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 .
Status of Claims
Applicant’s response dated 08/04/2025 has been received and entered into the application file.
Claims 18-19, 22-23, and 26-31 are pending. Claims 26-31 are new.
Claims 1-17, 20-21, and 24-25 are cancelled.
Claims 18-19, 22-23, and 26-31 are examined on the merits.
Election/Restrictions
Applicants elected Group 3, drawn to claims 18-25, without traverse in the reply filed on 04/08/2025.
Claim Interpretation
The definitions for the following terms are provided in the specification and are used for purposes of examination:
“Effective amount” of a kinase inhibitor in a pharmaceutical composition is defined as “such an amount as to treat cancer when combined with the other kinase inhibitor(s) for the pharmaceutical composition” (p 17, para 58). It is further noted that “The effective amount is determined as appropriate depending on type and ratio of each kinase inhibitor to be combined, usage, age of the subject, states of the disease and other conditions” (p 17, para 58; claims 18 and 22).
“Treatment” is defined as “encompass[ing] all types of therapeutic interventions medically acceptable for cure or temporary remission of diseases” (p 16, para 53; claims 18 and 22).
Status of Prior Objections and Rejections
RE: Claim Objections
Claims 20-21 and 24-25 are cancelled, rendering the objections thereof moot.
RE: Rejection of claims 21 and 25 under 35 USC § 112(b)
Claims 21 and 25 are cancelled, rendering the rejections thereof moot.
RE: Rejection of claims 18-25 under 35 U.S.C. 103 over Vallejo (Nature Communications, 2017, 8(1): 14294).
The rejection of claims 18-19 and 22-23 is withdrawn in light of the amendment to claim 18. Previously, claim 18 recited a generic AURK inhibitor, which includes alisertib as taught in Vallejo, in the Markush group. Amended claim 18 does not recite the generic AURK inhibitor, and instead limits the AURK inhibitor to BI-831266.
Claims 20-21 and 24-25 are cancelled, rendering the rejections thereof moot.
RE: Rejection of claims 18-25 under 35 U.S.C. 103 over Walters (Neoplasia, 2013, 15(2): 143-155), in view of Dittrich (Invest New Drugs, 2015, 33(2): 409-422).
The rejection of claims 19 and 23 is withdrawn in light of the amendments to claims 19 and 23, which require a third kinase inhibitor.
The rejection of claims 18 and 22 is maintained. Applicant’s arguments are addressed on p 9-11.
Claims 20-21 and 24-25 are cancelled, rendering the rejections thereof moot.
RE: Rejection of claims 18-25 under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155), in view of Cuneo (Journal of Clinical Oncology, 2019, 37(29): 2643-2650).
The rejection of claims 19 and 23 is withdrawn in light of the amendments to claims 19 and 23, which require a third kinase inhibitor.
The rejection of claims 18 and 22 is maintained. Applicant’s arguments are addressed on p 9-11.
Claims 20-21 and 24-25 are cancelled, rendering the rejections thereof moot.
RE: Rejection of claims 18-25 under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155), in view of Bhattacharjee (WO/2019/032561).
The rejection of claims 19 and 23 is withdrawn in light of the amendments to claims 19 and 23, which require a third kinase inhibitor.
The rejection of claims 18 and 22 is maintained. Applicant’s arguments are addressed on p 9-11.
Claims 20-21 and 24-25 are cancelled, rendering the rejections thereof moot.
New and Maintained Grounds of Rejection
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.
Claims 18, 22, 26, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155; cited in IDS 06/04/24), in view of Bhattacharjee (WO/2019/032561; cited in IDS 10/19/23).
Regarding claims 18 and 26: Walters teaches an experiment wherein patient-derived pancreatic tumors were orthotopically implanted into pancreases of immunocompromised mice (p 151, col 1, para 2). After growing for 1 to 2 weeks, the tumors were treated with drugs including trametinib, allowed to grow for 4 to 5 weeks, then tumor mass and presence of liver metastasis were assessed at necropsy (p 151, col 1, para 2 – p 151, col 2, para 1). Walters teaches that treatment with trametinib resulted in significantly better inhibition of tumor growth relative to a vehicle control (p 151, col 2, para 1; Fig 6).
Walters does not teach administering trametinib in combination with a second kinase inhibitor selected from the group consisting of AD80, adavosertib, BI-831266, and Y-27632.
Bhattacharjee teaches that AD80 can be used to treat pancreatic cancer (para 338). Bhattacharjee teaches that AD80 exhibits synergistic effects with gemcitabine, a chemotherapy medication, in two human pancreatic cancer cell lines (para 347; Figs 21-22), and that experimental results “clearly show the therapeutic potential” of AD80 in combination with gemcitabine for treatment of pancreatic cancer (para 347).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the administration of trametinib to treat pancreatic cancer, as taught in Walters, with the administration of AD80 to treat pancreatic cancer, as taught in Bhattacharjee, to achieve the predicable result of obtaining an additive effect of each kinase inhibitor to treat pancreatic cancer. Combining prior art elements according to known methods to yield predictable results is considered to be obvious, absent a showing that the result of the combination yields more than predictable results. See MPEP 2143(I)(A).
Regarding claims 22 and 30: Claims 22 and 30 differ from claim 18 only in the order of administering the kinase inhibitors. Claim 18 recites administering the two types of kinase inhibitors in combination, whereas claims 22 and 30 recite that a first kinase inhibitor is administered before or after administering a second kinase inhibitor, respectively. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, as supported by legal precedent per In re Burhans, 154 F.2d 690, 69 USPQ 330. See MPEP 2144.04(IV)(C).
Claims 18, 22, 27, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155; cited in IDS 06/04/24), in view of Cuneo (Journal of Clinical Oncology, 2019, 37(29): 2643-2650).
The teachings of Walters are set forth above.
Regarding claims 18 and 27: Walters does not teach administering trametinib in combination with a second kinase inhibitor selected from the group consisting of AD80, adavosertib, BI-831266, and Y-27632.
Cuneo teaches administering adavosertib, a Wee1 kinase inhibitor that causes selective apoptosis of cancer cells (p 2644, col 1, para 2), to patients with locally advanced pancreatic cancer (abstract). Cuneo teaches that administration of adavosertib in combination with gemcitabine and radiation therapy resulted in substantially higher overall survival (reads on treatment) than administering gemcitabine with radiation therapy alone (abstract).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the administration of trametinib to a subject with pancreatic cancer, as taught in Walters, with the administration of adavosertib to a subject with pancreatic cancer, as taught in Cuneo, to achieve the predicable result of obtaining an additive effect of each kinase inhibitor to treat pancreatic cancer. Combining prior art elements according to known methods to yield predictable results is considered to be obvious, absent a showing that the result of the combination yields more than predictable results. See MPEP 2143(I)(A).
Regarding claims 22 and 30: Claims 22 and 30 differ from claim 18 only in the order of administering the kinase inhibitors. Claim 18 recites administering the two types of kinase inhibitors in combination, whereas claims 22 and 30 recite that a first kinase inhibitor is administered before or after administering a second kinase inhibitor, respectively. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, as supported by legal precedent per In re Burhans, 154 F.2d 690, 69 USPQ 330. See MPEP 2144.04(IV)(C).
Claims 18, 22, 28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155; cited in IDS 06/04/24), in view of Dittrich (Invest New Drugs, 2015, 33(2): 409-422).
The teachings of Walters are set forth above.
Regarding claims 18 and 28: Walters does not teach administering trametinib in combination with a second kinase inhibitor selected from the group consisting of AD80, adavosertib, BI-831266, and Y-27632.
Dittrich teaches that BI-831266, an Aurora kinase inhibitor, inhibits the proliferation of pancreatic cancer, and that in murine xenograft models, administration of BI-831266 resulted in tumor regression and growth inhibition (p 410, col 1, para 2). Dittrich further teaches that the administration of BI-831266 to a patient with pancreatic cancer resulted in stable disease (p 415, col 2, para 5; “stable disease” reads on treatment).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the administration of trametinib to a subject with pancreatic cancer, as taught in Walters, with the administration of BI-831266 to a subject with pancreatic cancer, as taught in Dittrich, to achieve the predicable result of obtaining an additive effect of each kinase inhibitor to treat pancreatic cancer. Combining prior art elements according to known methods to yield predictable results is considered to be obvious, absent a showing that the result of the combination yields more than predictable results. See MPEP 2143(I)(A).
Regarding claims 22 and 30: Claims 22 and 30 differ from claim 18 only in the order of administering the kinase inhibitors. Claim 18 recites administering the two types of kinase inhibitors in combination, whereas claims 22 and 30 recite that a first kinase inhibitor is administered before or after administering a second kinase inhibitor, respectively. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, as supported by legal precedent per In re Burhans, 154 F.2d 690, 69 USPQ 330. See MPEP 2144.04(IV)(C).
Claims 18, 22, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155; cited in IDS 06/04/24), in view of Mu (Experimental & Molecular Medicine, 2018, 50(5): 1-14).
The teachings of Walters are set forth above.
Regarding claims 18 and 28: Walters does not teach administering trametinib in combination with a second kinase inhibitor selected from the group consisting of AD80, adavosertib, BI-831266, and Y-27632.
Mu teaches that in a humanized mouse model implanted with human pancreatic PANC-1 cancer cells and treated with gastrin, which promotes pancreatic cancer progression, the administration of Y-27632 significantly inhibited the growth of primary pancreatic tumors (Fig 6d-e) and prevented metastasis to the liver (Fig 6f) (p 4, col 1, para 4).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the administration of trametinib to a subject with pancreatic cancer, as taught in Walters, with the administration of Y-27632 to a subject with pancreatic cancer, as taught in Mu, to achieve the predicable result of obtaining an additive effect of each kinase inhibitor to treat pancreatic cancer. Combining prior art elements according to known methods to yield predictable results is considered to be obvious, absent a showing that the result of the combination yields more than predictable results. See MPEP 2143(I)(A).
Regarding claims 22 and 30: Claims 22 and 30 differ from claim 18 only in the order of administering the kinase inhibitors. Claim 18 recites administering the two types of kinase inhibitors in combination, whereas claims 22 and 30 recite that a first kinase inhibitor is administered before or after administering a second kinase inhibitor, respectively. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, as supported by legal precedent per In re Burhans, 154 F.2d 690, 69 USPQ 330. See MPEP 2144.04(IV)(C).
Claims 18-19, 22-23, and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Walters (Neoplasia, 2013, 15(2): 143-155; cited in IDS 06/04/24), in view of Cuneo (Journal of Clinical Oncology, 2019, 37(29): 2643-2650), and Mu (Experimental & Molecular Medicine, 2018, 50(5): 1-14).
The teachings of Walters, Cuneo, and Mu are set forth above.
Walters, in view of either Cuneo or Mu, renders obvious claims 18, 22, and 30.
Regarding claims 19, 23, and 31:
Cuneo teaches the use of adavosertib, which is a WEE inhibitor.
Mu teaches the use of Y-27632, which is a ROCK inhibitor.
Walters, in view of either Cuneo or Mu alone, does not teach the use of a third kinase inhibitor selected from the group consisting of an FRK inhibitor, a WEE inhibitor, an, AURK inhibitor and a ROCK inhibitor, wherein the second kinase inhibitor and the third kinase inhibitor are different.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the administration of trametinib to a subject with pancreatic cancer, as taught in Walters, with the administration of adavosertib to a subject with pancreatic cancer, as taught in Cuneo, and the administration of Y-27632 to a subject with pancreatic cancer, as taught in Mu, to achieve the predicable result of obtaining an additive effect of each kinase inhibitor to treat pancreatic cancer. Combining prior art elements according to known methods to yield predictable results is considered to be obvious, absent a showing that the result of the combination yields more than predictable results. See MPEP 2143(I)(A).
Response to Arguments
In the previous Office Action, claims 18 and 22 were rejected under 35 U.S.C. 103 as being unpatentable over:
Walters (Neoplasia, 2013, 15(2): 143-155), in view of Dittrich (Invest New Drugs, 2015, 33(2): 409-422),
Walters (Neoplasia, 2013, 15(2): 143-155), in view of Cuneo (Journal of Clinical Oncology, 2019, 37(29): 2643-2650), and
Walters (Neoplasia, 2013, 15(2): 143-155), in view of Bhattacharjee (WO/2019/032561).
Each of these grounds of rejection are maintained, as discussed above.
Applicant argues: Walters and Dittrich, Walters and Cuneo, and Walters and Bhattacharjee do not teach or suggest each and every limitation of claim 18. For example, these references do not disclose administering to a subject a combination of trametinib with AD80, adavosertib, BI-831266, or Y-27632 for treatment of pancreatic cancer.
More importantly, Examples 3, 4, and 6, and Figures 4, 5, 7 A, and 7B in the specification of the instant application as filed show unexpected synergistic effects on treatment of pancreatic cancer with a combination of trametinib with BI-831266, AD80, adavosertib, or Y-27632. In view of these unexpected results, the Examiner has failed to establish a prima facie case of obviousness.
In response: Applicant’s arguments have been fully considered, but are not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s arguments regarding unexpected results, the data provided in Examples 3, 4, and 6 (relating to Figures 4, 5, and 7A-B, respectively) of the specification are not commensurate in scope with the method of claim 18. Claim 18 is drawn to a method for treatment of pancreatic cancer, comprising administering to a subject in need thereof effective amounts of at least two types of kinase inhibitors. The specification does not define subject, but recites examples of mammalian subjects, and further recites that a “[p]referred subject is human” (p 17, para 54).
Example 3 (Fig 4) is an in vivo assay using fruit flies. Although this experiment does show the synergistic effect of trametinib and the other kinase inhibitors used in the experiment, the scope of this effect is limited to a situation wherein the subject is a Drosophila melanogaster comprising specific mutations as recited in Example 3 (i.e., “4-hit flies”).
Example 4 (Fig. 5) is an in vitro assay using the human pancreatic cancer cell line MIA PaCa-2. Trametinib alone reduced cell viability in dose-dependent manner. Each of the combination of trametinib and BI-831266, AD80, adavosertib, or Y-27632 “greatly reduced the cell viability compared to that of trametinib used alone, suggesting synergistic effect” (para 80). This experiment does not demonstrate the effects of the kinase inhibitors in vivo, as required by claim 18.
Furthermore, this experiment does not demonstrate synergetic effect, as the experiment does not provide data regarding the effect of BI-831266, AD80, adavosertib, or Y-27632 alone on cell viability. In the absence of these data, it cannot be concluded that the effect resulting from a combination of each of these kinase inhibitors with trametinib is synergistic.
Example 6 (Fig 7A-B) is an in vivo assay using a humanized mouse model of pancreatic cancer, wherein immunodeficient nude mice have been implanted with MIA PaCa-2 cells. Although this experiment does show the synergistic effect of trametinib and BI-831266, the scope of this effect is limited to a humanized mouse model, wherein the humanized mice bear MIA PaCa-2 cells.
Therefore, Example 4 of the specification does not demonstrate unexpected results or a synergistic effect, and the unexpected synergistic results disclosed in Examples 3 and 6 of the specification are not commensurate in scope with the method of claim 18.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/ Examiner, Art Unit 1632
/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632