mediated rejection of a solid organ transplant (i.e., a kidney transplant) in a subject (i.e., a macaque), comprising IV administration of an anti-CD38 antibody (i.e., daratumumab) to the subject, prior to organ transplant, at a dose of 16 mg/kg/week for 4 weeks.
It is noted that Kwun does not explicitly teach the sequences associated with the antibody daratumumab. However, the sequence(s) is/are inherent to the daratumumab antibody, and were known in the prior art as evidenced by Jansson.
Jansson teaches that daratumumab comprises the heavy chain variable region (VH) and the light chain variable region (VL) amino acid sequences shown in SEQ ID NOs: 4 and 5, respectively, the HCDRl, the HCDR2 and the HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively, the LCDRI, the LCDR2 and the LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively; the daratumumab heavy chain amino acid sequence is shown in SEQ ID NO: 12 and light chain amino acid sequence shown in SEQ ID NO: 13 (Paragraph 0136). It is specifically noted that Jansson HCDRs 1-3 corresponding to SEQ ID NOs 6-8, respectively, and LCDRs 1-3 corresponding to SEQ ID NOs: 9-11, respectively, are exact matches to instant SEQ ID NOs: 6-8 and instant SEQ ID NOs: 9-11, respectively. Furthermore, Jansson VH and VL SEQ ID NOs: 4-5, respectively, are an exact match to instant SEQ ID NOs: 4-5, respectively.
Kwun therefore anticipates instant claims 1, 3, 6, 10, 13, 15, 17-18, and 26-27, as evidenced by Jansson.
Claim Rejections - 35 USC § 103 - New
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-5, 6, 10, 13-15, 17-18, 21-23, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Kwun et. al. (Am. J. Transplant., 2017, 17(suppl 3), 1 Page; herein after referred to as “Kwun”), US 2017/0121414 A1 (herein after referred to as “Jansson”), and non-patent literature by Singh et. al. (Transplantation Reviews, 2009, 23, 34-46; previously cited on PTO-892; herein after referred to as "Singh").
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Kwun teaches that the presence of donor-specific antibodies (DSA) leads to antibody-mediated rejection (AMR) and decreased graft survival; therefore efforts continue to be made to reduce DSA in these patients (Introduction). Kwun studies desensitization through drug therapy using Daratumumab (anti-CD38 mAb) and Mozobil (anti-CXCR4 mAb) through a model of sensitization established in rhesus macaques (Id.). Monkeys were sensitized by two sequential skin grafts between mismatched donor-recipient pairs, and six weeks prior to kidney transplantation, weekly IV doses of Mozobil (0.24 mg/kg) and Daratumumab (16 mg/kg) for desensitization was given (n=4) and results compared to animals without desensitization (n=4) (Methods). Despite early transient changes with therapy, lymphocytes, monocytes, or T and B cells did not change significantly in numbers or percentages. The study demonstrated that (i) plasma cells (PCs) initially declined in the peripheral blood (0.7% vs. 6.7% of total non T/B cells) but returned to baseline levels (10.7%) after desensitization treatment; (ii) the level of DSA significantly declined during desensitization compared to untreated controls (57.9% vs. 13% reduction); (iii) targeting PCs with daratumumab and mozobi1 induced more Ki67+IgD- B cells, suggesting that the B cell/PC repertoire may change from a donor-specific to non-donor-specific population; and (iv) desensitization with Daratumumab and Mozobil resulted in prolonged graft survival compared to controls (28.0d vs. 5.2d: p<0.01) (Result; see also the Figure reproduced below).
Targeting PCs and memory B cells with Daratumumab and Mozobil significantly reduced OSA and prolonged graft survival; based on the repopulation of PC and B cells daratumumab/mozobil may promote PC and B cell repertoire changes, wherein the treatment prevented AMR, with grafts eventually succumbing to cell-mediated rejection (Conclusion). Thus, Kwun discloses a method of inhibiting/reducing antibody-mediated rejection of a solid organ transplant (i.e., a kidney transplant) in a subject (i.e., a macaque), comprising IV administration of an anti-CD38 antibody (i.e., daratumumab) to the subject, prior to organ transplant, at a dose of 16 mg/kg/week for 4 weeks.
Jansson teaches subcutaneous formulations of anti-CD38 antibodies and their uses (Abstract). Jansson suggests that subcutaneous administration of the anti-CD38 antibody may have reduced infusion related reaction and achieve improved response rates when compared to the intravenous administration of the anti-CD38 antibody (Paragraph 0053). Jansson discloses that daratumumab comprises the heavy chain variable region (VH) and the light chain variable region (VL) amino acid sequences shown in SEQ ID NOs: 4 and 5, respectively, the HCDRl, the HCDR2 and the HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively, the LCDRI, the LCDR2 and the LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively; the daratumumab heavy chain amino acid sequence is shown in SEQ ID NO: 12 and light chain amino acid sequence shown in SEQ ID NO: 13 (Paragraph 0136). It is specifically noted that Jansson HCDRs 1-3 corresponding to SEQ ID NOs 6-8, respectively, and LCDRs 1-3 corresponding to SEQ ID NOs: 9-11, respectively, are exact matches to instant SEQ ID NOs: 6-8 and instant SEQ ID NOs: 9-11, respectively. Furthermore, Jansson VH and VL SEQ ID NOs: 4-5, respectively, are an exact match to instant SEQ ID NOs: 4-5, respectively.
However, neither Kwun nor Jansson teach administering daratumumab to a subject (i) who has previously undergone standard-of-care treatment and (ii) is further resistant or has acquired resistance to immunosuppressive treatment. This deficiency is remedied by Singh.
Singh teaches that antibody-mediated rejection (AMR) defines all allograft rejection caused by antibodies directed against donor-specific HLA molecules, blood group antigen (ABO)-isoagglutinins, or endothelial cell antigens wherein antibody-mediated rejection can be a recalcitrant process, resistant to therapy, and carries an ominous prognosis to the graft (Abstract). Treatment protocols for AMR use permutations of a multiple-prong approach that include (1) the suppression of the T-cell dependent antibody response, (2) the removal of donor reactive antibody, (3) the blockade of the residual alloantibody, and (4) the depletion of naive and memory B-cells (Id.). In one study, a single dose of IVIg and pulse intravenous steroids in combination with cyclophosphamide (n = 1) and/or TAC (n = 1) were used to treat 7 kidney and 3 cardiac allograft recipients with biopsy-proven refractory AMR of whom only 4 patients had detectable DRSA at the time of rejection; IVIg was effective at reversing rejection in all patients within 2-5 days of infusion, with recurrence of rejection in only 2 patients, both heart transplant recipients, which resulted in the loss of the graft (i.e., standard-of-care treatment was ineffective) (Page 40, Column 1, Paragraph 3). In another study, the outcomes of 61 highly sensitized kidney transplant recipients undergoing desensitization with high-dose IVIg were analyzed wherein thirty-six percent of all patients had acute rejection most of which were C4d positive (32%); patients with C4d positive rejection were treated with a regimen of high dose-IVIg, pulse steroids and/or PE or ATG, and patients with C4d negative rejection received pulse steroids (Page 40, Column 1, Paragraph 4). In most patients, C4d positive rejections were responsive to IVIg and steroids (15/20; 75%); however, a subgroup (8.1% [5/61]) developed a recalcitrant form of AMR resistant to all forms of therapy (Id.). Thus, standard-of-care therapy was ineffective and a subset of patients also were resistant to/became resistant to steroids as well.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Kwun such that the anti-CD38 antibody (i.e., daratumumab, comprising the instantly claimed sequences as disclosed by Jansson) was administered (i) via IV infusion as suggested by Kwun, (ii) via subcutaneous injection as suggested by Jansson at a dose of 16 mg/kg/week for 4 weeks, as suggested by Kwun, wherein such a method is used to treat ABMR in patients refractory to standard-of-care and immunosuppressive therapies. One would have been motivated to make such modifications because (i) Singh teaches that antibody-mediated rejection (AMR) defines all allograft rejection caused by antibodies directed against donor-specific HLA molecules and that standard-of-care therapy can be ineffective in patients, and wherein in a subset of patients also were resistant to/became resistant to steroids as well; (ii) Kwun teaches a method of inhibiting/reducing ABMR in the context of kidney transplants; and (iii) and Jansson teaches the advantages of subcutaneous formulations of anti-CD38 antibodies, including daratumumab. One of ordinary skill in the art would have a reasonable expectation of success in treating a patient cohort suffering from and/or at risk of ABMR, wherein in said patient cohort standard-of-care therapies (e.g., IVIG) are ineffective and said patients are further refractory to immunosuppressive therapies such as corticosteroids, because Kwun discloses a method of inhibiting/reducing antibody-mediated rejection by reducing the number of donor-specific antibodies (which would correspond to anti-HLA antibodies in human subjects) of a solid organ transplant (i.e., a kidney transplant) in a subject comprising IV administration of an anti-CD38 antibody (i.e., daratumumab) to the subject, prior to organ transplant, at a dose of 16 mg/kg/week for 4 weeks and Jansson teaches the advantages of subcutaneous formulations of anti-CD38 antibodies, including daratumumab.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Kwun et. al. (Am. J. Transplant., 2017, 17(suppl 3), 1 Page; herein after referred to as “Kwun”), US 2017/0121414 A1 (herein after referred to as “Jansson”), and non-patent literature by Singh et. al. (Transplantation Reviews, 2009, 23, 34-46; previously cited on PTO-892; herein after referred to as "Singh"), as applied to claims 1, 3-5, 6, 10, 13-15, 17-18, 21-23, and 26-27 above, and in further view of non-patent literature by Sureshkumar et. al. (Expert Opinion on Pharmacotherapy, 2007, 8(7), 913-921; previously cited on PTO-892; herein after referred to as " Sureshkumar").
The method of claim 1 is rendered obvious by the combination of Kwun, Jansson, and Singh. However, none of the cited references teach/suggest administering the anti-CD38 antibody in combination with tacrolimus and/or mycophenolate mofetil. This deficiency is remedied by Sureshkumar.
Sureshkumar teaches that antibody-mediated rejection (AMR) accounts for 20-30% of all acute rejection episodes following renal transplantation and that AMR is generally less responsive to conventional anti-rejection therapy, resulting in poor allograft survival; therapeutic options are evolving and include plasmapheresis, intravenous immunoglobulin, immunoadsorption and rituximab, together with intensification of immunosuppression with a tacrolimus/mycophenolate mofetil (MMF) combination (Abstract). MMF inhibits in vitro antibody production by B-cells and reduces in vivo humoral response in renal transplant
recipients wherein the mechanism of action involves blockade of lymphocyte-specific isoforms of inosine monophosphate dehydrogenase; the combination of MMF with tacrolimus can
limit B-cell responses in renal allograft recipients presenting with AMR wherein the usual dose of MMF is 2 g/day (Page 916, Column 2, Paragraph 3).
Thus, it would have been prima facie obvious to further modify the method rendered obvious by Kwun, Jansson, and Singh such that the method further comprises administering the anti-CD38 antibody in combination with tacrolimus and/or mycophenolate mofetil, because Sureshkumar teaches that antibody-mediated rejection (AMR) accounts for 20-30% of all acute rejection episodes following renal transplantation and that AMR is generally less responsive to conventional anti-rejection therapy, resulting in poor allograft survival, and suggests intensification of immunosuppression with a tacrolimus/mycophenolate mofetil (MMF) combination to limit B-cell responses in renal allograft recipients presenting with AMR. One of ordinary skill in the art would have a reasonable expectation of success because the method rendered obvious by Kwun, Jansson, and Singh on its own would reasonably be expected to inhibit/reduce AMR in kidney transplant patients who are resistant to conventional therapies, and Sureshkumar suggests that in conventional therapy resistant populations intensification of immunosuppression with a tacrolimus/mycophenolate mofetil (MMF) combination can serve to limit B-cell responses in renal allograft recipients presenting with AMR; thus the administration of tacrolimus/mycophenolate mofetil in addition to daratumumab as in the method rendered obvious by Kwun, Jansson, and Singh would reasonably be expected to improve the outcomes of patients with/at risk of AMR.
Claims 19-20 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over as being unpatentable over non-patent literature by Kwun et. al. (Am. J. Transplant., 2017, 17(suppl 3), 1 Page; herein after referred to as “Kwun”), US 2017/0121414 A1 (herein after referred to as “Jansson”), and non-patent literature by Singh et. al. (Transplantation Reviews, 2009, 23, 34-46; previously cited on PTO-892; herein after referred to as "Singh"), as applied to claims 1, 3-5, 6, 10, 13-15, 17-18, 21-23, and 26-27 above, and in further view of US 2017/0022280 A1 (previously cited on PTO-892; herein after referred to as "Jordan").
The methods of claim 17 and claim 21 are rendered obvious by the combination of Kwun, Jansson, and Singh. However, none of the cited reference teach/suggest selecting a subject exhibiting a symptom of ABMR before or at the time of administering the anti-CD38 antibody, nor administering an anti-CD38 antibody after solid organ transplantation. This deficiency is remedied by Jordan.
Jordan teaches methods for treating, inhibiting and/or reducing the severity of ABMR of an organ transplant in a subject in need thereof wherein the methods include providing an inhibitor of IL-6 and administering an effective amount of the IL-6 inhibitor to the subject in need thereof, so as to treat, inhibit and/or reduce the severity of ABMR of an organ transplant in the subject (Paragraph 0010). Further provided are methods for reducing and/or eliminating donor specific HLA antibodies in a subject that has undergone organ transplant wherein the methods include providing an inhibitor of IL-6 and administering an effective amount of the IL-6 inhibitor to the subject, so as to reduce and/or eliminate donor specific HLA antibodies in the subject (Paragraph 0011). In some embodiments, the subject has undergone an organ transplant and exhibits symptoms of antibody mediated rejection (ABMR) of the transplanted organ (Paragraph 0013) wherein symptoms of ABMR are any one or more of: (i) deterioration of allograft function measured by serum Creatinin and estimated Glomerular filtration rate (eGFR); (ii) presence of donor-specific antibodies; (iii) biopsy evidence of capillaritis, inflammation and complement (C4d) deposition, or (iv) combinations thereof (Paragraph 0016). The inhibitor can be administered during (concurrently with) organ transplantation, after organ transplantation, and/or both during and after organ transplantation (Paragraph 0058). While it is acknowledged that Jordan teaches treating ABMR with a different therapeutic agent than instantly claimed, support for an anti-CD38 agent, whereby the anti-CD38 antibody reduces the number of donor-specific antibodies, is supported by Kwun. As such the teachings of Jordan are solely relied upon to teach that a patient can be selected for treatment based on showing symptoms of ABMR and that ABMR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation wherein the number of donor-specific antibodies (i.e., donor-specific anti-HLA antibodies in human subjects) are reduced and/or eliminated.
Thus, it would have been prima facie obvious to further modify the method rendered obvious by Kwun, Jansson, and Singh such that the method comprises administering the anti-CD38 antibody after kidney transplantation, because Jordan suggests that a patient can be selected for treatment based on showing symptoms of ABMR and that ABMR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation wherein the number of donor-specific antibodies (i.e., donor-specific anti-HLA antibodies in human subjects) are reduced and/or eliminated, which is the result observed by the method rendered obvious by Kwun, Jansson, and Singh. One of ordinary skill in the art would have a reasonable expectation of success because the method rendered obvious by Kwun, Jansson, and Singh on its own would reasonably be expected to inhibit/reduce AMR in kidney transplant patients who are resistant to conventional therapies, and Jordan suggests that reducing and/or eliminating donor-specific antibodies can be useful to treat patients showing symptoms of ABMR, for example during and/or after kidney transplant; thus the administration of daratumumab during and/or after kidney transplantation in patients showing symptoms of ABMR would reasonably be expected to improve the outcomes of said patients as it would still be expected that daratumumab would reduce the number of donor-specific antibodies, therefore treating ABMR.
Response to Arguments
Specifically with regard to Applicant’s argument of unexpected results at Page 8 of Remarks wherein Applicant argues that (i) they have discovered that the claimed anti-CD38 dosing in a short duration of no more than 4 weeks is remarkably effective for clinically significantly reducing HLA antibodies, including persisted reduction in HLA class I antibodies for 6 months post-daratumumab, showing no further evidence of active or chronic ABMR and (ii) this persisted effect is well beyond the half-life of daratumumab and unexpected, the following are noted:
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The recitation(s) of “reducing or removing donor-specific anti-human lymphocyte antigen (HLA) antibodies”, “treating, inhibiting, or reducing severity of antibody-mediated rejection”, “stabilizing or reducing antibody-mediated rejection (ABMR) response”, and/or “desensitizing a subject by reducing donor-specific anti-human lymphocyte antigen (HLA) antibodies” are not limiting because the body of the claim describes a complete invention (i.e., a complete method with active steps) and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Furthermore, the determination of whether, for example, “whereby” clauses are a limitation in a claim depends on the specific facts of the case. > See, e.g., Griffin v. Bertina, 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002)(finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). < In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.
Applicant’s arguments with regard to unexpected results have been fully considered, but in view of the above and the new grounds of rejection presented herein, Applicant’s arguments are deemed not persuasive.
Conclusion
Claims 1, 3-6, 10, 13-24, and 26-27 are pending. Claims 1, 3-6, 10, 13-24, and 26-27 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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