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
The Amendment filed 11/21/2025 in response to Office Action of 8/21/2025, is acknowledged and has been entered. Claims 1-3, 5, 6, 8, 10, 12, 13, 15-17, 19-21, 27, 29-33, 39, 42 and 43 and are currently being examined.
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.
Claim(s) 1-3, 5, 6, 8, 10, 12-13, 15-17, 19-21, 27, 29-32, 39, and 42 remain rejected under 35 U.S.C. 103 as being unpatentable over Peterson et al (WO2018201016 A1; Published 11/1/2018; of record), in view of Nishikawa et al (Phase II study of the effectiveness and safety of trastuzumaband paclitaxel for taxane- and trastuzumab-na€ıve patients withHER2-positive, previously treated, advanced, or recurrentgastric cancer (JFMC45-1102), International Journal of Cancer, 140, 188-196, 2017; of record) and Wilke et al (Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial, The Lancet, Oncology, Vol 15, p1224-1235, oct 2014; of record).
Peterson teaches a method of treating HER2 cancer comprising administering a combination therapy comprising an anti-HER2 antibody, tucatinib, chemotherapeutic agent. [0007; claim 1] Peterson teaches that the anti-HER2 antibody is trastuzumab. [0008, 0013] Peterson teaches that the combination of tucatinib and trastuzumab is active in HER2 amplified cancer and a synergistic effect was observed in this combination. [Example 3]
Regarding claim 3, Peterson teaches that trastuzumab is administered at a dose of about 6 mg/kg. [0075, 0077]
Regarding claims 12 and 32, Peterson teaches that the chemotherapeutic agent may be a taxane, such as paclitaxel or docetaxel. [0052]
Regarding claims 5 and 6, Peterson teaches that tucatinib is administered to the subject at a dose of about 150 mg twice daily. [0142, 0198,
Regarding claims 13 and 19, Peterson teaches that that the cancer treated may be breast cancer or gastric cancer, and that the cancer is unresectable or metastatic cancer. [0007; claim 54]
Regarding claims 20, 27, 29, and 30, Peterson teaches that the subject had been previously treated with an anti-HER2 antibody, such as trastuzumab or Pertuzumab, or has cancer that is refractory to at least one anticancer therapy. [0009, 0070, Claim 56; 0114] Peterson teaches that the cancer has metastasized to the brain. [0045, 02337]
Regarding claims 31 and 39, Peterson teaches that the subject has one or more adverse events after starting combination therapy comprising tucatinib, trastuzumab and an additional chemotherapeutic agent, comprising administering at least one component of the combination therapy at a reduced level. [0133-0137] Peterson teaches that the initial dose ranges from 150 mg to about 650 mg and reduced to about 150 mg twice daily. [0142, 0198]
However, Peterson does not explicitly teach that the combination comprises a vascular growth factor receptor 2 (VEGFR-2) antagonist, such as ramucirumab, the dose of paclitaxel, that the gastric cancer treated is gastric adenocarcinoma, or gastroesophageal junction (GEC) adenocarcinoma, or treatment naïve patients (claim 21)
Nishikawa teaches a method of treating gastric cancer, comprising administering trastuzumab in combination with paclitaxel, in both treatment naïve as well as previously treated HER2-positive gastric cancer. Nishikawa teaches that paclitaxel is administered at a dose of about 80 mg/m2. [pg 190, Treatment] Nishikawa also teaches that several studies have examined the safety and effectiveness of ramucirumab, a VEGFR-2 antagonist, in patients with gastric cancer, and that the combination of ramucirumab + paclitaxel versus placebo and paclitaxel led to an increase overall survival in patients with gastric or gastric esophageal junction adenocarcinoma. [pg 195-196]
Wilke teaches the combination of ramucirumab and paclitaxel for the treatment of gastric or gastro-esophageal junction adenocarcinoma. Wilke teaches that the dose of paclitaxel administered in this combination was 80 mg/m2, and ramucirumab was administered at a dose of about 8 mg/kg. [pg 1225, Procedures] Wilke teaches that overall survival was significantly increased in the ramucirumab and paclitaxel group compared with the placebo and paclitaxel group. [pg 1227]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add a VEGFR-2 antagonist, such as ramucirumab at a dose of 8 mg/kg, in the method of Peterson. One would have been motivated to, and have a reasonable expectation of success, because: (1) Peterson teaches a method of treating a HER2 positive cancer comprising trastuzumab, tucatinib, and a chemotherapy, such as taxane, (2) Peterson teaches that the combination of trastuzumab and tucatinib amplified cancer treatment and led to synergistic effects, (3) Nishikawa teaches the combination of trastuzumab and paclitaxel, as well as ramucirumab and paclitaxel, for the treatment of cancer, (4) Wilke teaches the combination of ramucirumab and paclitaxel in the treatment of cancer, wherein ramucirumab was administered at a dose of 8 mg/kg, and (5) Wilke and Nishikawa both teach that the combination of ramucirumab and paclitaxel both significantly increased overall survival.
Those of skill in the art recognize that the four agents, tucatinib, trastuzumab, a taxane, and a VEGFR-2 inhibitor, are all known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive effects through the combination of the four agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective at treating cancer in various combinations (trastuzumab/tucatinib/paclitaxel or trastuzumab/paclitaxel or ramucirumab and paclitaxel), thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating cancer.
Is it noted that claims 13 and 15 require that paclitaxel is administered at dose of about 80 mg/m2. This limitation would have been obvious to those of ordinary skill in the art because: (1) Peterson teaches a method of treating a HER2 positive cancer comprising trastuzumab, tucatinib, and paclitaxel, (2) Nishikawa teaches the combination of trastuzumab and paclitaxel, wherein paclitaxel is administered at dose of 80 mg/m2, and (3) Wilke teaches the combination of ramucirumab and paclitaxel in the treatment of cancer, wherein paclitaxel was administered at a dose of 80 mg/m2. Given the known need to treat cancer, and given the known doses of paclitaxel in the treatment of cancer, one of skilled in the art would have pursued administering paclitaxel at dose of 80 mg/m2 with a reasonable expectation of success.
Is it noted that claim 17 requires that the cancer treated is gastric adenocarcinoma or GEC. This limitation would have been obvious to those of ordinary skill in the art because: (1) Peterson teaches a method of treating a HER2 positive cancer comprising trastuzumab, tucatinib, and paclitaxel, wherein the cancer is gastric cancer (2) Nishikawa teaches the combination of trastuzumab and paclitaxel, for the treatment of gastric or gastric esophageal junction adenocarcinoma, and (3) Wilke teaches the combination of ramucirumab and paclitaxel in the treatment of cancer, wherein the cancer treated is gastric or gastric esophageal junction adenocarcinoma.
Is it noted that claim 21 requires that the subject has not been previously treated an anti-HER2, anti-EGFR tyrosine kinase inhibitor, anti-HER2-directed antibody-drug conjugate, and/or an anthracycline. This limitation would have been obvious to those of ordinary skill in the art because: (1) Peterson teaches a method of treating a HER2 positive cancer comprising trastuzumab, tucatinib, and paclitaxel, and (2) Nishikawa teaches the combination of paclitaxel and trastuzumab, in both treatment native as well as previously treated patients. Given the recognized need to treat cancer, including in subjects who have not previously been treated with anti-HER2, anti-EGFR tyrosine kinase inhibitor, anti-HER2-directed antibody-drug conjugate, and/or an anthracycline, one of skill in the art could have pursued applying the combination to treat subjects who have not been previously treated prior.
Response to Arguments
Applicant argues that adding therapeutic agents together requires more than just using hindsight to pick which agents to combine. Applicants argue that therapeutic agents have side effect profiles that may amplify another agent thus reducing a agents therapeutic index. Applicant argues that two agents that have synergy together may lose such synergy with the addition of one or more agent.
Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this instant case, the claims are drawn to the combination of agents: tucatinib, trastuzumab, a taxane, and a VEGFR-2 antagonist for the treatment of HER2 cancer. The primary reference, Peterson, teaches a method of treating HER2+ cancer, comprising administering an anti-HER2 antibody, tucatinib, and a chemotherapeutic agent, such as paclitaxel or docetaxel (a taxane). Thus, Peterson teaches 3/4 agents taught in the combination. Although, Peterson does not teach the fourth agent, a VEGFR-2 antagonist, the Examiner relied on the secondary references to remedy this deficiency:
Nishikawa teaches the treatment of cancer comprising administering paclitaxel and ramucirumab, a VEGFR-2 antagonist and Wilke teaches the treatment of cancer comprising administering paclitaxel and ramucirumab;
Thus, the purpose of the 103 rejection is to remedy the deficiency of Peterson, which does not include a VEGFR-2 antagonist, however, it would have been obvious to a person skilled in the art to add a VEGFR-2 antagonist based on the teachings of the combined references.
Claim(s) 33 and 43 remain rejected under 35 U.S.C. 103 as being unpatentable over Peterson et al (WO2018201016 A1; Published 11/1/2018 of record), Nishikawa et al (Phase II study of the effectiveness and safety of trastuzumaband paclitaxel for taxane- and trastuzumab-na€ıve patients withHER2-positive, previously treated, advanced, or recurrentgastric cancer (JFMC45-1102), International Journal of Cancer, 140, 188-196, 2017 of record) and Wilke et al (Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial, The Lancet, Oncology, Vol 15, p1224-1235, oct 2014; of record), as applied to claims 1-3, 5, 6, 8, 10, 12-13, 15-17, 19-21, 27, 29-32, 39, and 42 above, and further in view of Taxol FDA Package Insert (last revised 2011; of record) and CRYAMZA FDA Package Insert (2014); of record.
The teachings of Peterson, Nishikawa and Wilke are recited above. However, they do not teach that reduced doses of paclitaxel and ramucirumab after a patient experiences an adverse event after starting treatment, as required by claims 33 and 43.
The TAXOL (Paclitaxel) package insert teaches that in the event of adverse effects due to taxol, a dose reduction of about 20% is recommended. [pg 22, 23, and 46]
The CRYAMZA (ramucirumab) package insert teaches that in the event of an adverse event due to ramucirumab, a dose decrease up to 5 mg of ramucirumab is recommended. [pg 4, Table 1]
Is it noted that claims 33 and 34, require dose reduction of paclitaxel and ramucirumab, respectively, when a subject experiences an adverse event related to the combination. This limitation would have been obvious to those of ordinary skill in the art because: (1) Peterson teaches a method of treating HER2 positive cancer in a subject that has exhibited one or more adverse events related to the one of the agents, comprising administering least one component of the combination therapy at a reduced level, (2) Peterson teaches that one of these agents includes a chemotherapeutic agent, and (3) the package inserts of both paclitaxel and ramucirumab both explicitly state to administer the agents at lower doses when the patient experiences an adverse events. Given the known need to treat cancer, and given the known methods of reducing the dose of agents when patients experience adverse events, one of skill in the art could have pursued administering either paclitaxel and ramucirumab at a lower dose when the patient experiences an adverse event.
Response to Arguments
Applicant argue that the above arguments apply to this 103 rejection and that the FDA package inserts do not add anything of substance to the rejection.
Applicant’s arguments have been considered but are not persuasive. The purpose of the FDA package insert is to demonstrate the known side effects of both taxol and ramucirumab. Both of these package inserts teach that in the event of adverse events, the doses of taxol and ramucirumab are reduced. Claim 31 recites that if the subject experiences an adverse event after starting the combination therapy, administering at least one component at a reduced level. Thus, reducing the levels of these agents are known by the art as taught by the FDA Package insert.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600