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 .
Claims 21 and 23 have been amended. Clams 21-24 and 27-36 are pending and under consideration.
The rejection of claims 21, 23, 24, and 27-36 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a hematopoietic proliferative disease characterized by proliferating cells expressing CD19, does not reasonably provide enablement for (i) a method of treating a hematopoietic proliferative disease characterized wherein the proliferating cells do not express CD19 or (ii) a method of treating a non-hematopoietic proliferative disease is withdrawn in light of applicant’s amendments of claims 21 and 23.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
The rejection of claims 21-24, 27, 29 and 31-35 under 35 U.S.C. 103 as being unpatentable over Van Berkel et al (WO2014/057117,cited in the prior Office action) in view of Arthur et al (WO2017/160954,cited in the prior Office action), Tiberghien et al (ACS Medicinal chemistry Letters, 2016, Vol. 7, pp. 983-987) and Antonow and Thurston (Chemical Reviews, 2011, Vol. 111, pp. 2815-2864) is maintained for reasons of record.
Van Berkel et al teach an anti-CD19 ADC comprising the structural limitations of the instant linker-drug moiety (claims 21 and 22 of ‘117). ConjE of claim 100 of ‘117 meets the specific limitation of the linker-drug of instant claim 21:
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Van Berkel et al teach that the resulting conjugate of the linker drug with the anti-CD19 antibody as an integer from 1 to 8 (claim 105 of ‘117) which meets the limitation of claim 24.
Van Berkel et al teach that the anti-CD19 antibody comprises the VH of SEQ ID NO: 2 paired with any one of the VL of SEQ ID NO: 7, 8, 9, 10, 11 or 12, which meets the limitation of the instant claims requiring VH of SEQ ID NO: 2 paired with the light chain of SEQ ID NO:8 in claim 26. It is noted that SEQ ID NO: 7 of ‘117 is identical to the instant SEQ ID NO: 8.
Van Berkel et al teach that the compound of the invention may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the disorder to be treated (page 84, lines 4-5) which meets the limitations of “before”, “after” or "simultaneous with” in claim 27. Van Berkel et al teach that disorders treatable by the administration of the inventive conjugates include, but are not limited to, non-Hodgkin Lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukemia (ALL) (page 82, second full paragraph) which meet the requirement of claim 23, the disorder of cancer in claim 31, the disorder of NHL in claim 32, CLL of claim 33 and ALL of claim 35. Van Berkel et al teach that the subject is a human (page 93, line 11) which meets the limitation of claim 29.
Van Berkel et al do not teach the combination of the inventive anti-CD19 PBD conjugate compounds with venetoclax as the chemotherapeutic agent for the synergistic treatment of non-Hodgkin Lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukemia.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD33 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD123 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the highest level of synergy was seen in DLBCL cells and AML cells that expressed high level of BCL-2 for the combination of ABT-199 (venetoclax) and the CD19 antibody, hBu12EC, conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 (paragraphs [0143]-[0144]).
Arthur et al teach that the combination of sub-optimal doses of both ABT-199 and CD19-ADC provided greater than 90% survival during the course of a 40-day experiment with transplanted cell lines lymphoma cell lines expressing CD19, and that the combined agents at sub-optimal doses exhibited synergy relative to sub-optimal doses of ABT-199 and sub-optimal doses of ABT-199 as single agents (paragraph [[0146]).
Tiberghien et al teach that the structure of SGD-1910/Talirine is
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and that the structure of SGD-3249/tesirine, required by the instant claims is:
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(page 983, second column).
Tiberghien et al teach that tesirine/SG3249 was the result of improvements on the design of SGD-1910 which lowered hydrophobicity while maintaining potency (page 983, first column, line 8-9 of the third paragraph to page 984, first column, line 2). Tiberghien et al teach that the alteration of the warhead of SGD-1910 to the warhead of tesirine was based on rational modifications of the warhead of SGD-1910 (page 984, first column, first full paragraph). Tiberghien et al teach that the resulting lower hydrophobicity contributes to low aggregation (page 986, first column, second full paragraph).
Antonow and Thurston teach that the mechanism of action of pyrrolobenzodiazepines (PBDs) is the covalent binding of PBD to the C2- amino group of guanine within the DNA minor groove (page 2818, Figure 4).
It would have been prima facie obvious at the time of the effective filing date to use ABT-199/Venetoclax in combination with the ConjE of Van Berkel et al especially for the treatment of non-Hodgkin Lymphomas/Leukemias expressing CD19 including DLBCL, CLL and ALL, thus fulfilling the limitations of claims 32, 33 and 35. One of skill in the art would understand from the teachings of Arthur et al that the cytotoxic synergy was not specific to the targeting antibody since synergy was observed with all of CD33, CD123 and CD19 targeting antibodies, and thus, synergy was not an unexpected result confined to a specific antibody targeted SGD-1910 in combination with venetoclax. One of skill in the art would be motivated to use the ConjE/ SG3249/tesirine of VanBerkel et al because Tiberghien et al teach that the identical structure of SG3249/tesirine, was an improvement over SGD-1910 due to lowered hydrophobicity, while maintaining cytotoxic potency. One of skill would also understand that both of SGD-1910 and ConjE/SG3249/tesirine formed the adduct with guanine in the minor groove of DNA. One of skill in the art would conclude that venetoclax would exhibit synergy when combined with an ADC comprising the instant anti-CD19 antibody comprising SEQ ID NO: 2 and 8 because Arthur et al teach synergy between anti-CD33 SGD-1910, anti-CD12-SGD-1910 and a different anti-CD19-SGD-1910, leading to the conclusion that the targeting antibody, or the specific targeted receptor, was not governing the observed synergistic interaction. Further, based on the teachings of Arthur et al and Antonow and Thurston, one of skill in the art would reasonably conclude that SG3249/tesirine, made to be an improvement over SGD-1910, and based on rational design principles for modifying SGD-1910, would have the same ability to bind to guanine in the minor groove of DNA and exert cytotoxicity in the picomolar range.
Regarding claims 27 it would have been prima facie obvious to administer the venetoclax before, after or simultaneous with the ConjE-anti-CD19 because Van Berkel et al teach that other agents may be administered before, after or simultaneous with the ConjE-anti-CD19.
Applicant argues that the anti-CD19 ADC disclosed in Arthur comprises a hBu12EC antibody which is different than the claimed antibody and a drug-linker which is different than the claimed drug linker. This has been considered but not found persuasive. Arthur et al teach synergy between anti-CD33 SGD-1910, anti-CD12-SGD-1910 and a different anti-CD19-SGD-1910, leading to the conclusion that neither the targeting antibody, nor the specific targeted receptor, was governing the observed synergistic interaction with venetoclax. Thus, applicants argument that the instant hBu12EC antibody would act differently from the prior art CD19 antibody conjugate is unpersuasive. With regard to the different linker, Tiberghien et al teach that the instant linker in tesirine/SG3249 was the result of improvements on the design of SGD-1910 which lowered hydrophobicity while maintaining potency. Tiberghien et al teach that the alteration of the warhead of SGD-1910 to the warhead of tesirine was based on rational modifications of the warhead of SGD-1910. Tiberghien et al teach that the resulting lower hydrophobicity contributes to low aggregation. Thus, it would not be expected that the linker in tesirine/SG3249 would be detrimental to the delivery of the pyrrolobenzodiazepine dimer to the minor groove of DNA where it would exert cytotoxicity. One of skill in the art would reasonably conclude that the resulting cytotoxicity combined with venetoclax would be synergistic based on the teachings of Arthur et al.
Applicant argues that the rejection fails to provide motivation for modification of Arthur’s anti-CD19 ADC to the specific combination of antibody and drug-linker recited in the claims. This has been considered but not found persuasive. The motivation to change to tesirine/SG3249 would be to lower hydrophobicity to decrease aggregation. Jain et al (Pharmaceutical Research, 2015, Vol. 32, pp. 3526-3540) teaches that linkers can have a profound effect on the physico-chemical properties of the ADC, in particular when the payloads are hydrophobic, a hydrophobic linker can create problems due to aggregation. (page 3527, lines 9-14 under the heading “The Linker”) Jain et al teach that ADC aggregates are insoluble and limit the achievable drug loading onto the antibody; are sequestered in the liver leading to hepatotoxicity and contribute to increased immunogenicity against the administered ADC /9page 3528, first column, lines 1-5). Thus, one of skill in the art would understand that aggregation of ADC is undesirable. One of skill in the art would be motivated to substitute the linker in tesirine for the linker in SGD-1910. Regarding the instant anti-CD19 antibody, Van Berkel et al teach that the anti-CD19 antibody comprises the VH of SEQ ID NO: 2 paired with any one of the VL of SEQ ID NO: 7, 8, 9, 10, 11 or 12, which meets the limitation of the instant claims requiring VH of SEQ ID NO: 2 paired with the light chain of SEQ ID NO:8 in claim 26. It is noted that SEQ ID NO: 7 of ‘117 is identical to the instant SEQ ID NO: 8. Arthur et al that the cytotoxic synergy was not specific to the targeting antibody since synergy was observed with all of CD33, CD123 and CD19 targeting antibodies, and thus, synergy was not an unexpected result confined to a specific antibody targeted SGD-1910 in combination with venetoclax. Thus, one of skill in the art would expect that any of the ADC based on antibodies comprising SEQ ID NO:2 paired with any of SEQ ID NO: 7, 8, 9, 10, 11 or 12 would be expected to synergize with venetoclax against hematopoietic cancers expressing CD19.
Applicant argues that the instant claimed combination exhibits synergy which is significantly better than any synergy shown in Arthur because Arthur lists multiple cell lines having low BCL2 expression levels where administration of venetoclax and the anti-CD19 antibody of Arthur resulted in no , or very little synergy such as DLBCL cell lines with low BLC-2 expression. Applicant argues that this is in contrast with post-filing data which shows that 8 DLBCL patients, 3 follicular lymphoma patients and 2 patients with Waldenstrom macroglobulinemia showed response rates in 7 out of 11 patients with complete remission in the 2paitnets with Waldenstrom macroglobulinemia. Applicant concludes that one of skill in the art reading the references cited by the office would not have anticipated the unexpected and improved results. This has been considered but not found persuasive. One of skill in the art would have understood that the combination of two therapeutic agents, A and B would only provide a therapeutic enhancement if the target of both drugs were present on the pathological cells. It is not unexpected that cell lines expressing low levels of BCL-2 would not have been subject to greater cytotoxic effect when venetoclax was used on combination with the ADC because the target for venetoclax was low. Applicant’s reference to post-filing clinical; results provide no information as to the expression level of BCL-2 in the treated patients
Claims 21-24, 27-29 and 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over Van Berkel et al, Arthur et al, Tiberghien et al, and Antonow and Thurston as applied to claims 21-24, 27, 29 and 31-35 above, and further in view of Davids et al (Journal of Clinical Oncology, 2017, Vol. 35, pp. 826-833, cited in the previous action).
The combined teachings of Van Berkel et al, Arthur et al, Tiberghien et al, and Antonow and Thurston render obvious the limitations of claims 21-24, 27, 29 and 31-35 for the reasons set forth above. None of Van Berkel et al, Arthur et al, Tiberghien et al, and Antonow and Thurston teach or suggest the administration of an additional chemotherapeutic agent as required in claim 28.
Davids et al teach the admisntration of venetoclax as a single agent to patients with relapsed or refractory NHL (Title). Davids et al teach that the activity of venetoclax varied among the different subtypes of NHL (page 825, in the paragraph labeled “result”) with the highest response of 75% observed in patients with Mantle Cell Lymphoma (page 831, second column, first full paragraph), and the lowest response of 18% was seen in patients with DLBCL (page 832, first column, first full paragraph). Davids et al teach that inhibition of Bcl2 will have greater impact when venetoclax is combined with other agents and that venetoclax will have a greater clinical impact when combined with other agents (page 832, second column, lines 6-9). Davids et al teach that preclinical data suggest that abbreviated use of venetoclax in combination with DNA-damaging cytotoxic agents may be sufficient to achieve durable remission. (page 832, bridging paragraph between the first and second columns). Davids et al teach that studies are underway to assess the safety and efficacy of combining venetoclax with chemotherapy, monoclonal antibodies and B-cell receptor signaling inhibitors (page 832, first column, first sentence of the bottom paragraph). Davids et al teach that rituximab augmented the efficacy of the less selective Bcl2 inhibitor, navitoclax, and similar studies with venetoclax are ongoing (page 832, second column, lines 1-3) and that the favorable toxicity profile and unique mechanism of action venetoclax lends itself to use in combination regimens.
It would have been prima facie obvious to administer a chemotherapy agent or rituximab as an additional agent in the method rendered obvious by the combined teachings of Van Berkel et al, Arthur et al, Tiberghien et al, and Antonow and Thurston. One of skill in the art would have been motivated to do so by the teachings of Davids et al regarding the favorable toxicity profile and unique mechanism of action suggesting that the use of venetoclax in combination regimens, and that studies are underway to test the safety and efficacy of venetoclax in combination with chemotherapy and rituximab.
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.
The rejection of claims 21-24, 27, 29, 31-35 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-15 and 17-19 of U.S. Patent No. 11,938,192 in view of Arthur et al (WO2017/160954), Tiberghien et al (ACS Medicinal chemistry Letters, 2016, Vol. 7, pp. 983-987) and Antonow and Thurston (Chemical Reviews, 2011, Vol. 111, pp. 2815-2864) is withdrawn after further consideration based on a lack of a claim requiring a combination with a chemotherapeutic agent.
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The rejection of claims 21-24, 27-29, and 31-34 on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No.9,931,414 in view of Arthur et al (WO2017/160954), Tiberghien et al (ACS Medicinal chemistry Letters, 2016, Vol. 7, pp. 983-987), Antonow and Thurston (Chemical Reviews, 2011, Vol. 111, pp. 2815-2864) and Davis et al (Journal of Clinical Oncology, 2017, Vol. 35, pp. 826-833, cited in the previous action) is maintained for reasons of record..
Claims 1, 7, 8, 11, 13 and 16 of the ‘414 patent teach the conjugate of ConjE, wherein the antibody comprises the Vh and Vl domains of SEQ ID NO:2 and 8, respectively. Claim 11 teaches a method of treating a CD19 overexpressing cancer comprising the administration of ConjE. Claim 12 of the patent teaches the method of claim 11 wherein the patient is administered a chemotherapeutic agent in combination with the conjugate.
Claim 10 teaches the pharmaceutical composition of claim 9 further comprising a therapeutically effective amount of a chemotherapeutic agent.
The claims of the patent do not teach a composition or method of treating cancer comprising the admisntration of ConjE targeted by an antibody comprising the Vh and Vl domains of SEQ ID NO:2 and 8, respectively in combination with venetoclax as the chemotherapeutic agent. The claims of the patent do not teach the particular disorders of interest treated by the claimed methods.
Section 804IIb of the M.P.E.P. states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)
In the instant case, the specification of the ‘414 patent teach:
Disorders of particular interest include, but are not limited to, non-Hodgkin Lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukaemia (ALL).
Thus, rendering obvious instant claims 32-35.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD33 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD123 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the highest level of synergy was seen in DLBCL cells and AML cells that expressed high level of BCL-2 for the combination of ABT-199 (venetoclax) and the CD19 antibody, hBu12EC, conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 (paragraphs [0143]-[0144]).
Arthur et al teach that the combination of sub-optimal doses of both ABT-199 and CD19-ADC provided greater than 90% survival during the course of a 40-day experiment with transplanted cell lines lymphoma cell lines expressing CD19, and that the combined agents at sub-optimal doses exhibited synergy relative to sub-optimal doses of ABT-199 and sub-optimal doses of ABT-199 as single agents (paragraph [[0146]).
Tiberghien et al teach that the structure of SGD-1910/Talirine is
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and that the structure of SGD-3249/tesirine, required by the instant claims is:
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(page 983, second column).
Tiberghien et al teach that tesirine/SG3249 was the result of improvements on the design of SGD-1910 which lowered hydrophobicity while maintaining potency (page 983, first column, line 8-9 of the third paragraph to page 984, first column, line 2). Tiberghien et al teach that the alteration of the warhead of SGD-1910 to the warhead of tesirine was based on rational modifications of the warhead of SGD-1910 (page 984, first column, first full paragraph). Tiberghien et al teach that the resulting lower hydrophobicity contributes to low aggregation (page 986, first column, second full paragraph).
Antonow and Thurston teach that the mechanism of action of pyrrolobenzodiazepines (PBDs) is the covalent binding of PBD to the C2- amino group of guanine within the DNA minor groove (page 2818, Figure 4).
Claims 14 and 15 of the ‘414 patent teach the combination of the CD19ADC with rituximab. The claims do not teach that the rituximab is administered in combination with the Bcl2 inhibitor, venetoclax and the CD19 ADC of the patent
Davids et al teach the admisntration of venetoclax as a single agent to patients with relapsed or refractory NHL (Title). Davids et al teach that the activity of venetoclax varied among the different subtypes of NHL (page 825, in the paragraph labeled “result”) with the highest response of 75% observed in patients with Mantle Cell Lymphoma (page 831, second column, first full paragraph), and the lowest response of 18% was seen in patients with DLBCL (page 832, first column, first full paragraph). Davids et al teach that inhibition of Bcl2 will have greater impact when venetoclax is combined with other agents (page 832, second column, lines 6-9). Davids et al teach that studies are underway to assess the safety and efficacy of combining venetoclax with chemotherapy, monoclonal antibodies and B-cell receptor signaling inhibitors (page 832, first column, first sentence of the bottom paragraph). Davids et al teach that rituximab augmented the efficacy of the less selective Bcl2 inhibitor, navitoclax, and similar studies with venetoclax are ongoing (page 832, second column, lines 1-3) and that the favorable toxicity profile and unique mechanism of action venetoclax lends itself to use in combination regimens.
It would have been prima facie obvious at the time of the effective filing date to use ABT-199/Venetoclax in combination with the ConjE ADC of the patent, especially for the treatment of non-Hodgkin Lymphomas/Leukemias expressing CD19 including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukemia (ALL) DLBCL, CLL and ALL, thus fulfilling the limitations of claims 32- 35. One of skill in the art would understand from the teachings of Arthur et al that the cytotoxic synergy was not specific to the targeting antibody since synergy was observed with all of CD33, CD123 and CD19 targeting antibodies, and thus, synergy was not an unexpected result confined to a specific antibody targeted SGD-1910 in combination with venetoclax. One of skill in the art would be motivated to use the conjugate of claim 4 of the patent because Tiberghien et al teach that the identical structure of SG3249/tesirine, was an improvement over SGD-1910 due to lowered hydrophobicity, while maintaining cytotoxic potency. One of skill would also understand that both of SGD-1910 and SG3249/tesirine formed the adduct with guanine in the minor groove of DNA. One of skill in the art would conclude that venetoclax would exhibit synergy when combined with an ADC comprising the instant anti-CD19 antibody comprising SEQ ID NO: 2 and 8 because Arthur et al teach synergy between anti-CD33 SGD-1910, anti-CD12-SGD-1910 and a different anti-CD19-SGD-1910, leading to the conclusion that the targeting antibody, or the specific targeted receptor, was not governing the observed synergistic interaction. Further, based on the teachings of Arthur et al and Antonow and Thurston, one of skill in the art would reasonably conclude that SG3249/tesirine, made to be an improvement over SGD-1910, and based on rational design principles for modifying SGD-1910, would have the same ability to bind to guanine in the minor groove of DNA and exert cytotoxicity in the picomolar range. It would have been further obvious to administer the venetoclax before, after or simultaneously with the ADC of claim 4 of the patent because these represent all the alternative for co-administration.
The rejection of claims 21-29, 31-34, 37 and 38 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10, 11, 14 and 15 of U.S. Patent No.11,318,211 in view of Arthur et al (WO2017/160954) in view of Tiberghien et al (ACS Medicinal chemistry Letters, 2016, Vol. 7, pp. 983-987), Antonow and Thurston (Chemical Reviews, 2011, Vol. 111, pp. 2815-2864) and Davids (Journal of Clinical Oncology, 2017, Vol. 35, pp. 826-833) is maintained for reason of record.
Claims 1-7, 10, 11, 14 and 15 of the ‘211 patent either disclose or render obvious the limitations of the instant claims for the reasons set forth above with the exception of the combination of the anti-CD19 ADC with venetoclax.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD33 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD123 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the highest level of synergy was seen in DLBCL cells and AML cells that expressed high level of BCL-2 for the combination of ABT-199 (venetoclax) and the CD19 antibody, hBu12EC, conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 (paragraphs [0143]-[0144]).
Arthur et al teach that the combination of sub-optimal doses of both ABT-199 and CD19-ADC provided greater than 90% survival during the course of a 40-day experiment with transplanted cell lines lymphoma cell lines expressing CD19, and that the combined agents at sub-optimal doses exhibited synergy relative to sub-optimal doses of ABT-199 and sub-optimal doses of ABT-199 as single agents (paragraph [[0146]).
Tiberghien et al teach that the structure of SGD-1910/Talirine is
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and that the structure of SGD-3249/tesirine, required by the instant claims is:
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(page 983, second column).
Tiberghien et al teach that tesirine/SG3249 was the result of improvements on the design of SGD-1910 which lowered hydrophobicity while maintaining potency (page 983, first column, line 8-9 of the third paragraph to page 984, first column, line 2). Tiberghien et al teach that the alteration of the warhead of SGD-1910 to the warhead of tesirine was based on rational modifications of the warhead of SGD-1910 (page 984, first column, first full paragraph). Tiberghien et al teach that the resulting lower hydrophobicity contributes to low aggregation (page 986, first column, second full paragraph).
Antonow and Thurston teach that the mechanism of action of pyrrolobenzodiazepines (PBDs) is the covalent binding of PBD to the C2- amino group of guanine within the DNA minor groove (page 2818, Figure 4).
It would have been prima facie obvious at the time of the effective filing date to use ABT-199/Venetoclaxin combination with the ConjE ADC of the patent, especially for the treatment of non-Hodgkin Lymphomas/Leukemias expressing CD19 including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukemia (ALL) DLBCL, CLL and ALL, thus fulfilling the limitations of claims 32- 35. One of skill in the art would understand from the teachings of Arthur et al that the cytotoxic synergy was not specific to the targeting antibody since synergy was observed with all of CD33, CD123 and CD19 targeting antibodies, and thus, synergy was not an unexpected result confined to a specific antibody targeted SGD-1910 in combination with venetoclax. One of skill in the art would be motivated to use the conjugate of claim 4 of the patent because Tiberghien et al teach that the identical structure of SG3249/tesirine, was an improvement over SGD-1910 due to lowered hydrophobicity, while maintaining cytotoxic potency. One of skill would also understand that both of SGD-1910 and SG3249/tesirine formed the adduct with guanine in the minor groove of DNA. One of skill in the art would conclude that venetoclax would exhibit synergy when combined with an ADC comprising the instant anti-CD19 antibody comprising SEQ ID NO: 2 and 8 because Arthur et al teach synergy between anti-CD33 SGD-1910, anti-CD12-SGD-1910 and a different anti-CD19-SGD-1910, leading to the conclusion that the targeting antibody, or the specific targeted receptor, was not governing the observed synergistic interaction. Further, based on the teachings of Arthur et al and Antonow and Thurston, one of skill in the art would reasonably conclude that SG3249/tesirine, made to be an improvement over SGD-1910, and based on rational design principles for modifying SGD-1910, would have the same ability to bind to guanine in the minor groove of DNA and exert cytotoxicity in the picomolar range. It would have been further obvious to administer the venetoclax before, after or simultaneously with the ADC of claim 4 of the patent because these represent all the alternative for co-administration.
Claims 14 and 15 of the ‘414 patent teach the combination of the CD19ADC with rituximab. The claims do not teach that the rituximab is administered in combination with the Bcl2 inhibitor, venetoclax and the CD19 ADC of the patent.
Davids et al teach the admisntration of venetoclax as a single agent to patients with relapsed or refractory NHL (Title). Davids et al teach that the activity of venetoclax varied among the different subtypes of NHL (page 825, in the paragraph labeled “result”) with the highest response of 75% observed in patients with Mantle Cell Lymphoma (page 831, second column, first full paragraph), and the lowest response of 18% was seen in patients with DLBCL (page 832, first column, first full paragraph). Davids et al teach that inhibition of Bcl2 will have greater impact when venetoclax is combined with other agents (page 832, second column, lines 6-9). Davids et al teach that studies are underway to assess the safety and efficacy of combining venetoclax with chemotherapy, monoclonal antibodies and B-cell receptor signaling inhibitors (page 832, first column, first sentence of the bottom paragraph). Davids et al teach that rituximab augmented the efficacy of the less selective Bcl2 inhibitor, navitoclax, and similar studies with venetoclax are ongoing (page 832, second column, lines 1-3) and that the favorable toxicity profile and unique mechanism of action venetoclax lends itself to use in combination regimens.
It would have been prima facie obvious at the time of the effective filing date to combine rituximab with the ADC of the patent and venetoclax, thus rendering obvious the limitations of claim 28. One of skill in the art would have been motivated to do so by the teachings of Davids et al on the on-going study involving the combination of venetoclax and rituximab. Thus, claims 14 and 15 of the patent used as an auxiliary therapeutic agent meets the limitations of claim 28 requiring an additional chemotherapeutic agent.
Thus, claim 14 of the patent used as an auxiliary therapeutic agent meets the limitations of instant claim 28 requiring an additional chemotherapeutic agent.
The rejection of claims 21-24, 27, 29, 31-34, on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No.11,771,775 in view of Arthur et al (WO2017/160954), Tiberghien et al (ACS Medicinal chemistry Letters, 2016, Vol. 7, pp. 983-987), Antonow and Thurston (Chemical Reviews, 2011, Vol. 111, pp. 2815-2864)
and Davids (Journal of Clinical Oncology, 2017, Vol. 35, pp. 826-833) is maintained for reasons of record.
Claims 1-18 of the ‘775 patent teach a method of treating a lymphoma by administering, in part, ConjE, wherein the antibody comprises the Vh of SEQ ID NO:2 and the Vl of SEQ ID NO:8, and wherein the method further comprises the administration of a chemotherapeutic agent. The claims of the patent do not disclose that the chemotherapeutic agent is venetoclax.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD33 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the combination of ABT-199 (venetoclax) and an anti-CD123 antibody conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 exhibited marked synergistic cytotoxic activity in AML cell lines, greater than that exhibited by the conjugate in combination with 5-azacytidine or decitabine.
Arthur et al teach that the highest level of synergy was seen in DLBCL cells and AML cells that expressed high level of BCL-2 for the combination of ABT-199 (venetoclax) and the CD19 antibody, hBu12EC, conjugated to the pyrrolobenzodiazepine dimer drug linker SGD-1910 (paragraphs [0143]-[0144]).
Arthur et al teach that the combination of sub-optimal doses of both ABT-199 and CD19-ADC provided greater than 90% survival during the course of a 40-day experiment with transplanted cell lines lymphoma cell lines expressing CD19, and that the combined agents at sub-optimal doses exhibited synergy relative to sub-optimal doses of ABT-199 and sub-optimal doses of ABT-199 as single agents (paragraph [[0146]).
Tiberghien et al teach that the structure of SGD-1910/Talirine is
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72
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and that the structure of SGD-3249/tesirine, required by the instant claims is:
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372
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(page 983, second column).
Tiberghien et al teach that tesirine/SG3249 was the result of improvements on the design of SGD-1910 which lowered hydrophobicity while maintaining potency (page 983, first column, line 8-9 of the third paragraph to page 984, first column, line 2). Tiberghien et al teach that the alteration of the warhead of SGD-1910 to the warhead of tesirine was based on rational modifications of the warhead of SGD-1910 (page 984, first column, first full paragraph). Tiberghien et al teach that the resulting lower hydrophobicity contributes to low aggregation (page 986, first column, second full paragraph).
Antonow and Thurston teach that the mechanism of action of pyrrolobenzodiazepines (PBDs) is the covalent binding of PBD to the C2- amino group of guanine within the DNA minor groove (page 2818, Figure 4).
It would have been prima facie obvious at the time of the effective filing date to use ABT-199/Venetoclax in combination with the ConjE ADC of the patent, especially for the treatment of non-Hodgkin Lymphomas/Leukemias expressing CD19 including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v) and Acute Lymphoblastic Leukemia (ALL) DLBCL, CLL and ALL, thus fulfilling the limitations of claims 32- 35. One of skill in the art would understand from the teachings of Arthur et al that the cytotoxic synergy was not specific to the targeting antibody since synergy was observed with all of CD33, CD123 and CD19 targeting antibodies, and thus, synergy was not an unexpected result confined to a specific antibody targeted SGD-1910 in combination with venetoclax. One of skill in the art would be motivated to use the conjugate of claim 4 of the patent because Tiberghien et al teach that the identical structure of SG3249/tesirine, was an improvement over SGD-1910 due to lowered hydrophobicity, while maintaining cytotoxic potency. One of skill would also understand that both of SGD-1910 and SG3249/tesirine formed the adduct with guanine in the minor groove of DNA. One of skill in the art would conclude that venetoclax would exhibit synergy when combined with an ADC comprising the instant anti-CD19 antibody comprising SEQ ID NO: 2 and 8 because Arthur et al teach synergy between anti-CD33 SGD-1910, anti-CD12-SGD-1910 and a different anti-CD19-SGD-1910, leading to the conclusion that the targeting antibody, or the specific targeted receptor, was not governing the observed synergistic interaction. Further, based on the teachings of Arthur et al and Antonow and Thurston, one of skill in the art would reasonably conclude that SG3249/tesirine, made to be an improvement over SGD-1910, and based on rational design principles for modifying SGD-1910, would have the same ability to bind to guanine in the minor groove of DNA and exert cytotoxicity in the picomolar range. It would have been further obvious to administer the venetoclax before, after or simultaneously with the ADC of claim 4 of the patent because these represent all the alternative for co-administration.
Claim 18 of the ‘775 patent teach the combination of the CD19ADC with rituximab. The claim does not teach that the rituximab is administered in combination with the Bcl2 inhibitor, venetoclax and the CD19 ADC of the patent.
Davids et al teach the admisntration of venetoclax as a single agent to patients with relapsed or refractory NHL (Title). Davids et al teach that the activity of venetoclax varied among the different subtypes of NHL (page 825, in the paragraph labeled “result”) with the highest response of 75% observed in patients with Mantle Cell Lymphoma (page 831, second column, first full paragraph), and the lowest response of 18% was seen in patients with DLBCL (page 832, first column, first full paragraph). Davids et al teach that inhibition of Bcl2 will have greater impact when venetoclax is combined with other agents (page 832, second column, lines 6-9). Davids et al teach that studies are underway to assess the safety and efficacy of combining venetoclax with chemotherapy, monoclonal antibodies and B-cell receptor signaling inhibitors (page 832, first column, first sentence of the bottom paragraph). Davids et al teach that rituximab augmented the efficacy of the less selective Bcl2 inhibitor, navitoclax, and similar studies with venetoclax are ongoing (page 832, second column, lines 1-3) and that the favorable toxicity profile and unique mechanism of action venetoclax lends itself to use in combination regimens.
It would have been prima facie obvious at the time of the effective filing date to combine rituximab with the ADC of the patent and venetoclax, thus rendering obvious the limitations of claim 28. One of skill in the art would have been motivated to do so by the teachings of Davids et al on the on-going study involving the combination of venetoclax and rituximab. Thus, claim 18 of the patent used as an auxiliary therapeutic agent meets the limitations of instant claim 28 requiring an additional chemotherapeutic agent.
Applicant argues that because the double-patenting rejections rely on the teachings of Arthur, Tiberghien and Antonow the rejections should be withdrawn in light of the unexpected results over the teachings of said references as discussed above. This has been considered but not found persuasive because the results discussed by applicant were unpersuasive.
All claims are rejected
All other rejections and/or objection as set forth or maintained in the prior Office action are withdrawn.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643