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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/24/2025 has been entered.
Claim Status
Claims 2, 7-9, and 11-12 have been cancelled; claims 1, 3, 10, 13-17, and 21 have been amended; and, claim 25 has been newly added, as requested in the amendment filed on 11/24/2025. Following the amendment, claims 1, 3-6, 10, and 13-25 are pending in the instant application.
Claims 1, 3-6, 10, and 13-25 are under examination in the instant office action.
Priority - Updated
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, and 13-24 have an effective filing date of March 8, 2019 corresponding to PRO 62/815,958.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. PCT/US20/21690 and/or PRO 62/815,958, fail to provide adequate support in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically with regard to new claim 25, it is noted that neither of the above-listed prior filed applications mention or describe acute lymphoblastic leukemia subjects, let alone excluding such a subject population.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 9 and 11 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 US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi").
Claims 9 and 11 have been cancelled, rendering the rejection moot. As such, the rejection of claims 9 and 11 under 35 U.S.C. 103 as being unpatentable over Muro and Doshi is withdrawn.
Claim Rejections - 35 USC § 112 - New
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 25 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically with regard to new claim 25, it is noted that the instant specification does not describe acute lymphoblastic leukemia subjects in any capacity, let alone excluding such a subject population from the instantly claimed methods. As such, claim 25 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim Rejections - 35 USC § 103 - New/Updated
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 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, 6, 10, 13-15, 17-18, 21-22, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (herein after referred to as “Labotka”).
With regard to claim 1, Labotka teaches methods for treating cancer, or preventing cancer recurrence or progression wherein the methods comprise administering to a patient in need thereof (i) a proteasome inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, and (ii) an anti-CD38 antibody (Paragraph 0007). In certain embodiments, the anti-CD38 antibody comprises a VL region having the amino acid sequence of SEQ ID NO: 4 and a VH region having the amino acid sequence of SEQ ID NO: 9 (Paragraphs 0047-0049); it is specifically noted that Labotka discloses that SEQ ID NOs: 4 and 9 are the VL and VH corresponding to daratumumab (see Paragraph 0022) and it is further noted that Labotka SEQ ID NOs: 4 and 9 comprise 100% matches to instant SEQ ID NOs: 9-11 and 6-8, respectively. Additionally, in some embodiments, the anti-CD38 antibody is daratumumab (Paragraph 0057). Labotka further discloses that the methods of the invention are also useful in treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder wherein the term "proteasome-mediated disorder" includes any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity and also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial (Paragraphs 0098-0099); methods of the invention are useful in treatment of disorders mediated via proteins (e.g., NFκB, p27Kip, p21WAF/CIP1, p53) which are regulated by proteasome activity, and exemplary proteasome-mediated disorders include autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection) and antibody-mediated disease (e.g., antibody-mediated rejection in organ transplantation, antibody-mediated rejection in kidney transplantation, antibody-mediated rejection in lung transplantation, antibody-mediated rejection in heart transplantation, antibody-mediated rejection in liver transplantation, antibody-mediated rejection in pancreas transplantation) (Paragraphs 0100-0101; emphasis added). In certain embodiments, the anti-CD38 antibody is administered to a patient in need thereof in a dose of from about 1-100 mg/kg, about 2-50 mg/kg, about 2-40 mg/kg, about 2-30 mg/kg, about 4-20 mg/kg, about 8 mg/kg, or about 16 mg/kg (Paragraphs 0110-0116). The anti-CD38 antibody may be administered daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every four weeks; in certain embodiments, the anti-CD38 antibody is administered once weekly for 2 to 20 weeks, such as for 3 to 12 weeks, such as for 4 to 8 weeks (Paragraphs 0117-0118). Thus, Labotka teaches/suggests a method of treating antibody-mediated disorders, including antibody-mediated rejection in organ transplantation, comprising administering an anti-CD38 antibody (e.g., daratumumab) at doses of about 4-20 mg/kg wherein said doses may be once a week for between 2-20 weeks (including 2-4 weeks).
Labotka is considered to be analogous to the present invention as they are in the same field of anti-CD38 therapeutics, including for antibody-mediated rejection. Thus, while the preferred embodiments of the methods of Labotka are to treat cancer, Labotka further suggests embodiments wherein the methods comprising administering an anti-CD38 antibody (e.g., daratumumab) may be used to treat antibody-mediated disorders, including antibody-mediated rejection in organ transplantation, wherein aid anti-CD38 antibody may be administered at doses of about 4-20 mg/kg wherein said doses may be administered once a week for between 2-20 weeks (including 2-4 weeks). Combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success, wherein Labotka explicitly suggests method of administering an anti-CD38 antibody for the therapeutic treatment of antibody-mediated rejection in organ transplantation. methods antibody-mediated disorders, including antibody-mediated rejection in organ transplantation. Furthermore, with regard to instant claim 1, it is specifically noted that the recitation of “reducing or removing donor specific anti-human leukocyte antigen (HLA) antibodies in a subject, or treating, inhibiting, or reducing severity of antibody- mediated rejection (ABMR) response to an organ transplant” and “thereby reducing or removing the donor specific anti-HLA antibodies or treating, inhibiting, or reducing severity of the ABMR response in the subject” are merely intended results of the instantly claimed method. As such, any method/obvious method comprising the active step of administering to the subject an anti-CD38 antibody or a CD38-binding fragment of the anti-CD38 antibody in about 12-20 mg/kg/week for a period of no more than 4 weeks, wherein the anti-CD38 antibody comprises daratumumab, or wherein the anti-CD38 antibody or the CD38-binding fragment of the anti-CD38 antibody comprises heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, would necessarily cause the intended result.
With regard to claim 3, Labotka discloses that in certain embodiments, the anti-CD38 antibody comprises a VL region having the amino acid sequence of SEQ ID NO: 4 and a VH region having the amino acid sequence of SEQ ID NO: 9 (Paragraphs 0047-0049); it is specifically noted that Labotka discloses that SEQ ID NOs: 4 and 9 are the VL and VH corresponding to daratumumab (see Paragraph 0022) and it is further noted that Labotka SEQ ID NOs: 4 and 9 comprise 100% matches to instant SEQ ID NOs: 9-11 and 6-8, respectively. Additionally, in some embodiments, the anti-CD38 antibody is daratumumab (Paragraph 0057). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 6, Labotka further discloses that the methods of the invention are also useful in treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder wherein the term "proteasome-mediated disorder" includes any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity and also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial (Paragraphs 0098-0099); methods of the invention are useful in treatment of disorders mediated via proteins (e.g., NFκB, p27Kip, p21WAF/CIP1, p53) which are regulated by proteasome activity, and exemplary proteasome-mediated disorders include autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection) and antibody-mediated disease (e.g., antibody-mediated rejection in organ transplantation, antibody-mediated rejection in kidney transplantation, antibody-mediated rejection in lung transplantation, antibody-mediated rejection in heart transplantation, antibody-mediated rejection in liver transplantation, antibody-mediated rejection in pancreas transplantation) (Paragraphs 0100-0101; emphasis added). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 10, Labotka discloses that in certain embodiments, the anti-CD38 antibody comprises a VL region having the amino acid sequence of SEQ ID NO: 4 and a VH region having the amino acid sequence of SEQ ID NO: 9 (Paragraphs 0047-0049); it is specifically noted that Labotka discloses that SEQ ID NOs: 4 and 9 are the VL and VH corresponding to daratumumab (see Paragraph 0022) and it is further noted that Labotka SEQ ID NOs: 4 and 9 comprise 100% matches to instant SEQ ID NOs: 5 and 4, respectively. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 13-15, Labotka teaches that one or more of the antibodies
used in the invention (i.e., anti-CD38 antibodies) are administered parenterally; the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous,
intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrastemal injection and infusion (Paragraph 0085). Furthermore, in certain embodiments, the anti-CD38 antibody is administered to a patient in need thereof in a dose of from about 1-100 mg/kg, about 2-50 mg/kg, about 2-40 mg/kg, about 2-30 mg/kg, about 4-20 mg/kg, about 8 mg/kg, or about 16 mg/kg (Paragraphs 0110-0116). The anti-CD38 antibody may be administered daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, or once every four weeks; in certain embodiments, the anti-CD38 antibody is administered once weekly for 2 to 20 weeks, such as for 3 to 12 weeks, such as for 4 to 8 weeks (Paragraphs 0117-0118). Thus, Labotka discloses weekly dosing for as few as 2 weeks. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 17-18 and 21-22, it is noted that the teachings of Labotka address all claim limitations as detailed above: Labotka teaches/suggests a method of treating antibody-mediated disorders, including antibody-mediated rejection in organ transplantation, comprising administering an anti-CD38 antibody (e.g., daratumumab, the sequences of which comprise 100% matches to the instantly claimed sequences) at doses of about 4-20 mg/kg wherein said doses may be once a week for between 2-20 weeks (including 2-4 weeks). Additionally, it is noted that, the recitation of “preventing, stabilizing or reducing antibody-mediated rejection (ABMR) response” and “desensitizing a subject by reducing and/or eliminating donor specific anti-human leukocyte antigen (HLA) antibodies in the subject” in claims 17 and 21, respectively, are merely intended results of the instantly claimed methods. As such, any method/obvious method comprising the active step of administering to the subject an anti-CD38 antibody or a CD38-binding fragment of the anti-CD38 antibody in about 12-20 mg/kg/week for a period of no more than 4 weeks, wherein the anti-CD38 antibody comprises daratumumab, or wherein the anti-CD38 antibody or the CD38-binding fragment of the anti-CD38 antibody comprises heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, would necessarily cause the intended result. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 25, it is noted that while the preferred embodiments of Labotka disclose methods of treating cancer (which may include acute lymphoblastic leukemia (ALL) as indicated in Paragraph 0104), Labotka also suggests embodiments wherein the methods of the invention are also useful in treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder wherein the term "proteasome-mediated disorder" includes any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity and also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial (Paragraphs 0098-0099); methods of the invention are useful in treatment of disorders mediated via proteins (e.g., NFκB, p27Kip, p21WAF/CIP1, p53) which are regulated by proteasome activity, and exemplary proteasome-mediated disorders include autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection) and antibody-mediated disease (e.g., antibody-mediated rejection in organ transplantation, antibody-mediated rejection in kidney transplantation, antibody-mediated rejection in lung transplantation, antibody-mediated rejection in heart transplantation, antibody-mediated rejection in liver transplantation, antibody-mediated rejection in pancreas transplantation) (Paragraphs 0100-0101; emphasis added). As such, the methods of Labotka may be used in subjects having/at risk of antibody-mediated rejection of an organ transplant, and said embodiment is separate from the treatment of ALL; thus, subjects undergoing treatment for antibody-mediated rejection of an organ transplant do not necessarily have ALL. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (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").
Labotka renders the method of claim 1 obvious. However, Labotka does not explicitly teach that a subject has undergone standard-of-care treatment that was ineffective (claim 4) or wherein the subject is resistant to immunosuppressive treatment (claim 5). These deficiencies are remedied by Singh.
With regard to claims 4-5, 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.
Labotka and Singh are all considered to be analogous to the present invention as they are all in the same field of B cell related diseases/disorders/conditions (e.g., antibody-mediated disorders) and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to utilize the method rendered obvious by Labotka in cases wherein treatment of patients with standard-of-care is ineffective because combining prior art elements according to known methods would be expected to yield predictable result. Patients may be further resistant to treatment with steroids because blockade of the residual alloantibody and/or the depletion of naive and memory B cells are known therapeutic routes, as taught by Singh, and one of ordinary skill in the art would recognize that anti-CD38 therapies, as suggested by Labotka, would provide an alternate therapeutic route compared to the standard-of-care routes disclosed by Singh.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (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").
The method of claim 1 is rendered obvious by Labotka. However, while Labotka does disclose that additional therapeutic agents may be administered in combination with the proteasome inhibitor and anti-CD38 antibody of the invention based on the disease/condition being treated (see Paragraph 0067), the reference not disclose the administration of an anti-CD38 antibody/composition 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).
Labotka and Sureshkumar are all considered to be analogous to the present invention as they are in the same field of B cell related diseases/disorders/conditions (e.g., antibody-mediated disorders) and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to modify the method taught/suggested by Labotka such that the method further comprises administering tracolimus and/or mycophenolate mofetil because combining prior art elements according to known methods would be expected to yield predictable results; as taught by Sureshkumar, MMF inhibits in vitro antibody production by B-cells and reduces in vivo humoral response in renal transplant recipients and MMF with tacrolimus can limit B-cell responses in renal allograft recipients presenting with AMR and thus combining MMF with an additional B-cell based therapy such as an anti-CD38 antibody would be expected to improve therapeutic outcomes in patients presenting with AMR.
Claims 19-20 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0235986 A1 (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").
The methods of claims 17 and 21 are rendered obvious by Labotka as detailed above. However, Labotka does not explicitly detail selecting a subject exhibiting symptoms of AMBR before/at the time of administering the anti-CD38 antibody/composition (claims 19-20) nor specifically administering the anti-CD38 antibody/composition before/at the time of transplant or after the transplant (claims 23-24). 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 AMBR with a different therapeutic agent than instantly claimed, support for an anti-CD38 agent is supported by Labotka, and 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 AMBR and that AMBR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation.
Labotka and Jordan are considered to be analogous to the present invention as they are all in the same field of B cell related diseases/disorders/conditions (e.g., antibody-mediated disorders) and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to further modify the method of Labotka such that a patient can be selected for treatment based on showing symptoms of AMBR and that AMBR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation, as suggested by Jordan, because combining prior art elements according to known methods would be expected to yield predictable results. One of ordinary skill in the art would be motivated to treat subjects exhibiting AMBR symptoms to avoid unnecessary B-cell targeting therapy.
Claims 1, 3, 10, 13-15, 17-18, 21-22, and 25 are 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; herein after referred to as "Donk") and US 2015/0246975 A1 (previously cited on PTO-892; herein after referred to as "Doshi").
With regard to claim 1, Muro teaches that antibody-mediated rejection (AMR) in allograft transplantation can be defined with a rapid increase in the levels of specific serological parameters after organ transplantation, presence of donor specific antibodies (DSAs) against human leukocyte antigen (HLA) molecules, blood group (ABO) antigens and/or endothelial cell antigens (e.g., MICA, ECA, Vimentin, or ETAR) and also particular histological parameters wherein if AMR persists or progresses, the treatment to eliminate the humoral component of acute rejection include three sequential steps: (a) steroid pulses, antibody removal (plasma exchange or immuno-adsorption) and high doses of intravenous immunoglobulin-IVIG, (b) Rituximab (anti-CD20) or Bortezomib (anti-proteasome), and finally (c) Eculizumab (anti-CD5) and rescue splenectomy (Page 1, Column 1, Paragraph 2). The true role of DSA response to solid allograft and the role of the ontogeny of B cells are not fully understood in all types of transplant,
especially in liver transplantation, but it is known the eventual potential of B cell managing to prevent and treat an antibody mediated rejection (Page 1, Column 1, Paragraph 2); B-cell precursors, immature B cells, transitional B cells, activated B cells, memory B cells, plasmablast and plasma cells are all the possible cellular targets that block alloantibody production (Page 1, Column 1, Paragraph 3). Some molecules that appear in B cell ontogeny and may be of interest include CD10, CD23, CD24, CD25, CD38, CD52 or CD138 wherein some important agents that are commercially available are Daclizumab (CD25), Alemtuzumab (CD52), and new agents Lumiliximab (CD23) and Daratumumab (CD38) (Page 1, Column 2, Paragraph 4). Muro further teaches that B-cells not only participate in antibody production but also play an important role as antigen presenting cell (APC) to activate CD4 lymphocytes and that a specific subpopulation of B cells has also been identified as regulatory B-cell (Bregs) with capacity to release immunomodulatory cytokines (i.e., TGF-β, IL-10 and IL-35), and thus there is growing evidence that B-cells are essential contributors to transplant tolerance (Page 1, Column 2, Paragraph 6). Muro suggests that B-cell targets to prevention and treatment of antibody-mediated rejection will be a key point in a better graft survival outcome and define a therapeutic arsenal to avoid graft failure (Page 2, Column 1, Paragraph 2). Thus, Muro suggests the role of B cell activity in AMR/graft failure in cases of organ transplantation, targeting B cells can block alloantibody production, potential B cell targets (e.g., CD38), and some commercially available agents that are specific to said targets (e.g., daratumumab).
Donk teaches that CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions; the protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38, wherein the protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM) (Summary). Daratumumab binds a unique CD38 epitope and showed strong anti-tumor activity in preclinical models; the antibody engages diverse mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity (Id.). CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM wherein, more specifically, daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies; CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases (Id.). More specifically, Donk points to the use of anti-CD38 antibodies in autoimmune diseases, inflammatory processes/allergic conditions, and/or acute transplant rejection (Page 107, Column 1, Autoimmune Disorders). Autoantibody production by plasma cells plays an important role in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus (SLE), vasculitis, autoimmune cytopenias, and rheumatoid arthritis; B-cell depleting therapy with anti-CD20 or anti-CD22 monoclonal antibodies is frequently used in autoimmunity to reduce
autoantibody production, antigen presentation, cytokine production, and activation of T cells but long-lived autoreactive plasma cells largely resist B-cell-targeted therapy, and these non-eradicated plasma cells continue to produce autoantibodies wherein, recently, it was shown that CD19-negative bone marrow plasma cells, which express CD38, are enriched in chronically inflamed tissue and secrete autoantibodies (Id.). While CD38-targeting antibodies were initially developed to kill malignant plasma cells, these monoclonal antibodies may also abrogate the production of autoantibodies in autoimmune disorders and thereby reduce autoantibody-dependent effector mechanisms; therefore, treatment of patients with SLE and other autoimmune disorders with anti-plasma cell antibodies alone or in combination with standard-of-care therapies, may be a new therapeutic approach (Id.). Similarly, CD38 antibodies may mediate depletion of allergen-specific IgG, A, or E secreting plasma cells that maintain inflammatory processes wherein, by employing this anti-inflammatory action, anti-CD38 therapy may be beneficial in patients with severe allergic conditions (Id.). Additionally, in transplantation medicine reduction in alloantibody levels with an anti-CD38 antibody during acute rejection may
diminish transplant loss (Id.). Thus, Donk explicitly suggests the use of anti-CD38 antibodies to diminish transplant loss during acute rejection.
However, neither Muro nor Donk explicitly teach/suggest administering an anti-CD38 antibody to a patient at a dose of about 12-20 mg/kg/week for no more than 4 weeks. This deficiency is remedied by Doshi.
Doshi discloses that CD38 is a multifunctional protein having function in (i) receptor-mediated adhesion and signaling, as well as mediating calcium mobilization via its ecto-enzymatic activity catalyzing formation of cyclic ADP-ribose (cADPR) and ADPR; (ii) mediating cytokine secretion and activation and proliferation of lymphocytes; (iii) via its NAD glycohydrolase activity, regulates extracellular NAD+ levels, which have been implicated in modulating the regulatory T-cell compartment; and (iv) CD38 signaling occurs via cross-talk with antigen-receptor complexes on T and B cells or other types of receptor complexes, e.g., MHC molecules, involving CD38 in several cellular responses, but also in switching and secretion of IgG1 (Paragraph 0003). CD38 is a type II transmembrane glycoprotein expressed on hemopoietic cells such as medullary thymocytes, activated T- and B-cells, resting NK cells and monocytes, lymph node germinal center lymphoblasts, plasma B cells, intrafollicular cells and dendritic cells; a portion of normal bone marrow cells, particular precursor cells as well as umbilical cord cells are CD38-positive (Paragraph 0004). Doshi more specifically teaches a method of treating a subject having acute lymphoblastic leukemia (ALL), comprising administering to a patient in need thereof an anti-CD38 antibody that competes for binding to CD38 with an antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5, wherein the anti-CD38 antibody induces in vitro killing of ALL cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity (Paragraph 0034). It is specifically noted that the VH and VL of Doshi SEQ ID NOs: 4 and 5, respectively, comprise 100% matches to the instantly claimed HCDRs (instant SEQ ID NOs: 6, 7, and 8) and LCDRs (instant SEQ ID NOs: 9, 10, and 11), respectively (see Page 4). Additionally, Doshi teaches that the Fc portion of the antibody may mediate antibody effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC) wherein such function may be mediated by binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system; typically, the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of target cells, for example CD38-expressing cells (Paragraph 0039; emphasis added). Further, Doshi teaches that in some embodiments that ALL to be treated is B-cell lineage ALL (Paragraph 0070). Doshi further teaches that the anti-CD38 antibody may be administered to a patient by any suitable route, for example parentally by intravenous (i.v.) infusion or bolus injection, intramuscularly, subcutaneously, or intraperitoneally (Paragraph 0094). Additionally, the dose given to a patient having ALL is sufficient to alleviate or at least partially arrest the disease being treated ("therapeutically effective amount") and may be sometimes 0.005 mg to about 100 mg/kg, e.g., about 0.05 mg to about 30 mg/kg or about 5 mg to about 25 mg/kg, or about 4 mg/kg, about 8 mg/kg, about 16 mg/kg or about 24 mg/kg, or for example about 1, 2, 3, 4, 5, 6, 7, 8, 9or l0 mg/kg, but may even higher, for example about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg/kg (Paragraph 0095). Administration of the anti-CD38 antibody in the methods of the invention may be repeated after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or longer wherein repeated courses of treatment are also possible and may be at the same dose or at a different dose wherein, for example, the anti-CD38 antibody in the methods of the invention may be administered at 8 mg/kg or at 16 mg/kg at weekly interval for 8 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every two weeks for an additional 16 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every four weeks by intravenous infusion (Paragraph 0097). It is further noted that a "therapeutically effective amount" is defined as referring to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result wherein a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual (Paragraph 0033). Thus, as evidenced by the reference, it is noted that working dosages and related time periods are recognized as therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of dosages and related time periods for anti-CD38 antibodies/compositions would be seen as routine optimization. Thus, Doshi teaches the administration of an anti-CD38 antibody, which may comprise the instantly claim HCDRs and LCDRs to a patient. While it is acknowledged that Doshi teaches the administration of said antibody in the context of treating ALL, Doshi also teaches that the role of CD38 protein is multi-faceted and the antibody compositions of the invention are capable of targeting and subsequently inhibiting and/or depleting CD38-expressing cells generally, wherein the preferred method of the invention can treat ALL of B cell lineage, specifically.
Muro, Donk, and Doshi are considered to be analogous to the present invention as they are in the same field of B cell related diseases/disorders/conditions and CD38 as a therapeutic target for such diseases/disorders/conditions. With regard to instant claim 1, it is specifically noted that the recitation of “reducing or removing donor specific anti-human leukocyte antigen (HLA) antibodies in a subject, or treating, inhibiting, or reducing severity of antibody- mediated rejection (ABMR) response to an organ transplant” and “thereby reducing or removing the donor specific anti-HLA antibodies or treating, inhibiting, or reducing severity of the ABMR response in the subject” are merely intended results of the instantly claimed method. As such, any method/obvious method comprising the active step of administering to the subject an anti-CD38 antibody or a CD38-binding fragment of the anti-CD38 antibody in about 12-20 mg/kg/week for a period of no more than 4 weeks, wherein the anti-CD38 antibody comprises daratumumab, or wherein the anti-CD38 antibody or the CD38-binding fragment of the anti-CD38 antibody comprises heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, would necessarily cause the intended result. It would have been obvious to one of ordinary skill in the art to target CD38-expressing B cells in cases of antibody-mediated rejection in order to block alloantibody production in cases of organ transplantation, as suggested by both Muro and Donk, wherein the administration of an anti-CD38 antibody composition comprising the instantly claimed anti-CD38 antibody or antigen binding fragment thereof (e.g., daratumumab) at a dose of 12-20 mg/kg/week for no more than 4 weeks would be expected to be capable of inhibiting and/or depleting CD38-expressing cells, as suggested by Doshi, thereby treating antibody-mediated rejection in cases of organ transplantation; combining prior art elements according to known methods would be reasonably expected to yield predictable results. One of ordinary skill in the art would have been motivated to utilize the anti-CD38 antibody composition disclosed by Doshi in cases of antibody-mediated rejection because both Muro and Donk indicate that such an approach would have a reasonable expectation of success, wherein Doshi further indicates that the doses/dose schedule of such an antibody composition could be optimized for such cases, as dosing/dose schedules are recognized as result-effective variables.
With regard to claim 3, Muro teaches that daratumumab is a commercially available agent that can target CD38 (Page 1, Column 2, Paragraph 4) and Doshi teaches that an exemplary antibody that binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 is daratumumab (Paragraph 0036). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 10, Doshi further teaches the heavy chain and light chain amino acid sequences of daratumumab, corresponding to SEQ ID NOs: 12 and 13, respectively. It is noted that SEQ ID NOs: 12 and 13 comprise the instantly claimed HCDRs (instant SEQ ID NOs: 6, 7, and 8) and LCDRs (instant SEQ ID NOs: 9, 10, and 11), respectively (Page 4). Doshi SEQ ID NO: 12 also comprises 100% matches to the instantly claimed variable heavy region (instant SEQ ID NO: 4) and heavy chain (instant SEQ ID NO: 2) while Doshi SEQ ID NO: 13 comprises 100% matches to the instantly claimed variable light region (instant SEQ ID NO: 5) and light chain (instant SEQ ID NO: 3). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 13-15, Doshi further teaches that the anti-CD38 antibody may be administered to a patient by any suitable route, for example parentally by intravenous (i.v.) infusion or bolus injection, intramuscularly, subcutaneously, or intraperitoneally (Paragraph 0094). Additionally, the dose given to a patient having ALL is sufficient to alleviate or at least partially arrest the disease being treated ("therapeutically effective amount") and may be sometimes 0.005 mg to about 100 mg/kg, e.g., about 0.05 mg to about 30 mg/kg or about 5 mg to about 25 mg/kg, or about 4 mg/kg, about 8 mg/kg, about 16 mg/kg or about 24 mg/kg, or for example about 1, 2, 3, 4, 5, 6, 7, 8, 9or l0 mg/kg, but may even higher, for example about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg/kg (Paragraph 0095). Administration of the anti-CD38 antibody in the methods of the invention may be repeated after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or longer wherein repeated courses of treatment are also possible and may be at the same dose or at a different dose wherein, for example, the anti-CD38 antibody in the methods of the invention may be administered at 8 mg/kg or at 16 mg/kg at weekly interval for 8 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every two weeks for an additional 16 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every four weeks by intravenous infusion (Paragraph 0097). Thus, Doshi teaches treating ALL of B cell lineage (i.e., a B cell related disease/disorder/condition) with routes of administration and dosages falling within those described in the instant claims. It is further noted that a "therapeutically effective amount" is defined as referring to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result wherein a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual (Paragraph 0033). Thus, as evidenced by the reference, it is noted that working dosages and related time periods are recognized as therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of dosages and related time periods for anti-CD38 antibodies/compositions would be seen as routine optimization. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 17-18 and 21-22, it is noted that the teachings of Muro, Donk, and Doshi address all claim limitations as detailed above: Muro teaches reducing/inhibiting alloantibody (i.e., donor specific alloantibodies against HLA molecules) production, and subsequently treating AMR, by targeting B cell activities (e.g., via CD38), Donk further suggests using daratumumab in cases of acute rejection to prevent transplant loss, and Doshi specifically addresses mechanisms of anti-CD38 antibodies, including daratumumab and its sequences, with respect to targeting CD38-expressing cells (e.g., B cells). Additionally, it is noted that the recitation of “preventing, stabilizing or reducing antibody-mediated rejection (ABMR) response” and “desensitizing a subject by reducing and/or eliminating donor specific anti-human leukocyte antigen (HLA) antibodies in the subject” in claims 17 and 21, respectively, are merely intended results of the instantly claimed methods. As such, any method/obvious method comprising the active step of administering to the subject an anti-CD38 antibody or a CD38-binding fragment of the anti-CD38 antibody in about 12-20 mg/kg/week for a period of no more than 4 weeks, wherein the anti-CD38 antibody comprises daratumumab, or wherein the anti-CD38 antibody or the CD38-binding fragment of the anti-CD38 antibody comprises heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively, and light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively, would necessarily cause the intended result. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 25, it is noted that both Muro teaches that the true role of DSA response to solid allograft and the role of the ontogeny of B cells are not fully understood in all types of transplant, especially in liver transplantation, but it is known the eventual potential of B cell managing to prevent and treat an antibody mediated rejection (Page 1, Column 1, Paragraph 2); B-cell precursors, immature B cells, transitional B cells, activated B cells, memory B cells, plasmablast and plasma cells are all the possible cellular targets that block alloantibody production (Page 1, Column 1, Paragraph 3). Some molecules that appear in B cell ontogeny and may be of interest include CD10, CD23, CD24, CD25, CD38, CD52 or CD138 wherein some important agents that are commercially available are Daclizumab (CD25), Alemtuzumab (CD52), and new agents Lumiliximab (CD23) and Daratumumab (CD38) (Page 1, Column 2, Paragraph 4). Muro further teaches that B-cells not only participate in antibody production but also play an important role as antigen presenting cell (APC) to activate CD4 lymphocytes and that a specific subpopulation of B cells has also been identified as regulatory B-cell (Bregs) with capacity to release immunomodulatory cytokines (i.e., TGF-β, IL-10 and IL-35), and thus there is growing evidence that B-cells are essential contributors to transplant tolerance (Page 1, Column 2, Paragraph 6). Muro suggests that B-cell targets to prevention and treatment of antibody-mediated rejection will be a key point in a better graft survival outcome and define a therapeutic arsenal to avoid graft failure (Page 2, Column 1, Paragraph 2). Thus, Muro suggests the role of B cell activity in AMR/graft failure in cases of organ transplantation, targeting B cells can block alloantibody production, potential B cell targets (e.g., CD38), and some commercially available agents that are specific to said targets (e.g., daratumumab). Donk teaches CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM wherein, more specifically, daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies; CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases (Id.). More specifically, Donk points to the use of anti-CD38 antibodies in autoimmune diseases, inflammatory processes/allergic conditions, and/or acute transplant rejection (Page 107, Column 1, Autoimmune Disorders). Autoantibody production by plasma cells plays an important role in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus (SLE), vasculitis, autoimmune cytopenias, and rheumatoid arthritis; B-cell depleting therapy with anti-CD20 or anti-CD22 monoclonal antibodies is frequently used in autoimmunity to reduce
autoantibody production, antigen presentation, cytokine production, and activation of T cells but long-lived autoreactive plasma cells largely resist B-cell-targeted therapy, and these non-eradicated plasma cells continue to produce autoantibodies wherein, recently, it was shown that CD19-negative bone marrow plasma cells, which express CD38, are enriched in chronically inflamed tissue and secrete autoantibodies (Id.). While CD38-targeting antibodies were initially developed to kill malignant plasma cells, these monoclonal antibodies may also abrogate the production of autoantibodies in autoimmune disorders and thereby reduce autoantibody-dependent effector mechanisms; therefore, treatment of patients with SLE and other autoimmune disorders with anti-plasma cell antibodies alone or in combination with standard-of-care therapies, may be a new therapeutic approach (Id.). Similarly, CD38 antibodies may mediate depletion of allergen-specific IgG, A, or E secreting plasma cells that maintain inflammatory processes wherein, by employing this anti-inflammatory action, anti-CD38 therapy may be beneficial in patients with severe allergic conditions (Id.). Additionally, in transplantation medicine reduction in alloantibody levels with an anti-CD38 antibody during acute rejection may
diminish transplant loss (Id.). Thus, Donk explicitly suggests the use of anti-CD38 antibodies to diminish transplant loss during acute rejection and that anti-CD38 antibodies may be used to treat other conditions including autoimmune diseases, allergic conditions, and/or multiple myeloma. Thus, Muro and Donk both suggests the treatment of patient populations who do not have acute lymphoblastic leukemia with anti-CD38 agents (e.g., daratumumab). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 4-6 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; 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").
Muro, Donk, and Doshi render the method of claim 1 obvious. However, none of the cited references teach that a subject has undergone standard-of-care treatment that was ineffective (claim 4) or wherein the subject is resistant to immunosuppressive treatment (claim 5). These deficiencies are remedied by Singh.
With regard to claims 4-5, 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.
Muro, Donk, Doshi, and Singh are all considered to be analogous to the present invention as they are all in the same field of B cell related diseases/disorders/conditions and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to utilize the method rendered obvious by Muro, Donk, and Doshi in cases wherein treatment of patients with standard-of-care is ineffective because combining prior art elements according to known methods would be expected to yield predictable result. Patients may be further resistant to treatment with steroids because blockade of the residual alloantibody and/or the depletion of naive and memory B cells are known therapeutic routes, as taught by Singh, and one of ordinary skill in the art would recognize that anti-CD38 therapies, as suggested by the combination of Muro, Donk, and Doshi, would provide an alternate therapeutic route compared to the standard-of-care routes disclosed by Singh.
With regard to claim 6, Muro suggests targeting B cells/CD38 generically in cases of organ transplantation as detailed above, and Singh teaches specific cases of kidney and heart transplants, as detailed above. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim 16 is 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; 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").
The method of claim 1 is rendered obvious by Muro, Donk, and Doshi. However, none of the cited references disclose the administration of an anti-CD38 antibody/composition 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).
Muro, Donk, Doshi, and Sureshkumar are all considered to be analogous to the present invention as they are in the same field of B cell related diseases/disorders/conditions and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to modify the method taught by Muro, Donk, and Doshi such that the method further comprises administering tracolimus and/or mycophenolate mofetil because combining prior art elements according to known methods would be expected to yield predictable results; as taught by Sureshkumar, MMF inhibits in vitro antibody production by B-cells and reduces in vivo humoral response in renal transplant recipients and MMF with tacrolimus can limit B-cell responses in renal allograft recipients presenting with AMR and thus combining MMF with an additional B-cell based therapy such as an anti-CD38 antibody would be expected to improve therapeutic outcomes in patients presenting with AMR.
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; 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").
The methods of claims 17 and 21 are rendered obvious by Muro, Donk, and Doshi as detailed above. However, none of the cited references explicitly detail selecting a subject exhibiting symptoms of AMBR before/at the time of administering the anti-CD38 antibody/composition (claims 19-20) nor specifically administering the anti-CD38 antibody/composition before/at the time of transplant or after the transplant (claims 23-24). 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 AMBR with a different therapeutic agent than instantly claimed, support for an anti-CD38 agent is supported by Muro, Donk, and Doshi above, and 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 AMBR and that AMBR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation.
Muro, Donk, Doshi, and Jordan are considered to be analogous to the present invention as they are all in the same field of B cell related diseases/disorders/conditions and therapies for said B cell related diseases/disorders/conditions. Thus, it would have been obvious to one of ordinary skill in the art to further modify the method of Muro, Donk, and Doshi such that a patient can be selected for treatment based on showing symptoms of AMBR and that AMBR can be treated at the time of transplantation, after transplantation, and/or both during and after transplantation, as suggested by Jordan, because combining prior art elements according to known methods would be expected to yield predictable results. One of ordinary skill in the art would be motivated to treat subjects exhibiting AMBR symptoms to avoid unnecessary B-cell targeting therapy.
Response to Arguments
On Pages 6-8 of Remarks (11/24/2025), Applicant argues the following:
An important feature of the claimed method is 12-20 mg/kg/week of daratumumab (or an antibody fragment containing the six CDR sequences) for a period of no more than 4 weeks. The Applicant has discovered that such a dosing 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 (see Paragraphs 0148, 0156, 0162, and 0167 of the instant specification). The persisted effect is well beyond the half-life of daratumumab which has been reported to be only about 9 days to 18 days.
The combination of Muro and Doshi, even with Singh, Sureshkumar, and Jordan, fails to suggest the claimed treatment dosing regimen. Doshi only discloses a broad general dosage directed to ALL treatment. There is simply no guidance in Doshi alone or in combination with Muro or others to select daratumumab dosing regimen as specified for treating ABMR and reducing donor specific antibodies. Persistent reduction in HLA class I antibodies were observed 6 months after treatment in patients having received only 4 weeks of daratumumab treatment. That is a clinically relevant superior result from an unobvious dosage regimen in treating ABMR.
Applicant’s arguments have been fully considered, but in view of the new/updated claim rejections under 35 USC § 103 and the arguments presented below, Applicant’s arguments are deemed not persuasive.
With regard to Applicant’s arguments above, the following is noted:
With reference to the dosing regimen and which was “remarkably effective for clinically significantly reducing HLA antibodies”, it is noted that the data presented with regard to Paragraphs 0148, 0156, 0162, and 0167 of the instant specification (i.e., Figures 1-2), it is noted that there is no statistical analysis accompanying the data. MPEP 716.02b: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Furthermore, Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. It is further noted that the prior art reasonably suggests the results corresponding to Figures 1-2; Muro suggests the role of B cell activity in AMR/graft failure/T cell activation, including in cases of organ transplantation, wherein targeting B cells can block alloantibody production, and Muro identified potential B cell targets (e.g., CD38), and some commercially available agents that are specific to said targets (e.g., daratumumab). Donk points to the use of anti-CD38 antibodies in autoimmune diseases, inflammatory processes/allergic conditions, and/or acute transplant rejection, and discloses that B-cell depleting therapy with anti-CD20 or anti-CD22 monoclonal antibodies is frequently used in autoimmunity to reduce autoantibody production, antigen presentation, cytokine production, and activation of T cells but long-lived autoreactive plasma cells largely resist B-cell-targeted therapy, and these non-eradicated plasma cells continue to produce autoantibodies wherein, recently, it was shown that CD19-negative bone marrow plasma cells, which express CD38, are enriched in chronically inflamed tissue and secrete autoantibodies; while CD38-targeting antibodies were initially developed to kill malignant plasma cells, these monoclonal antibodies may also abrogate the production of autoantibodies (i.e., via targeting of B-cells) in autoimmune disorders and thereby reduce autoantibody-dependent effector mechanisms. Thus, it would be expected that administering an anti-CD38 agent (e.g., daratumumab) would reduce alloantibody production in cases of antibody-mediated rejection of organ transplants by targeting antibody-producing B cells and by subsequently activating T cells.
With regard to the argument of the combination of references, it is noted that the original claim rejections have been modified to further incorporate the Donk reference. While it is acknowledged that the Doshi reference is in reference to the therapeutic treatment of ALL, it is specifically noted that the rejection relies on the teachings of Muro and Donk in addition to Doshi; Muro and Donk both suggest the use of anti-CD38 agents (e.g., daratumumab) in cases of B-cell mediated disorders/conditions (e.g., antibody-mediated conditions which may include rejection of organ transplants). Thus, the rejection is based on it being obvious to one of ordinary skill in the art to target CD38-expressing B cells in cases of antibody-mediated rejection in order to block alloantibody production in cases of organ transplantation, as suggested by both Muro and Donk, wherein the administration of an anti-CD38 antibody composition comprising the instantly claimed anti-CD38 antibody or antigen binding fragment thereof (e.g., daratumumab) at a dose of 12-20 mg/kg/week for no more than 4 weeks would be expected to be capable of inhibiting and/or depleting CD38-expressing cells, as suggested by Doshi, thereby treating antibody-mediated rejection in cases of organ transplantation; combining prior art elements according to known methods would be reasonably expected to yield predictable results. One of ordinary skill in the art would have been motivated to utilize the anti-CD38 antibody composition disclosed by Doshi in cases of antibody-mediated rejection because both Muro and Donk indicate that such an approach would have a reasonable expectation of success, wherein Doshi further indicates that the doses/dose schedule of such an antibody composition could be optimized for such cases, as dosing/dose schedules are recognized as result-effective variables. Additionally, it is recognized that the combination of Muro, Donk, and Doshi render obvious the active steps of the instantly claimed method, and that as such the intended results instantly claimed would necessarily occur. The fact that applicant 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 mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. See In re Wiseman, 201 USPQ 658 (CCPA 1979). Furthermore, granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. See In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See MPEP § 2145.
Additionally, upon further consideration and with additional searching, the reference US 2018/0235986 A1 (herein after referred to as “Labotka”) has been utilized in a new set of claim rejections under 35 U.S.C. 103, wherein Labotka teaches/suggests a method of treating antibody-mediated disorders, including antibody-mediated rejection in organ transplantation, comprising administering an anti-CD38 antibody (e.g., daratumumab) at doses of about 4-20 mg/kg wherein said doses may be once a week for between 2-20 weeks (including 2-4 weeks).
Conclusion
Claims 1, 3-6, 10, and 13-25 are pending. Claims 1, 3-6, 10, and 13-25 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642