DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 25, 2026 has been entered.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 11-14, 16, 18-26, and 28-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites that the pediatric patient was “diagnosed with refractory and/or relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation”. It is unclear if the patient has relapsed following alloHSCT and is then administered the bispecific, or if the patient has relapsed disease following another therapeutic, perhaps front-line chemotherapy, and the bispecific antibody is to be administered after alloHSCT. Said another way, does “after allogeneic hematopoietic stem cell transplantation” characterized what the patient is refractory and/or relapsed to or does it define when the CD19xCD3 bispecific single chain antibody can be administered?
For the purpose of compact prosecution, after HSCT is interpreted as both characterizing what the patients disease is refractory and/or relapsed to and defining that the CD19xCD3 bispecific antibody should be administered following alloHSCT.
Claims 2, 11-14, 16, 18-26, and 28-31 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claims 25 and 26 recite “resulting from the treatment”. Claims 25 and 26 depend from claim 1 and claim 1 recites two potential treatments: allogeneic HSCT and the CD19xCD3 bispecific single chain antibody. It is unclear if “the treatment” in claims 25 and 26 refers to one or both of the treatments recites in claim 1.
For the purpose of compact prosecution, “the treatment” in claims 25 and 26 are interpreted as referring to the administration of the CD19xCD3 bispecific single chain antibody.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Claims 1, 2, 11-14, 16, 18-22, 25, 26, and 28 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013) in view of Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999).
Regarding claim 1, Bernett et al. teaches treating B-lineage acute lymphoblastic leukemia (ALL), and particularly pediatric acute lymphoblastic leukemia, by administering to the patient a CD19xCD3 bispecific single chain antibody, specifically MT103; see column 26, lines 60-63. Bernett et al. teaches antibody conjugates that target CD19 have been evaluated in clinical trials, including MT103, a CD19xCD3 bispecific single-chain. Bernett et al. teaches that acute lymphoblastic leukemia is most common in childhood; see column 4, lines 5-10. Regarding claims 1 and 16, Bernett et al. also teaches the dose of the antibody may range from .0001 to 100mg/kg of body weight or greater, equivalent to 2.5 ug/m2 to 2500mg/m2; see column 62, lines 25-35. Regarding claims 1, 13, and 14, Bernett et al. also teaches the antibody can be administered by multiple cycles of continuous infusion for 1-2 months, followed by a rest period of at least 2 weeks; see column 62, lines 35-40, lines 45-48, and 55-60. Additionally, Bernett et al. teaches the disease to be treated with the antibody is refractory; see Background.
Regarding claim 2, Bernett et al. teaches the antibody can be administered to treat a B-cell related disease, including B-cell acute lymphoblastic leukemia (B-ALL); see column 55, lines 55-60 and column 56, lines 20-25.
Regarding claim 22, Bernett et al. teaches tumors of precursor cells, including B precursor pediatric acute lymphoblastic leukemia among the cancers the antibody can be used to treat (Column 55, lines 50-60).
Bernett et al. teaches administering a CD19xCD3 bispecific antibody to treat ALL, but does not teach using minimal residual disease (MRD) associated with the disease to guide treatment. Additionally, while Bernett et al. teaches MT103 is an appropriate CD19xCD3 bispecific antibody to be used for treating ALL, the reference does not teach the structures of claims 1, 11, 12, and 18-21. Bernett et al. does not teach administering to a patient following relapse after allogenic HSCT.
Kufer et al. teaches pharmaceutical compositions and methods of treatment comprising administering a CD19xCD3 bispecific single chain antibody construct.
Regarding claim 1, Kufer et al. teaches pharmaceutical compositions and methods of treatment comprising administering a CD19xCD3 bispecific single chain antibody construct, including a method of treating a tumorous disease which may be a minimal residual cancer including leukemia, specifically B cell malignancies; see page 23, para 24, Claim 19. Kufer et al. teaches an anti-CD19 heavy chain comprised by reference SEQ ID NO: 65. Reference SEQ ID NO: 65 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NOs: 14, 15, and 16, respectively. Kufer et al. teaches an anti-CD19 light chain comprised by reference SEQ ID NO: 67. Reference SEQ ID NO: 67 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NOs: 11, 12, and 13 respectively. Kufer et al. teaches an anti-CD3 heavy chain comprised by reference SEQ ID NO: 51 . Reference SEQ ID NO: 51 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NO: 17, 18, and 19, respectively. Finally, Kufer et al. teaches an anti-CD3 light chain comprised by reference SEQ ID NO:51 . Reference SEQ ID NO: 51 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NO: 20, 21, and 22, respectively.
Regarding claim 11, Kufer et al. teaches the format VL(CD19)-VH(CD19)-VH(CD3)- VL(CD3); see Table 1.
Regarding claims 12 and 21, Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprising SEQ ID NO: 30; see Example 1. Reference SEQ ID NO: 30 is 100% identical to instantly claimed SEQ ID NO: 1.
Regarding claims 18-20, Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprises a CD19 VH amino acid sequence as set forth in reference SEQ ID NO: 65 and a CD19 VL amino acid sequence as set forth in SEQ ID NO: 67. Reference SEQ ID NO: 65 is 100% identical to instant SEQ ID NO: 3, and reference SEQ ID NO: 67 is 100% identical to instant SEQ ID NO: 5. Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprises a CD3 VH amino acid sequence as set forth in reference SEQ ID NO: 72 and a CD3 VL amino acid sequence as set forth in SEQ ID NO:74. Reference SEQ ID NO: 72 is 100% identical to instant SEQ ID NO: 7, and reference SEQ ID NO: 74 is 100% identical to instant SEQ ID NO: 9.
Regarding claim 25, Kufer et al. teaches the invention can be used to treat graft-versus-host disease (page 23).
Regarding claim 26, Kufer et al. teaches that in the case of proteinaceous medicaments for administration, it is important to optimize them, making them highly active and potent in order to avoid adverse side effects; page 4.
While Bernett et al. and Kufer et al. teach administering a broad range of doses, neither reference teaches administering the narrower dose range claimed in instant claim 16. Similar to Bernett et al., Kufer et al. does not teach administering to a patient following relapse after allogenic HSCT.
Regarding claims 1 and 16, Bauerle et al. teaches methods of treating B cell leukemias comprising administering a pharmaceutical composition of a CD19xCD3 bispecific single chain antibody construct to a human patient wherein the bispecific antibody is administered at a dose level of 15ug/m2 or between 10ug/m2 to 80ug/m2 as a continuous infusion for 4 weeks; see Description and claims 18, 21.
Regarding claim 26, Bauerle et al. also teaches that the human patient tolerated the medication and did not show any adverse side effects (page 7, last paragraph).
Bauerle et al. does not teach administering to a patient following relapse after allogenic HSCT.
Chi Kong et al. teaches that treatment of pediatric ALL with a HSCT, including from an unrelated donor (i.e. allogeneic) is not a first-line treatment for pediatric ALL; see second paragraph. Chi Kong et al. teaches that those who relapse following chemotherapy have resistant disease and that HSCT “offers better chance of [a] cure”. Socie et al. examines ALL patients (median age of 17 years old) having DFS for 2 years after allogeneic transplant; see Table 1. Socie et al. teaches that the primary cause of death among ALL patients having two-year DFS following allogeneic HSCT is relapse (48%).
Given that Chi Kong et al. teaches that pediatric ALL patients receiving allogeneic HSCT have chemotherapy resistant disease and that Socie et al. teaches that many ALL patients who received allogeneic HSCT will die due to disease relapse (48%) despite having two years of DFS, it would have been obvious to treat these pediatric ALL who relapse following allogeneic HSCT and who have chemotherapy resistant disease with the CD19xCD3 bispecific single chain antibody of Kufer et al. as taught by Bernett et al., Kufer et al., and Bauerle et al. One would have had a reasonable expectation of success treating these patients because Bernett et al. teaches that CD19xCD3 antibodies maybe used to treat cancer, including B-lineage ALL, and autoimmune disease, which includes GVHD; see column 4 lines 4-17, column 54 line 40, and column 56 line 54. Additionally, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating pediatric ALL by administering the CD19xCD3 antibody taught by Kufer et al. at a daily dose of 10ug to 100ug per square meter patient body surface area as a continuous infusion for at least four weeks, as taught by Bernett et al. in view of Bauerle et al. and Kufer et al. Regarding claims 25, 26, and 28, the patient having no signs of GVHD, not suffering from adverse side effects, or achieving MRD negative status naturally flows from the administration of the CD19xCD3 bispecific single chain antibody taught by Kufer et al.
Further, it would have been obvious to one of ordinary skill in the art to treat these pediatric ALL patients following relapse after allogeneic HSCT beyond the patient achieving minimal residual disease (MRD) negativity. Borowitz et al. teaches that ALL patients who achieve MRD negativity that the end of induction therapy tend to have a better 5-year EFS than those who are MRD positive, however, 51% of all treatment failures occurred in these MRD negative patients; page 5480 right column. Borowitz et al. teaches that MRD negativity does not define a group that needs no further treatment. Table S1 demonstrates that following induction therapy, patients were treated over several weeks, or at least 3 times, during consolidation therapy. Taken together, the teachings of Borowitz et al. support using MRD negative status as a prognostic, but not as a stop post for treatment. It would have been obvious to one of ordinary skill in the art would have had a reasonable expectation of success treating beyond the patient achieving MRD negative status, including for at least 3 times beyond achieving MRD negative status.
Claims 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013) in view of Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation ; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999) as applied to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28 above, and further in view of Manzke et al. (International Journal of Cancer. 80(5): 715-722; Published: March 1, 1999).
The teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. as related to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Bernett et al., Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. teach treating patients having cALL.
Manzke et al. teaches the cytolytic capacity of a CD19xCD3 bispecific antibody combined with a CD28 antibody in an autologous B cell-killing assay. Manzke et al. used patient samples from patients with ALL, including cALL, and incubating isolated tumor cells with effector cells in the presence of the antibodies and measuring cytolysis.
Given that Manzke et al. Figure 5 and Table 1 demonstrate that specific cytolysis is increased when cALL tumor cells are cocultured with autologous effector cells in the presence of CD19xCD3 bispecific single chain antibodies, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating pediatric patients having cALL after allogeneic HSCT based on the teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, Socie et al., and Manzke et al.
Claims 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013) in view of Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation ; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999) as applied to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28 above, and further in view of Szczepanski et al. (Leukemia. 21(4): 622-626; Published: February 15, 2007).
The teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. as related to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Bernett et al., Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. teach quantitative detection of MRD.
Regarding claim 29, Szczepanski teaches methods of quantitative detection of minimal residual disease in acute lymphoblastic leukemia. Szczepanski teaches RQ-PCR based quantification for identification of the most frequent fusion transcripts in acute lymphoblastic leukemia including: t(1;19)[E2A-PBX1], t(4;11)[AF4-MLL]; t(9;22)[BCR-ABL], (t12;21)[TEL-AML1]; page 623.
Regarding claim 30, Szczepanski teaches optimal MRD techniques should be characterized by sensitivity of at least one malignant cell per 10000 normal cells; page 262.
Although Szczepanski does not explicitly teach MRD negativity is measured as less than 1 leukemia cell per 10,000 bone marrow cells, it would have been prima facie obvious to use less than 1 leukemia cell per 10,000 bone marrow cells as a measure of MRD negativity given Szczepanski teaches that as the ideal sensitivity.
It would have been obvious to one of ordinary skill in the art to measure MRD negativity with quantitative detection of at least one cytogenetic abnormality, wherein the cytogenetic abnormality is detected by at least one marker with a sensitivity of greater than or equal to one in ten thousand cells, and wherein the MRD negativity is measured as less than 1 leukemia cell per 10,000 bone marrow cells, as part of a method of treating a pediatric patient diagnosed with refractory and/or relapsed ALL after allogeneic HSCT and administering a CD19xCD3 bispecific antibody as taught by the combined references. One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success because the combined references teach achieving minimal residual disease negativity in patients diagnosed with ALL and Szczepanski teaches quantitative and accurate methods of detecting MRD in ALL, including the accepted sensitivities for determining MRD negativity.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 11-14, 16, 18-22, 25, 26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,662,243 B2 in view of Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013), Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation; ; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999).
Regarding instant claims 1, 2, 11, 12, 16, and 18-21, issued claims 1-15 teach treating B-lineage ALL comprising administering a CD19xCD3 bispecific antibody at doses of 5-15 μg/m2/d and 15-60 μg/m2/d. The CD19xCD3 antibody comprises CDRs of SEQ ID NOs: 11-22 which are 100% identical to instant SEQ ID NOs: 11-22. Further, the CD19xCD3 antibody comprises SEQ ID NOs: 3 and 5, 7 and 9, or 1, which are 100% identical to the instant SEQ ID NO of the same number. SEQ ID NO: 1 comprises the domain order recited in instant claim 11.
The issued claims do not teach treating a pediatric patient diagnosed with refractory and/or relapsed ALL after allogeneic HSCT. The issued claims do not teach continuous infusion for at least four weeks followed by a 2-week treatment-free interval
Regarding claim 1, Bernett et al. teaches treating B-lineage acute lymphoblastic leukemia (ALL), and particularly pediatric acute lymphoblastic leukemia, by administering to the patient a CD19xCD3 bispecific single chain antibody, specifically MT103; see column 26, lines 60-63. Bernett et al. teaches antibody conjugates that target CD19 have been evaluated in clinical trials, including MT103, a CD19xCD3 bispecific single-chain. Bernett et al. teaches that acute lymphoblastic leukemia is most common in childhood; see column 4, lines 5-10. Regarding claims 1 and 16, Bernett et al. also teaches the dose of the antibody may range from .0001 to 100mg/kg of body weight or greater, equivalent to 2.5 ug/m2 to 2500mg/m2; see column 62, lines 25-35. Regarding claims 1, 13, and 14, Bernett et al. also teaches the antibody can be administered by multiple cycles of continuous infusion for 1-2 months, followed by a rest period of at least 2 weeks; see column 62, lines 35-40, lines 45-48, and 55-60. Additionally, Bernett et al. teaches the disease to be treated with the antibody is refractory; see Background.
Regarding claim 2, Bernett et al. teaches the antibody can be administered to treat a B-cell related disease, including B-cell acute lymphoblastic leukemia (B-ALL); see column 55, lines 55-60 and column 56, lines 20-25.
Regarding claim 22, Bernett et al. teaches tumors of precursor cells, including B precursor pediatric acute lymphoblastic leukemia among the cancers the antibody can be used to treat (Column 55, lines 50-60).
Bernett et al. teaches administering a CD19xCD3 bispecific antibody to treat ALL, but does not teach using minimal residual disease (MRD) associated with the disease to guide treatment. Additionally, while Bernett et al. teaches MT103 is an appropriate CD19xCD3 bispecific antibody to be used for treating ALL, the reference does not teach the structures of claims 1, 11, 12, and 18-21. Bernett et al. does not teach administering to a patient following relapse after allogenic HSCT.
Kufer et al. teaches pharmaceutical compositions and methods of treatment comprising administering a CD19xCD3 bispecific single chain antibody construct.
Regarding claim 1, Kufer et al. teaches pharmaceutical compositions and methods of treatment comprising administering a CD19xCD3 bispecific single chain antibody construct, including a method of treating a tumorous disease which may be a minimal residual cancer including leukemia, specifically B cell malignancies; see page 23, para 24, Claim 19. Kufer et al. teaches an anti-CD19 heavy chain comprised by reference SEQ ID NO: 65. Reference SEQ ID NO: 65 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NOs: 14, 15, and 16, respectively. Kufer et al. teaches an anti-CD19 light chain comprised by reference SEQ ID NO: 67. Reference SEQ ID NO: 67 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NOs: 11, 12, and 13 respectively. Kufer et al. teaches an anti-CD3 heavy chain comprised by reference SEQ ID NO: 51 . Reference SEQ ID NO: 51 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NO: 17, 18, and 19, respectively. Finally, Kufer et al. teaches an anti-CD3 light chain comprised by reference SEQ ID NO:51 . Reference SEQ ID NO: 51 comprises instantly claimed CDR1, CDR2, CDR3 with 100% identity to instant SEQ ID NO: 20, 21, and 22, respectively.
Regarding claim 11, Kufer et al. teaches the format VL(CD19)-VH(CD19)-VH(CD3)- VL(CD3); see Table 1.
Regarding claims 12 and 21, Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprising SEQ ID NO: 30; see Example 1. Reference SEQ ID NO: 30 is 100% identical to instantly claimed SEQ ID NO: 1.
Regarding claims 18-20, Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprises a CD19 VH amino acid sequence as set forth in reference SEQ ID NO: 65 and a CD19 VL amino acid sequence as set forth in SEQ ID NO: 67. Reference SEQ ID NO: 65 is 100% identical to instant SEQ ID NO: 3, and reference SEQ ID NO: 67 is 100% identical to instant SEQ ID NO: 5. Kufer et al. teaches a CD19xCD3 bispecific single chain antibody construct comprises a CD3 VH amino acid sequence as set forth in reference SEQ ID NO: 72 and a CD3 VL amino acid sequence as set forth in SEQ ID NO:74. Reference SEQ ID NO: 72 is 100% identical to instant SEQ ID NO: 7, and reference SEQ ID NO: 74 is 100% identical to instant SEQ ID NO: 9.
Regarding claim 25, Kufer et al. teaches the invention can be used to treat graft-versus-host disease (page 23).
Regarding claim 26, Kufer et al. teaches that in the case of proteinaceous medicaments for administration, it is important to optimize them, making them highly active and potent in order to avoid adverse side effects; page 4.
While Bernett et al. and Kufer et al. teach administering a broad range of doses, neither reference teaches administering the narrower dose range claimed in instant claim 16. Similar to Bernett et al., Kufer et al. does not teach administering to a patient following relapse after allogenic HSCT.
Regarding claims 1 and 16, Bauerle et al. teaches methods of treating B cell leukemias comprising administering a pharmaceutical composition of a CD19xCD3 bispecific single chain antibody construct to a human patient wherein the bispecific antibody is administered at a dose level of 15ug/m2 or between 10ug/m2 to 80ug/m2 as a continuous infusion for 4 weeks; see Description and claims 18, 21.
Regarding claim 26, Bauerle et al. also teaches that the human patient tolerated the medication and did not show any adverse side effects (page 7, last paragraph).
Bauerle et al. does not teach administering to a patient following relapse after allogenic HSCT.
Chi Kong et al. teaches that treatment of pediatric ALL with a HSCT, including from an unrelated donor (i.e. allogeneic) is not a first-line treatment for pediatric ALL; see second paragraph. Chi Kong et al. teaches that those who relapse following chemotherapy have resistant disease and that HSCT “offers better chance of [a] cure”. Socie et al. examines ALL patients (median age of 17 years old) having DFS for 2 years after allogeneic transplant; see Table 1. Socie et al. teaches that the primary cause of death among ALL patients having two-year DFS following allogeneic HSCT is relapse (48%).
Given that Chi Kong et al. teaches that pediatric ALL patients receiving allogeneic HSCT have chemotherapy resistant disease and that Socie et al. teaches that many ALL patients who received allogeneic HSCT will die due to disease relapse (48%) despite having two years of DFS, it would have been obvious to treat these pediatric ALL who relapse following allogeneic HSCT and who have chemotherapy resistant disease with the CD19xCD3 bispecific single chain antibody of issued claims as taught by the issued claims Bernett et al., Kufer et al., and Bauerle et al. One would have had a reasonable expectation of success treating these patients because Bernett et al. teaches that CD19xCD3 antibodies maybe used to treat cancer, including B-lineage ALL, and autoimmune disease, which includes GVHD; see column 4 lines 4-17, column 54 line 40, and column 56 line 54. Additionally, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating pediatric ALL by administering the CD19xCD3 antibody taught by issued claims at a daily dose of 10ug to 100ug per square meter patient body surface area as a continuous infusion for at least four weeks, as taught by Bernett et al. in view of Bauerle et al. and Kufer et al. One would have been motivated to administer the antibody in a continuous low-dose infusion for at least 4 weeks because Bauerle et al. and Kufer et al. teach that low-dose continuous infusion reduces the risk of adverse effects and fosters a favorable response by mimicking natural T cell activation. Regarding claims 25, 26, and 28, the patient having no signs of GVHD, not suffering from adverse side effects, or achieving MRD negative status naturally flows from the administration of the CD19xCD3 bispecific single chain antibody taught by Kufer et al.
Further, it would have been obvious to one of ordinary skill in the art to treat these pediatric ALL patients following relapse after allogeneic HSCT beyond the patient achieving minimal residual disease (MRD) negativity. Borowitz et al. teaches that ALL patients who achieve MRD negativity that the end of induction therapy tend to have a better 5-year EFS than those who are MRD positive, however, 51% of all treatment failures occurred in these MRD negative patients; page 5480 right column. Borowitz et al. teaches that MRD negativity does not define a group that needs no further treatment. Table S1 demonstrates that following induction therapy, patients were treated over several weeks, or at least 3 times, during consolidation therapy. Taken together, the teachings of Borowitz et al. support using MRD negative status as a prognostic, but not as a stop post for treatment. It would have been obvious to one of ordinary skill in the art would have had a reasonable expectation of success treating beyond the patient achieving MRD negative status, including for at least 3 times beyond achieving MRD negative status.
Claims 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,662,243 B2 in view of Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013), Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation ; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999) as applied to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28 above, and further in view of Manzke et al. (International Journal of Cancer. 80(5): 715-722; Published: March 1, 1999).
The teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. as related to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Bernett et al., Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. teach treating patients having cALL.
Manzke et al. teaches the cytolytic capacity of a CD19xCD3 bispecific antibody combined with a CD28 antibody in an autologous B cell-killing assay. Manzke et al. used patient samples from patients with ALL, including cALL, and incubating isolated tumor cells with effector cells in the presence of the antibodies and measuring cytolysis.
Given that Manzke et al. Figure 5 and Table 1 demonstrate that specific cytolysis is increased when cALL tumor cells are cocultured with autologous effector cells in the presence of CD19xCD3 bispecific single chain antibodies, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating pediatric patients having cALL after allogeneic HSCT based on the teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, Socie et al., and Manzke et al.
Claims 29-31 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,662,243 B2 in view of Bernett et al. (US Patent 8,524,867; PCT filed in English: August 14, 2007; Published: September 3, 2013), Kufer et al. (WO 2004/106381 A1; Published: December 9, 2004), Baeuerle et al. (WO2007068354 A1; Published: June 21, 2007), Borowitz et al. (Blood. 111(12): 5477-5485; Published: June 15, 2008), Li Chi-Kong (“Haematopoietic Stem Cell Transplantation in children.”; Hong Kong Society of Transplantation ; Published: January 2008), and Socie et al. (The New England Journal of Medicine. 341: 14-21; Published: July 1, 1999) as applied to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28 above, and further in view of Szczepanski et al. (Leukemia. 21(4): 622-626; Published: February 15, 2007).
The teachings of Bernett et al. in view of Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. as related to claim(s) 1, 2, 11-14, 16, 18-22, 25, 26, and 28, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Bernett et al., Kufer et al., Baeuerle et al., Borowitz et al., Li Chi-Kong, and Socie et al. teach quantitative detection of MRD.
Regarding claim 29, Szczepanski teaches methods of quantitative detection of minimal residual disease in acute lymphoblastic leukemia. Szczepanski teaches RQ-PCR based quantification for identification of the most frequent fusion transcripts in acute lymphoblastic leukemia including: t(1;19)[E2A-PBX1], t(4;11)[AF4-MLL]; t(9;22)[BCR-ABL], (t12;21)[TEL-AML1]; page 623.
Regarding claim 30, Szczepanski teaches optimal MRD techniques should be characterized by sensitivity of at least one malignant cell per 10000 normal cells; page 262.
Although Szczepanski does not explicitly teach MRD negativity is measured as less than 1 leukemia cell per 10,000 bone marrow cells, it would have been prima facie obvious to use less than 1 leukemia cell per 10,000 bone marrow cells as a measure of MRD negativity given Szczepanski teaches that as the ideal sensitivity.
It would have been obvious to one of ordinary skill in the art to measure MRD negativity with quantitative detection of at least one cytogenetic abnormality, wherein the cytogenetic abnormality is detected by at least one marker with a sensitivity of greater than or equal to one in ten thousand cells, and wherein the MRD negativity is measured as less than 1 leukemia cell per 10,000 bone marrow cells, as part of a method of treating a pediatric patient diagnosed with refractory and/or relapsed ALL after allogeneic HSCT and administering a CD19xCD3 bispecific antibody as taught by the combined references. One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success because the combined references teach achieving minimal residual disease negativity in patients diagnosed with ALL and Szczepanski teaches quantitative and accurate methods of detecting MRD in ALL, including the accepted sensitivities for determining MRD negativity.
Response to Arguments
Applicant’s amendments filed February 25, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
On page 7, Applicant argues that one would not have found it obvious to achieve MRD negativity in a pediatric ALL patient treated with a CD19xCD3 bispecific single chain antibody. Achievement of MRD negativity naturally flows from the administration of the CD19xCD3 antibody by continuous infusion according to claim 1. The method requires nothing more than the single active step of administering the CD19xCD3 antibody.
On page 8, Applicant argues there exists an unmet need for better treatment options. Applicant submits as evidence von Stackelberg et al. who teaches that pediatric ALL patients who relapse following chemotherapy and HSCT have “no realistic chance of a cure”. The instant disclosure demonstrates favorable response in two pediatric ALL patients. The first pediatric patient was followed for 1 year after CD19xCD3 antibody treatment. Socie et al. demonstrates that ALL patients may relapse despite having two year of DFS. And the second patient was followed for merely 4 weeks after treatment. These two case studies do not support that the invention satisfies the long-felt need for a “cure” in patients who have relapsed following chemotherapy and HSCT.
To the extent that Applicant may cite to unexpected results using the findings presented on pages 8-9, it is noted that unexpected results must be commensurate in scope with the claimed invention; see MPEP 716.02(d). The findings presented show the treatment of two patients with B-cell ALL administered with 15 μg/m2/d of the CD19xCD3 antibody. At present, claim 1 includes patients with T-cell ALL administered a broad range of CD19xCD3 antibody. There is no evidence that the higher doses of the range would induce GvL with GvHD. In fact, the instant Specification suggests a low dose of the T cell engager is required; see page 49 third paragraph.
On page 10, Applicant argues that Bernett et al. does not teach CD19xCD3 bispecific antibodies and that mention of MT103, the instantly claimed CD19xCD3 bispecific antibody, is limited to the CD19 binding domain and not the overall structure. First, claim 1 of Bernett et al. recites an anti-CD19 antibody comprising the CD19-binding sequences, which encompasses antibodies having more than a CD19-binding domain, such as CD19xCD3 antibodies. Columns 63 and 64 teach that CD19 antibody of claim 1 may be administered with additional antibodies, including CD3. Column 22 lines 44-47 states that the invention includes bispecific antibodies, column 17 line 57 defines “antibody” as including bispecific single chain antibodies, and column 25 line 15 Bernett et al. incorporates by reference Kufer et al. which teaches the sequences of MT103. Thus, Applicants argument that mention of MT103 refers to only the CD19 binding domain is unpersuasive.
Conclusion
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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