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 .
1. The Amendment filed June 11, 2026 in response to the Office Action of February 18, 2026, is acknowledged and has been entered. Claims 1, 3, 10-12, 20-24, 26, 29-31, 33-35, 38, 70, 102, 122, 128, 129, 145, 146, 150, 151, 193, 231, 269, 320, 321, 325 are now pending. Claims 1, 10, 11, 70 are amended. Claim 6 is canceled. Claims 145, 146, 150, 151, 193, 231, 269, 320, 321, 325 remain withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1, 3, 10-12, 20-24, 26, 29-31, 33, 34, 38, 70, 102, 122, 128, 129 are currently under prosecution as drawn to the elected species of immunoconjugate polatuzumab vedotin-piiq.
Note: It is reiterated that the terms “polatuzumab vedotin” and “polatuzumab vedotin-piiq” refer to the same immunoconjugate.
Maintained Rejections
Claim Rejections - 35 USC § 102
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.
2. Claim(s) 1, 3, 10-12, 20-24, 26, 29-31, 33-35, 38, 70, 102, 128, and 129 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent 2017/0304438, Polson et al.
Polson teaches a method for treating relapsed/refractory (R/R) follicular lymphoma (FL) in a human comprising administering to the human an effective amount of:
(a) polatuzumab vedotin-piiq immunoconjugate;
(b) venetoclax (Bcl-2 inhibitor); and
(c) anti-CD20 antibody rituximab or obinituzumab (claims 1-30, 33, 35-41; [79-84]; [136-138]; [147-152]; [155-161]; [181]; Example 7 [456-463]);
wherein polatuzumab is an anti-CD79b antibody comprising heavy and light chain SEQ ID NOs:36 and 38, respectively ([21-22]; [166]; claims 24 and 26), that are 100% identical to instant SEQ ID NOs:36 and 38 and comprise instant CDR SEQ ID NOs:21-26 (see sequence alignments below);
wherein polatuzumab vedotin is administered intravenously (IV) to the individual at a dose of 1.8 mg/kg or 1.4 mg/kg; the venetoclax is administered orally at a dose of 800 mg; and the obinutuzumab is administered IV at a dose of 1000 mg and on the following days of six 21-day induction cycles and in the order listed below:
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115
468
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270
412
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wherein the venetoclax and obinutuzumab are administered as a maintenance phase and administration of venetoclax precedes administration of obinutuzumab:
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241
412
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wherein maintenance therapy comprises:
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133
458
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and wherein inclusion criteria for treatment is:
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271
462
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149
464
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255
464
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Given Polson teaches administering the same claimed drugs to the same claimed patients and at the same claimed doses, routes, and regimens, the method of Polson would necessarily produce the same claimed results of: achieving complete response (CR) during or after administration of the combination; result in a complete response in at least about 55% to at least about 100% of humans during or after administration of the combination; result in an objective response in at least about 70% to at least about 100% of humans during or after administration of the combination; not result in peripheral neuropathy of Grade 3 or greater; not result in tumor lysis syndrome; result in Grade 3 or 4 adverse event in about 64%, about 59% or about 73% or less of the humans treated; result in a duration of CR at least about 1 month to about 3 months or more; result in a CR after the six 21-day cycles; result in a CR in at least 55% to about 100% of humans treated after the six 21-day cycles, wherein the CR lasts at least about 1 month to at least about 3 months or more; and achieves a CR during or after the induction phase (as recited in instant claims 1, 11, 12, 24, 26, 70, and 102).
Instant SEQ ID NO:36 aligned with Polson SEQ ID NO:36
US-15-440-917-36
Filing date in PALM: 2017-02-23
Sequence 36, US/15440917
Publication No. US20170304438A1
GENERAL INFORMATION
APPLICANT: GENENTECH, INC.
TITLE OF INVENTION: METHODS OF USING ANTI-CD79B IMMUNOCONJUGATES
FILE REFERENCE: P32333-US-4
CURRENT APPLICATION NUMBER: US/15/440,917
CURRENT FILING DATE: 2017-02-23
PRIOR APPLICATION NUMBER: 14/863,125
PRIOR FILING DATE: 2015-09-23
PRIOR APPLICATION NUMBER: 62/136,324
PRIOR FILING DATE: 2015-03-20
PRIOR APPLICATION NUMBER: 62/076,823
PRIOR FILING DATE: 2014-11-07
PRIOR APPLICATION NUMBER: 62/054,257
PRIOR FILING DATE: 2014-09-23
NUMBER OF SEQ ID NOS: 55
SEQ ID NO 36
LENGTH: 446
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
ALIGNMENT:
Query Match 100.0%; Score 2385; Length 446;
Best Local Similarity 100.0%;
Matches 446; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNY 60
Qy 61 NEIFKGRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSSAST120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEIFKGRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSSAST120
Qy 121 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY180
Qy 181 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV240
Qy 241 FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY300
Qy 301 RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK360
Qy 361 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG420
Qy 421 NVFSCSVMHEALHNHYTQKSLSLSPG 446
||||||||||||||||||||||||||
Db 421 NVFSCSVMHEALHNHYTQKSLSLSPG 446
Instant SEQ ID NO:38 aligned with Polson SEQ ID NO:38
US-15-440-917-38
Filing date in PALM: 2017-02-23
Sequence 38, US/15440917
Publication No. US20170304438A1
GENERAL INFORMATION
APPLICANT: GENENTECH, INC.
TITLE OF INVENTION: METHODS OF USING ANTI-CD79B IMMUNOCONJUGATES
FILE REFERENCE: P32333-US-4
CURRENT APPLICATION NUMBER: US/15/440,917
CURRENT FILING DATE: 2017-02-23
PRIOR APPLICATION NUMBER: 14/863,125
PRIOR FILING DATE: 2015-09-23
PRIOR APPLICATION NUMBER: 62/136,324
PRIOR FILING DATE: 2015-03-20
PRIOR APPLICATION NUMBER: 62/076,823
PRIOR FILING DATE: 2014-11-07
PRIOR APPLICATION NUMBER: 62/054,257
PRIOR FILING DATE: 2014-09-23
NUMBER OF SEQ ID NOS: 55
SEQ ID NO 38
LENGTH: 218
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
ALIGNMENT:
Query Match 100.0%; Score 1131; Length 218;
Best Local Similarity 100.0%;
Matches 218; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLES 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLES 60
Qy 61 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIKRTVAAPSVF120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIKRTVAAPSVF120
Qy 121 IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS180
Qy 181 STLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC 218
||||||||||||||||||||||||||||||||||||||
Db 181 STLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC 218
Response to Arguments
3. Applicants argue that claims 1 is amended to recite the immunoconjugate is administered at a dose of about 1.8 mg/kg, the venetoclax is administered at a dose of about 800 mg, and the anti-CD20 antibody administered is obinutuzumab. Applicants argue that Polson does not anticipate claims 38, 70, 102 and amended claim 1. Applicants argue the claims recite a specific combination of drugs and doses that Polson does not teach. Applicants argue that because Polson does not teach the limitations of the specific combination of drugs and doses claimed, the method of Polson cannot inherently result in the same claimed results. Applicants argue that Polson does not teach the specific combination of immunoconjugate administered at a dose of about 1.8 mg/kg, venetoclax administered at a dose of about 800 mg, and the anti-CD20 antibody obinutuzumab as a single operative embodiment. Applicants argue that Polson does not teach the results of their study including complete response. Applicants argue that clinical trials are unpredictable and the results of the method disclosed by Polson cannot be predicted.
4. The arguments have been considered but are not persuasive. First, Examiner disagrees that Polson does not teach the reagents and doses administered in a single embodiment. The paragraphs disclosed by Polson copied and pasted above in the rejection of record clearly demonstrate the reagents and doses are disclosed in a single embodiment. Polson teaches the patients are treated in a dose escalation phase trial. This means Polson teaches administering increasing amounts of the drugs to successive groups of participants as the treatment progresses, and Polson specifically identifies administering 1.4 mg/kg and 1.8 mg/kg of immunoconjugate Polatuzumab, and specifically identifies administering 400, 600, and 800 mg of venetoclax with 1000mg of Obinutuzumab. These specific drugs and escalating doses are all disclosed in a single embodiment and taught to be administered to FL patients. Therefore, the claimed limitations of drugs and doses are met by Polson.
Contrary to arguments, Polson is not required to disclose a working example with results to anticipate the claimed method. Polson discloses treating the same patient population claimed with the same drugs and doses claimed. MPEP 2121 states:
I. PRIOR ART IS PRESUMED TO BE OPERABLE/ENABLING
When the reference relied on expressly anticipates or makes obvious all of the elements
of the claimed invention, the reference is presumed to be operable. Once such a
reference is found, the burden is on applicant to provide facts rebutting the presumption
of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also
MPEP § 716.07.
III. A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006).
Second, the claims are broader than Applicants are arguing. The claims recite administering “about 1.8mg/kg” of immunoconjugate, “about 800 mg” of venetoclax, and obinutuzumab or obinutuzumab at a dose of about 1000mg. The instant specification discloses:
[0060] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
Given the broad definition of “about” disclosed in the specification, the escalating doses of 1.4 mg/kg and 1.8 mg/kg of immunoconjugate taught by Polson are reasonably encompassed by “about 1.8 mg/kg” of immunoconjugate claimed. Given the definition of “about” above, the escalating doses of 400, 600, and 800 mg of venetoclax taught by Polson are reasonably encompassed by “about 800 mg” of venetoclax claimed. Therefore, Polson does teach and anticipate the claimed drugs and doses administered.
As stated in the rejection, given Polson teaches administering the same claimed drugs to the same claimed patients and at the same claimed doses, routes, and regimens, the method of Polson would necessarily produce the same claimed results of: achieving complete response (CR) during or after administration of the combination; result in a complete response in at least about 55% to at least about 100% of humans during or after administration of the combination; result in an objective response in at least about 70% to at least about 100% of humans during or after administration of the combination; not result in peripheral neuropathy of Grade 3 or greater; not result in tumor lysis syndrome; result in Grade 3 or 4 adverse event in about 64%, about 59% or about 73% or less of the humans treated; result in a duration of CR at least about 1 month to about 3 months or more; result in a CR after the six 21-day cycles; result in a CR in at least 55% to about 100% of humans treated after the six 21-day cycles, wherein the CR lasts at least about 1 month to at least about 3 months or more; and achieves a CR during or after the induction phase (as recited in instant claims 1, 11, 12, 24, 26, 70, and 102).
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.
5. Claim(s) 1 and 122 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent 2017/0304438, Polson et al; in view of Herrera et al (Blood, 2016, 128(22):4194) and Yazdy et al (2017. Blood and Lymphatic Cancer: Targets and Therapy, 7, 73–83).
Polson teaches a method for treating follicular lymphoma (FL) patients as set forth above.
Polson does not teach treating the patients with G-CSF if a Grade 3 or 4 adverse event of neutropenia occurs.
Herrera teaches treating R/R FL patients with combination therapy encompassing polatuzuamb vedotin administered at 1.8 mg/kg IV and either rituximab or obinutuzumab administered at 1000 mg, wherein the most common Grade 3/4 adverse events in ≥10% of FL patients were neutropenia and thrombocytopenia (Results).
Yazdy teaches treating follicular lymphoma patients with obinutuzumab or rituximab combination therapies and teaches (p. 79, col. 2): “Administration of granulocyte colony stimulating factor (G-CSF) should be considered in patients with symptomatic grade 3–4 neutropenia.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer G-CSF if a Grade 3 or 4 adverse event of neutropenia occurred in the method of Polson. One would have been motivated to, and
have a reasonable expectation of success to because Herrera teaches this adverse event occurs in FL patients treated with polatuzuamb vedotin and obinutuzumab; and Yazdy teaches G-CSF is a known treatment for Grade 3 or 4 adverse events of neutropenia in FL patients.
Response to Arguments
6. Applicants reiterate arguments above that Polson does not anticipate the specifically claimed drugs and doses. Applicants argue that Polson describes an exploratory clinical trial where doses of immunoconjugate and venetoclax change in increments in a dose-escalation study. Applicants argue that Polson does not disclose any safety and efficacy data. Applicants argue the study was not conducted at the time of Polson’s disclosure, therefore no patient received the drugs and escalated doses suggested by Polson and there is no reasonable expectation of success to achieve the claimed results.
Applicants argue that Herrera and Yazdy do not remedy this deficiency. Applicants argue that neither reference provides one of ordinary skill in the art with any guidance for selection of an efficacious dose of venetoclax, the claimed immunoconjugate, and obinutuzumab for use in a method for treating follicular lymphoma (FL) in a human in need thereof. Applicants argue that a person skilled in the art would not have a reasonable expectation of success in treating follicular lymphoma with the claimed combination of obinutuzumab, venetoclax at a dose of about 800 mg, and the claimed immunoconjugate at a dose of about 1.8 mg/kg, based on the disclosures of Polson, Herrera, or Yazdy, alone or in combination, especially in the absence of any safety or efficacy data for the treatment of follicular lymphoma with the claimed compounds at the recited doses.
Applicants argue that the claimed combination of the claimed immunoconjugate (exemplified by polatuzumab vedotin) at a dose of about 1.8 mg/kg, venetoclax at a dose of about 800 mg, and obinutuzumab resulted in unexpectedly superior response rates in treating patients with relapsed or refractory follicular lymphoma (R/R FL), in spite of the fact that the majority of patients were refractory to their last line of treatment (see [0585] of PCT/US2021/028921). Applicants state that the objective response rate for the FL expansion phase was 87% as assessed by an independent review committee and 93% as assessed by the investigator, and the complete response rate was 60% (see [0592] and Table 18). These results compared favorably with historical response rates seen in treating R/R FL, such as with polatuzumab + rituximab¹ (ORR of 70% and a CR rate of 45%), polatuzumab + obinutuzumab² (ORR of 78% and a CR rate of 30%), or venetoclax + rituximab³ (ORR of 35% and a CR rate of 17%). Applicants argue that the claimed combination showed an unexpectedly high level of efficacy in a cohort of patients with a heavy prehistory, having undergone a median of three prior treatments (see Table 13) and in which approximately half of the patients were refractory to their last prior regiment and more than half were refractory to an anti-CD20 agent (see Table 13). Applicants argue that this unexpectedly high efficacy could not have been predicted by a person skilled in the art at the time of filing of the instant application, even in light of the teachings of Polson, Herrera, or Yazdy, alone or in combination.
7. The arguments have been considered but are not persuasive. First, arguments that Polson does not anticipate the method of claim 1 that achieves complete response (CR) are not persuasive for the reasons stated above.
Second, Applicants are arguing unexpected superior results for limitations not recited in the claims. Applicants argue unexpected superior response rates in treating the specific population of patients with relapsed or refractory follicular lymphoma (R/R FL), in particular, a cohort of patients with a heavy prehistory, having undergone a median of three prior treatments. However, the claims do not recite this population and are not limited to this population. Therefore, Applicants are arguing unexpected superior results for limitations not recited in the claims. MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
The claimed patients are not limited to the specific cohort argued by Applicants as having unexpected superior results.
Third, claim 122 is directed to additionally administering different treatments, which Applicants have not specifically argued that Herrera and Yazdy fail to obviate. Claim 122 recites the method further comprises:
(a) administering a prophylactic treatment for tumor lysis syndrome (TLS), wherein the prophylactic treatment for TLS comprises a uric acid-reducing agent and/or a hydration regimen prior to the start of treatment; and/or
(b) administering granulocyte colony stimulating factor (G-CSF) if a Grade 3 or Grade 4 adverse event of neutropenia occurs.
Herrera and Yazdy render obvious treating the patients in the method of Polson with G-CSF if a Grade 3 or 4 adverse event of neutropenia occurs, for the reasons stated of record.
8. Claim(s) 1, 3, 10-12, 20-24, 26, 29-31, 33-35, 38, 70, 102, 128, and 129 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent 2017/0304438, Polson et al; in view of Herrera et al (Blood, 2016, 128(22):4194); and Zinzani et al (Blood, 2016, 128(22): 617).
Polson teaches a method for treating R/R follicular lymphoma (FL) patients as set forth above. Polson further teaches efficacy objectives include measuring complete response (CR), partial response (PR), and objective response (CR or PR) after treatment ([151]; [422]; [424]; [452-455]).
Although Polson anticipates the instantly claimed methods for the reasons stated above, Polson does not teach or demonstrate the subsequent results of: achieving complete response (CR) during or after administration of the combination; result in a complete response in at least about 55% to at least about 100% of humans during or after administration of the combination; result in an objective response in at least about 70% to at least about 100% of humans during or after administration of the combination; not result in tumor lysis syndrome; result in Grade 3 or 4 adverse event in about 64%, about 59% or about 73% or less of the humans treated; result in a duration of CR at least about 1 month to about 3 months or more; result in a CR after the six 21-day cycles; result in a CR in at least 55% to about 100% of humans treated after the six 21-day cycles, wherein the CR lasts at least about 1 month to at least about 3 months or more; and achieve a CR during or after the induction phase (as recited in instant claims 1, 11, 12, 24, 26, 70, and 102).
Herrera teaches treating R/R FL patients with combination therapy encompassing polatuzuamb vedotin administered at 1.8 mg/kg IV and either rituximab or obinutuzumab administered at 1000 mg. Response was assessed after only 3 cycles of treatment. Herrera teaches the treatment resulted in an objective response rate (= complete response (CR) + partial response (PR)) of 100% in R/R FL patients (Table 2; Results). The majority of patients who achieved a CR or PR remained in response (Results).
Zinzani teaches treating R/R FL patients by administering venetoclax combined with rituximab. Zinzani teaches objective response with treatment was 33% even in a highly refractory patient population, and 64% among non-refractory patients (Conclusion). Zinzani teaches only 54% to 78% of patients suffered Grade 3-4 adverse events (Table 2), and only 1-6% of patients suffered tumor lysis syndrome (Table 2, meaning most did not suffer tumor lysis syndrome).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Polson to achieve complete response (CR) during or after administration of the combination; result in a complete response in at least about 55% to at least about 100% of humans during or after administration of the combination; result in an objective response in at least about 70% to at least about 100% of humans during or after administration of the combination; not result in tumor lysis syndrome; result in Grade 3 or 4 adverse event in about 64%, about 59% or about 73% or less of the humans treated; result in a duration of CR at least about 1 month to about 3 months or more; result in a CR after the six 21-day cycles; result in a CR in at least 55% to about 100% of humans treated after the six 21-day cycles, wherein the CR lasts at least about 1 month to at least about 3 months or more; and achieve a CR during or after the induction phase. One would have been motivated to, and have a reasonable expectation of success to because: (1) Polson provides motivation to achieve CR and PR as efficacy objectives; (2) Herrera teaches that treatment of R/R FL patients with a combination therapy comprising polatuzuamb vedotin and either rituximab or obinutuzumab successfully resulted in an objective response rate of 100% in R/R FL patients, wherein the majority of patients who achieved a CR or PR remained in response, providing reasonable expectation of success to achieve high CR and PR percentages and long lasting response for the method of Polson comprising polatuzuamb vedotin and rituximab or obinutuzumab combination therapies; and (3) Zinzani teaches that treatment of R/R and non-R/R FL patients with a combination therapy comprising venetoclax and rituximab successfully resulted in 33% and 64% objective response rate, respectively, as well as only 54% to 78% of patients suffering Grade 3-4 adverse events and only 1-6% of patients suffering tumor lysis syndrome, providing a reasonable expectation of success to achieve the response rates and minimal Grade 3-4 adverse events and tumor lysis syndrome for the method of Polson comprising venetoclax and rituximab or anti-CD20 antibody combination therapies.
Response to Arguments
9. Applicants argue that they amended claim 1 to recite the anti-CD20 antibody is obinutuzumab. Applicants argue that the specification demonstrates the CR was 60% for the claimed method of treating FL patients with about 1.8 mg/kg immunoconjugate, about 800 mg venetoclax, and obinutuzumab. Applicants argue that Herrera treated R/R FL patients with a different regimen of polatuzuamb vedotin administered at 1.8 mg/kg IV and either anti-CD20 antibody rituximab or obinutuzumab administered at 1000 mg, but no venetoclax. Applicants argue that one would not have a reasonable expectation of success to achieve the claimed results based on a different treatment regimen.
Applicants argue that Zinzani teaches an OR rate of 33% in a highly refractory FL patient population for treatment with venetoclax combined with anti-CD20 antibody rituximab, which is a different treatment regimen than claimed. Applicants argue that their specification discloses an OR rate of 87%, more than double the efficacy disclosed in Zinzanzi.
Applicants argue that efficacy in treatment of R/R FL patients is unpredictable and one would not have a reasonable expectation of success to treat FL in a human in need thereof comprising administering to the human the claimed combination of drugs and doses.
10. The arguments have been considered but are not persuasive.
Applicants are arguing limitations not required. Claims 11 and 24 list several alternative possible results of practicing the claimed method, and do not require all of the argued CR and OR % rates to occur. Further, claim 11 lists the CR or OR results as an alternative result to many others listed, including about less than 64% or 73% humans suffering Grade 3-4 adverse events, and does not result in tumor lysis syndrome. Therefore, the combination of cited references in the rejection need only obviate one of the results listed in claims 11 and 24, and did so for the reasons stated in the rejection above. Applicants have argued only the limitations of CR and OR % rates.
With regards to the claimed limitations of achieving a complete response (CR) at least about 55% of the humans treated, or achieving an objective response (OR) of at least 87%, Herrera teaches that treating R/R FL human patients with combination therapy encompassing polatuzuamb vedotin administered at 1.8 mg/kg IV and either rituximab or obinutuzumab administered at 1000 mg resulted in an objective response (CR+PR) of 100% in R/R FL patients (Table 2; Results). The majority of patients who achieved a CR or PR remained in response (Results). Herrera demonstrated that administration of only 2 of the instantly claimed agents to the R/R FL human patient population successfully resulted in a CR and an objective response rate of 100%, providing a reasonable expectation of success for at least the combination of polatuzuamb vedotin administered at 1.8 mg/kg IV and either rituximab or obinutuzumab administered at 1000 mg to achieve a CR of at least 55% as instantly claimed, and to achieve an objective response rate of at least 87%, even in the absence of additional agent venetoclax. Although the treatment regimen is different than instantly claimed because it lacks venetoclax, it still comprises 2 of the same claimed drugs at the same claimed doses: polatuzuamb vedotin administered at 1.8 mg/kg IV and obinutuzumab administered at 1000 mg. Therefore, Herrera provides a reasonable expectation of success for a method of treating FL patients, particularly R/R, to achieve a CR of at least 55%, and to achieve an OR of at least 87%, by administering at least polatuzuamb vedotin at 1.8 mg/kg IV and obinutuzumab at 1000 mg.
Herrera teaches treatment of R/R FL patients with a combination of polatuzuamb vedotin administered at 1.8 mg/kg IV and either rituximab or obinutuzumab administered at 1000 mg was predictably successful, as stated above, demonstrating either anti-CD20 antibody obinutuzumab or rituximab yielded the same successful CR and OR rates.
Zinzani teaches treating FL patients by administering venetoclax combined with rituximab. Zinzani teaches objective response with treatment was 33% even in a highly refractory patient population, and 64% among non-refractory patients (Conclusion). Therefore, Zinzani demonstrates that a method comprising only two reagents, venetoclax and anti-CD20 antibody rituximab (demonstrated as an equivalent to obinutuzumab in Herrera), successfully treated FL patients resulting in a range of OR 33% to 64%, even in the absence of immunoconjugate polatuzuamb vedotin.
As stated above, claims 11 and 24 recite the method can produce alternative results. Zinzani teaches only 54% to 78% of patients suffered Grade 3-4 adverse events (Table 2), and only 1-6% of patients suffered tumor lysis syndrome (Table 2, meaning most did not suffer tumor lysis syndrome), providing motivation and reasonable expectation of success to achieve the claimed results of about less than 64% or 73% humans suffering Grade 3-4 adverse events, and does not result in tumor lysis syndrome, as recited in claim 11.
Contrary to arguments, treatment of R/R FL patients is not unpredictable, and the cited references demonstrate success doing so with various combinations of immunoconjugate polatuzuamb vedotin + obinutuzumab or rituximab, and venetoclax + rituximab.
11. Claim(s) 122 remains rejected under 35 U.S.C. 103 as being unpatentable over US Patent 2017/0304438, Polson et al; Herrera et al (Blood, 2016, 128(22):4194); and Zinzani et al (Blood, 2016, 128(22): 617); as applied to claims 1, 3, 10-12, 20-24, 26, 29-31, 33-35, 38, 70, 102, 128, and 129 above, and further in view of Herrera et al (Blood, 2016, 128(22):4194); and Zinzani et al (Blood, 2016, 128(22): 617).
Polson, Herrera, and Zinzanzi (the combined references) teach a method for treating R/R follicular lymphoma (FL) patients and achieving the CR after treatment, as set forth above.
The combined references do not teach treating the patients with G-CSF if a Grade 3 or 4 adverse event of neutropenia occurs.
Herrera and Yazdy teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer G-CSF if a Grade 3 or 4 adverse event of neutropenia occurred in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because Herrera teaches this adverse event occurs in FL patients treated with polatuzuamb vedotin and obinutuzumab; and Yazdy teaches G-CSF is a known treatment for Grade 3 or 4 adverse events of neutropenia in FL patients.
Response to Arguments
12. Applicants argue that claim 1 as amended is non-obvious over the argued references for the reasons stated above, as is claim 122 which depends therefrom.
13. Applicants’ arguments were addressed above and not found persuasive for the reason stated above.
14. Conclusion: No claim is allowed.
Conclusion
15. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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