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 .
DETAILED ACTION
Claims 1, 5-12, and 16-22 are pending in the instant application.
Claim Rejections – 35 USC § 112(a)
Claims 12 and 16-22 are 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.
Claim 12 is for a method of preventing a CCR7 expressing cancer, but the specification does not show an effective method to prevent cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n. Claims 16-22 are further dependent on claim 12 without requiring only cancer treatment and not prevention.
Scope of the claimed genus
Claims 12 and 16-22 are for a method of preventing or treating a CCR7 expressing cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n..
Summary of Species disclosed in the original specification
The specification only shows an effective cancer treatment method with 121G12.CysMab.DAPA.MPET. DM4 in Figures 10-20 of CCR7 expressing cancer cells. Fig. 22 depicts a graph illustrating concentration time profiles of GLP 121G12.CYSMAB.DAPA.MPET.DM4 in monkeys, but for pharmacokinetic evaluation not for the purposes of cancer prevention. The cancer cells are already cancerous before treatment. There are no effective cancer prevention studies in the instant specification.
State of the Relevant Art;
López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone (López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471) (page 469, right column, second paragraph). López-Giral taught CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes [47 (42,117) vs. 21(16,22)] (page 464, right column, third paragraph). Thus, CCR7 expression is known to be higher in cancer cells compared to its cell of origin.
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017; 22(5); 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee KW et al. Nature Reviews Cancer 2011 11 211-218, page 211, left column last paragraph) Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
Conclusion
The Applicant does not have written description for a method of preventing a CCR7 expressing cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n in claims 12 and 16-22. The specification does not teach a method to prevent cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n.
Claims 12 and 16-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: 1) cancer treatment, does not reasonably provide enablement for 1) cancer prevention. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 12 is for a method of preventing a CCR7 expressing cancer, but the specification and the state of the art do not show an effective method to prevent cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n. Claims 16-22 are further dependent on claim 12 without requiring only cancer treatment and not prevention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Claims 12 and 16-22 are for a method of preventing or treating a CCR7 expressing cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n..
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The specification only shows an effective cancer treatment method with 121G 12.CysMab.DAPA.MPET.DM4 in Figures 10-20 of CCR7 expressing cancer cells. Fig. 22 depicts a graph illustrating concentration time profiles of GLP 121G12.CYSMAB.DAPA.MPET.DM4 in monkeys, but for pharmacokinetic evaluation not for the purposes of cancer prevention. The cancer cells are already cancerous before treatment. There are no cancer prevention studies in the instant specification.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone (López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471) (page 469, right column, second paragraph). López-Giral taught CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes [47 (42,117) vs. 21(16,22)] (page 464, right column, third paragraph). Thus, CCR7 expression is known to be higher in cancer cells compared to its cell of origin.
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017; 22(5); 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee KW et al. Nature Reviews Cancer 2011 11 211-218, page 211, left column last paragraph) Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
Conclusion
The Applicant does not have enablement for a method of preventing a CCR7 expressing cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n in claims 12 and 16-22. The specification and the state of the art do not teach an effective method to prevent cancer by administering a CCR7 targeting antibody conjugate of formula Ab-(L-(DM4)m)n.
Claim Rejections – 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 12, 16-19, 21-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/142322 (Bender S et al. IDS reference) and evidenced by Tweeddale ME et al. The Presence of Clonogenic Cells in High-Grade Malignant Lymphoma: A Prognostic Factor. (Blood 1987 69(5) 1307-13-14).
Regarding instant claims 12, 16-19, 21-22, ‘322 taught a method of effectively treating a patient with DLBCL (instant claim 18), which is a relapsed DLBCL OCI-LY3 tumor (instant claim 19) as evidenced by Tweeddale (Tweeddale, page 1309, Table 2, line 3, OCI-LY3), comprising intravenously (instant claim 22) administering a pharmaceutical composition comprising 0.5, 1, or 2 mg/kg 121G12.CysMab.DAPA. MPET.DM4 with a drug to antibody ratio of about 4 once every two weeks, which would be a 2 cycle regimen with one dose every other week (instant claim 21) wherein the treatment was dose-responsive (pages 245-246, [00492]- [00493], Table 26, and Fig. 15), wherein the DLBCL OCI-Ly3 cancer cells express CCR7 (pages 237-238, Table 22), wherein the 121G12 CysMab DAPA antibody comprised a heavy chain comprising ‘322 SEQ ID NO:47 and a light chain comprising ‘322 SEQ ID NO:63 (Table 1, page 94 and page 96) which is identical to a heavy chain comprising instant SEQ ID NO:47 and a light chain comprising instant SEQ ID NO:63, wherein the structure is Ab-(L-(DM4)m)n , a non-salt form (instant claim 17), and
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with an m of 1 and an n of about 4 (page 215, [00406])(instant claims 12 and 16).
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 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.
Claims 1, 5-7, 12, and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/142322 (Bender S et al. IDS reference), López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471), and Younes A et al. (J Clin Oncol 2012 30(22):2776-82. doi: 10.1200/JCO.2011.39.4403.).
‘322 taught the limitations of claims 12, 16-19, 21-22 for the reasons set forth above.
‘322 is described above. ‘322 further taught an immunoconjugate dosing interval of once every 3 weeks (page 131, [00337]). ‘322 taught a therapeutically acceptable amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved (page 33, [00105]).
‘322 did not describe: 1) treatment of follicular lymphoma; or 2) a single embodiment of a method of treating cancer with an ADC comprising Ab-(L-(DM4)m)n , wherein the ADC is administered at about 0.1 mg/kg to about 10 mg/kg, but this is obvious in view of the teachings of ‘322, López-Giral, and Younes.
López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone (page 469, right column, second paragraph). López-Giral taught CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes [47 (42,117) vs. 21(16,22)] (page 464, right column, third paragraph).
Younes taught SAR3419 (huB4-DM4) is a humanized IgG1 anti-CD19 monoclonal antibody, wherein the DM4 payload is conjugated to an antibody via a disulfide linker (page 2776, right column, last paragraph). Younes taught patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of an antibody drug conjugate SAR3419 that comprised DM4 given by intravenous infusion once every 21 days (3 weeks) (abstract). Younes taught administration of the ADC comprising the DM4 payload was effective wherein the overall response rate was 30% for patients with follicular lymphoma treated and reduced tumor size in DLBCL patients (page 2780, left column, forth column and Fig. 3).
Regarding instant claims 1, 5-7, and 20, it would have been obvious for a person having ordinary skill in the art to take the method of ‘322 of effectively treating a patient with cancer, comprising intravenously administering a pharmaceutical composition comprising 2 mg/kg of 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of about 4 once every two weeks – and: 1) treat follicular lymphoma in view of López-Giral and Younes; 2) treat relapsed or refractory follicular lymphoma in view of López-Giral and ‘322; and 3) exchange the administration frequency to once every three weeks in view of ‘322 and Younes.
This is obvious because:
1a) López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone, wherein CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes. Thus, the CCR7 target was more highly expressed in follicular lymphoma cancer cells;
1b-2) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322. Thus, the DM4 payload is known to be effective in treating relapsed or refractory lymphomas and follicular lymphoma;
3a) ‘322 taught an immunoconjugate dosing interval of once every 3 weeks;
3b) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322.
There is a reasonable expectation of success because:
1a) López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone, wherein CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes. Thus, the CCR7 target is more highly expressed in follicular lymphoma cancer cells and would be specifically targeted;
1b-2) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322. Thus, the DM4 payload is known to be effective in treating relapsed or refractory lymphomas and follicular lymphoma;
3a) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322.Thus, it would be reasonable to expect an ADC with the same drug payload DM4 to be effective when administered once every 21 days.
This would produce a method of treating a patient with relapsed or refractory (instant claim 5) follicular lymphoma wherein the patient in need thereof is intravenously administered a pharmaceutical composition comprising 2 mg/kg of 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every three weeks (instant claim 20), wherein the cancer cells express CCR7, wherein the 121G12 CysMab DAPA antibody comprises a heavy chain comprising ‘322 SEQ ID NO:47 and a light chain comprising ‘322 SEQ ID NO:63 which is identical to a heavy chain comprising instant SEQ ID NO:47 and a light chain comprising instant SEQ ID NO:63, wherein the structure is Ab-(L-(DM4)m)n , which is a non-salt form (instant claim 7), and
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with an m of 1 and an n of about 4 (instant claims 1 and 6).
Claims 1, 5-10, 12, and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/142322 (Bender S et al. IDS reference), López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471), and Younes A et al. (J Clin Oncol 2012 30(22):2776-82. doi: 10.1200/JCO.2011.39.4403.) as applied to claims 1, 5-7, 12, and 16-22 above, and further in view of Gopal AK et al. (Clin Cancer Res (2020) 26 (11): 2524–2534. Published 3/6/2020).
‘322, López-Giral, and Younes are described above.
Regarding instant claims 8-10, ‘322 further taught a method of treating cancer in a patient comprising administering to said patient the antibody drug conjugates or the pharmaceutical compositions, wherein the cancer expresses CCR7 and one or more additional therapeutic compounds is selected from a standard of care chemotherapeutic, a costimulatory molecule, or a checkpoint inhibitor, wherein the costimulatory molecule is an agonist of 4-1BB or the checkpoint inhibitor is selected from an inhibitor of PD-1 (page 11, [0025]-[0026]).
‘322 did not describe: 1) a single embodiment of a method of treating follicular lymphoma cancer with an ADC comprising Ab-(L-(DM4)m)n and a costimulatory 4-1BB agonist, but this is obvious in view of the Gopal.
Gopal taught administration of a pharmaceutical composition comprising the 4-1BB agonist utomilumab in paired biopsies from a relapsed/refractory follicular lymphoma (FL) patient led to a complete response, wherein increased T-cell infiltration and cytotoxic activity occurred in tumors (abstract). Gopal taught studies have shown that 4-1BB/CD137 agonistic antibodies can deliver costimulatory signals, enhancing antibody-dependent cellular cytotoxicity and potentially eliciting T-cell–mediated antitumor immune responses (page 2525, left column, Translational Relevance).
Gopal taught utomilumab can induce human leukocyte proliferation and has demonstrated significant antitumor activity as a single agent in human peripheral blood lymphocyte (PBL) SCID xenograft tumor models (page 2524, right column, second to last paragraph).
Regarding instant claims 8-10, it would have been obvious for a person having ordinary skill in the art to take the method of ‘322, López-Giral and Younes above of a method of treating a patient with relapsed or refractory follicular lymphoma wherein the patient in need thereof is intravenously administered a pharmaceutical composition comprising 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every three weeks, wherein the cancer cells express CCR7 – and: 1) further include administration of the 4-1BB costimulatory agonist molecule utomilumab as a therapeutic compound in view of Gopal.
This is obvious because:
1a) ‘322 taught administering an ADC and one or more additional therapeutic compounds of a costimulatory molecule, wherein the costimulatory molecule is an agonist of 4-1BB;
1b) Gopal taught administration of a pharmaceutical composition comprising the 4-1BB agonist utomilumab in paired biopsies from a relapsed/refractory follicular lymphoma (FL) patient led to a complete response, wherein increased T-cell infiltration and cytotoxic activity occurred in tumors.
There is a reasonable expectation of success because:
1) Gopal taught administration of a pharmaceutical composition comprising the 4-1BB agonist utomilumab in paired biopsies from a relapsed/refractory follicular lymphoma (FL) patient led to a complete response, wherein increased T-cell infiltration and cytotoxic activity occurred in tumors. Thus, 4-1BB agonists are effective in follicular lymphoma.
This would produce a method of treating a patient with relapsed or refractory follicular lymphoma wherein the patient in need thereof is intravenously administered a pharmaceutical composition comprising the therapeutic 4-1BB agonist utomilumab (instant claims 8-10) and 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every three weeks, wherein the cancer cells express CCR7.
Claims 1, 5-9, 11-12, and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/142322 (Bender S et al. IDS reference), López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471), and Younes A et al. (J Clin Oncol 2012 30(22):2776-82. doi: 10.1200/JCO.2011.39.4403.) as applied to claims 1, 5-7, 12, and 16-22 above, and further in view of Lesokhin AM et al. (J Clin Oncol 2016 34, 2698-2704).
‘322, López-Giral, and Younes are described above.
Regarding instant claims 8-10, ‘322 further taught a method of treating cancer in a patient comprising administering to said patient the antibody drug conjugates or the pharmaceutical compositions, wherein the cancer expresses CCR7 and one or more additional therapeutic compounds is selected from a standard of care chemotherapeutic, a costimulatory molecule, or a checkpoint inhibitor, wherein the costimulatory molecule is an agonist of 4-1BB or the checkpoint inhibitor is selected from an inhibitor of PD-1 (page 11, [0025]-[0026]).
‘322 did not describe: 1) a single embodiment of a method of treating follicular lymphoma cancer with an ADC comprising Ab-(L-(DM4)m)n and checkpoint inhibitor of PD-1, but this is obvious in view of the Lesokhin.
Lesokhin taught cancer cells exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity (abstract). Lesokhin taught administration of the anti-PD-1 monoclonal antibody nivolumab to patients with follicular lymphoma was well tolerated and exhibited antitumor activity (abstract).
Regarding instant claims 8-9, and 11, it would have been obvious for a person having ordinary skill in the art to take the method of ‘322, López-Giral and Younes above of a method of treating a patient with relapsed or refractory follicular lymphoma wherein the patient in need thereof is intravenously administered a pharmaceutical composition comprising 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every three weeks, wherein the cancer cells express CCR7 – and: 1) further include administration of the PD-1 checkpoint inhibitor nivolumab as a therapeutic compound in view of Lesokhin.
This is obvious because:
1a) ‘322 taught administering an ADC and one or more additional therapeutic compounds of a checkpoint inhibitor, wherein the checkpoint inhibitor is an inhibitor of PD-1;
1b) Lesokhin taught cancer cells exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity;
1c) Lesokhin taught administration of the anti-PD-1 monoclonal antibody nivolumab to patients with follicular lymphoma was well tolerated and exhibited antitumor activity.
There is a reasonable expectation of success because:
1) Lesokhin taught cancer cells exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity and administration of the anti-PD-1 monoclonal antibody nivolumab to patients with follicular lymphoma was well tolerated and exhibited antitumor activity. Thus, PD-1 checkpoint inhibitors are effective in follicular lymphoma.
This would produce a method of treating a patient with relapsed or refractory follicular lymphoma wherein the patient in need thereof is intravenously administered a pharmaceutical composition comprising the therapeutic PD-1 checkpoint inhibitor nivolumab (instant claims 8-9 and 11) and 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every three weeks, wherein the cancer cells express CCR7.
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, 5-12, and 16-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,634,497 in view of WO 2018/142322 (Bender S et al. IDS reference), López-Giral S et al. (Journal of Leukocyte Biology 2004 76(2) 462–471), and Younes A et al. (J Clin Oncol 2012 30(22):2776-82. doi: 10.1200/JCO.2011.39.4403.)
The claims of ‘497 taught CCR7 antibodies, antibody drug conjugates of formula Ab-(L-(D)m)n , and methods of treating cancer that expresses CCR7 in patented claims 1-26. ‘497 taught an antibody drug conjugate (ADC) comprising the formula Ab-(L-(D)m)n , wherein Ab is an antibody or antigen binding fragment thereof according to claim 1; L is a linker; D is a drug moiety; m is an integer from 1 to 8; and n is an integer from 1 to 12 in patented claim 4, wherein the ADC is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier in patented claim 5, and a method of treating cancer in a patient in need thereof, comprising administering to said patient the ADC above, wherein the cancer expresses CCR7 in patented claim 15, wherein the antibody drug conjugate is administered to the patient in combination with one or more additional therapeutic compounds in patented claim 16, wherein the one or more additional therapeutic compound is a 4-1BB costimulatory molecule therapeutic in patented claims 17-18, wherein the one or more additional therapeutic compound is a PD-1 checkpoint inhibitor therapeutic in patented claims 17 and 19, wherein the cancer is Non-Hodgkin's lymphoma (NHL) in patented claim 20, wherein the cancer is DLBCL in patented claim 21. ‘497 taught an antibody drug conjugate having the following formula:
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wherein n is about 3 to about 4, and Ab is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:47, and a light chain comprising the amino acid sequence of SEQ ID NO:63; or a pharmaceutically acceptable salt thereof in patented claim 13.
The claims of ‘497 do not teach: 1) treatment of follicular lymphoma (FL); 2) administration of about 0.1 mg/kg to about 10 mg/kg of an ADC, but this is obvious in view of ‘322, López-Giral, and Younes.
Regarding instant claims 12, 16-19, 21-22, ‘322 taught a method of effectively treating a patient with DLBCL, which is a relapsed DLBCL OCI-LY3 tumor as evidenced by Tweeddale (Tweeddale, page 1309, Table 2, line 3, OCI-LY3), comprising intravenously administering a pharmaceutical composition comprising 0.5, 1, or 2 mg/kg 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every two weeks, which would be a 2 cycle regimen with one dose every other week (instant claim 21) wherein the treatment was dose-responsive (pages 245-246, [00492]- [00493], Table 26, and Fig. 15), wherein the DLBCL OCI-Ly3 cancer cells express CCR7 (pages 237-238, Table 22), wherein the 121G12 CysMab DAPA antibody comprised a heavy chain comprising ‘322 SEQ ID NO:47 and a light chain comprising ‘322 SEQ ID NO:63 (Table 1, page 94 and page 96), which is a non-salt form, and
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with an m of 1 and an n of about 4 (page 215, [00406]). ‘322 further taught an immunoconjugate dosing interval of once every 3 weeks (page 131, [00337]). ‘322 taught a therapeutically acceptable amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved (page 33, [00105]).
López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone (page 469, right column, second paragraph). López-Giral taught CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes [47 (42,117) vs. 21(16,22)] (page 464, right column, third paragraph).
Younes taught SAR3419 (huB4-DM4) is a humanized IgG1 anti-CD19 monoclonal antibody, wherein the DM4 payload is conjugated to an antibody via a disulfide linker (page 2776, right column, last paragraph). Younes taught patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of an antibody drug conjugate SAR3419 that comprised DM4 given by intravenous infusion once every 21 days (3 weeks) (abstract). Younes taught administration of the ADC comprising the DM4 payload was effective wherein the overall response rate was 30% for patients with follicular lymphoma treated and reduced tumor size in DLBCL patients (page 2780, left column, forth column and Fig. 3).
Regarding instant claims 1, 5-12, and 16-22, it would have been obvious for a person having ordinary skill in the art to take the method of ‘497 patented claims 4-5, 13, and 15-21 of a method of treating NHL or DLBCL cancer expressing CCR7 in a patient in need thereof, comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody drug conjugate having the following formula:
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wherein n is about 3 to about 4, and Ab is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:47, and a light chain comprising the amino acid sequence of SEQ ID NO:63, in combination with one or more additional therapeutic compounds, wherein the one or more additional therapeutic compound is a 4-1BB costimulatory molecule therapeutic or a PD-1 checkpoint inhibitor therapeutic – and alter the method to:
exchange the cancer treated for relapsed or refractory follicular lymphoma (FL) in view of López-Giral and Younes;
administer about 2 mg/kg of the ADC in view of ‘322;
administer 2 cycles of the ADC treatment in view of ‘322;
administer the ADC intravenously in view of ‘322;
administer the ADC treatment once every three weeks in view of ‘322 and Younes;
This is obvious because:
1a) López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone, wherein CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes. Thus, the CCR7 target was more highly expressed in follicular lymphoma cancer cells;
1b) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322. Thus, the DM4 payload is known to be effective in treating relapsed or refractory lymphomas and follicular lymphoma;
2-4) ‘322 taught a method of effectively treating a patient with DLBCL, which is a relapsed DLBCL OCI-LY3 tumor that is a Non-Hodgins lymphoma, comprising intravenously administering a pharmaceutical composition comprising 2 mg/kg 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every two weeks, which would be a 2 cycle regimen with one dose every other week, wherein the treatment was dose-responsive, wherein the DLBCL cancer cells express CCR7, wherein 121G12.CysMab.DAPA.MPET.DM4 is the same ADC as the instant ADC and ADC of ‘497.
5a) ‘322 taught an immunoconjugate dosing interval of once every 3 weeks with the same ADC;
5b) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322.
There is a reasonable expectation of success because:
1a) López-Giral taught most follicular lymphoma (FL) expressed significantly higher levels of CCR7 compared to cell of origin due to the oncogenic process or to other processes ongoing in the tumoral lymph node such as an inflammatory reaction or the antigenic stimulation of the malignant clone, wherein CD10+ FL expressed significantly higher levels of CCR7 than normal CD10+CD38+ germinal center-derived B lymphocytes. Thus, the CCR7 target is more highly expressed in follicular lymphoma cancer cells and would be specifically targeted;
1b) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322. Thus, the DM4 payload is known to be effective in treating relapsed or refractory lymphomas and follicular lymphoma;
2-4) ‘322 taught a method of effectively treating a patient with DLBCL, which is a relapsed DLBCL OCI-LY3 tumor that is a Non-Hodgins lymphoma, comprising intravenously administering a pharmaceutical composition comprising 2 mg/kg 121G12.CysMab.DAPA.MPET.DM4 with a drug to antibody ratio of 4 once every two weeks, which would be a 2 cycle regimen with one dose every other week, wherein the treatment was dose-responsive, wherein the DLBCL cancer cells express CCR7, wherein 121G12.CysMab.DAPA.MPET.DM4 is the same ADC as the instant ADC and ADC of ‘497.
5a) Younes taught patients with relapsed CD19+ B-cell lymphomas that included follicular lymphoma treated with a cancer targeting ADC that comprised DM4 given by intravenous infusion once every 21 days was effective and the payload DM4 is the same as the effective relapsed refractory cancer treatment in ‘322.Thus, it would be reasonable to expect an ADC with the same drug payload DM4 to be effective when administered once every 21 days.
This would produce a method of treating relapsed or refractory follicular lymphoma (FL) (instant claims 5 and 18-19) expressing CCR7 in a patient in need thereof, comprising intravenously (instant claim 22) administering 2 cycles (instant claim 21) of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and about 2 mg/kg of an antibody drug conjugate having the following formula:
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which is the non-salt form (instant claims 7 and 17), wherein n is about 3 to about 4, and Ab is an antibody comprising a heavy chain comprising the amino acid sequence of ‘497 SEQ ID NO:47, and a light chain comprising the amino acid sequence of ‘497 SEQ ID NO:63 which is identical to a heavy chain comprising the amino acid sequence of instant SEQ ID NO:47, and a light chain comprising the amino acid sequence of instant SEQ ID NO:63 (instant claims 6 and 16), once every three weeks (instant claim 20) in combination with one or more additional therapeutic compounds, wherein the one or more additional therapeutic compound is a 4-1BB costimulatory molecule therapeutic or a PD-1 checkpoint inhibitor therapeutic (instant claims 8-11) (instant claims 1 and 12).
Conclusion
Claims 1, 5-12, and 16-22 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643