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 .
Priority
The present application claims priority to the applications, 63/244,291 and PCT/US2022/076492, with the effective filing dates of 15 September 2021 and 15 September 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 8 June 2026.
Applicant’s election with traverse of Group III (claims 18-23 and 25) and the species of trametinib (MEK inhibitor) and GSK2334470 (PDPK1 inhibitor/PI3K inhibitor) in the reply filed 8 June 2026 is acknowledged. The traversal is on the ground(s) that a serious search burden does not exist.
However, this is not persuasive, because Applicant appears to have misunderstood the finding of lack of unity, which was based on a lack of special technical feature. Thus, the Examiner applied the standards for a National Phase (371) application and considered Groups I-III to have a common technical feature, which did not make a contribution over the prior art: Fedorenko (Oncogene, 2013, 32, 3009-3018; Table 1, entry 2; of record, see Requirement for Restriction mailed 13 April 2026). Regarding a serious search burden, Applicant applies a different standard to traverse the restriction requirement, which is irrelevant to 371 applications. Accordingly, the requirement is still deemed proper and is therefore made FINAL.
Claims 1-2, 5-6, 10-11, 14, 18-23, and 25 are pending.
Claims 1-2, 5-6, 10-11, and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group (Groups I and II), there being no allowable generic or linking claim.
Claims 18-23 and 25 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed on 20 June 2024, and the references cited therein have been considered, unless indicated otherwise.
Claim Interpretation
The Examiner notes that the protein, PDPK1, is 3-phosphoinositide-depedent protein kinase-1 and is also called PDK1, as evidenced by Wikipedia (“Phosphoinositide-dependent kinase-1,” Wikipedia, 2026, <en.wikipedia.org/wiki/Phosphoinositide-dependent_kinase-1>, accessed 22 June 2026; page 1, “Aliases,” Box 1).
Drawings
The Examiner notes that Applicant may wish to submit a petition for color drawings for clarity regarding Figures 1C-1F, 2A-2B, 3B, 3D, 4A-4C, 5A-5B, 6A-6C, 8D, 10A-10B, 11A-11B, 12A-12B, 13A, 13C-13D, 15A, 16A, 17A-17B, 17D, and 18A.
The Examiner further notes that Applicant may benefit from the use of color to distinguish the different data lines depicted in Figure 17D as several of the traces are indistinguishable (B6-control and B6-comb) as presented in the figure given the coloring of black and white. Alternatively, Applicant could consider utilizing different shapes to distinguish the traces.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
1. Claim(s) 18-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Sriskandarajah (BMC Cancer, 2020, 20(269), 1-14) in view of Lee (J. Investigative Dermatology, 2008, 128, 1358-1360) and Scortegagna (Oncogene, 2014, 33, 4330-4339).
Sriskandarajah teaches treating RAS-mutant multiple myeloma with trametinib and dexamethasone (a corticosteroid; abstract; page 2, bullet point 1). Sriskandarajah teaches that the RAS oncogene in particular has gained significant interest, because it is one of the most frequently mutated genes in human cancers (page 2, column 2, paragraph 2). Sriskandarajah teaches that corticosteroids are currently recommended to counteract the side effects of trametinib for the management of toxicities associated with BRAF and MEK inhibitors in melanoma patients (page 2, column 1, paragraph 3). Sriskandarajah teaches that in acute lymphoblastic leukemia, RAS-MAPK signaling drives resistance to dexamethasone but can be overcome when steroids are combined with a MEK inhibitor (page 2, column 1, paragraph 4). Sriskandarajah examined both KRAS and NRAS-resistant cell lines but focused on KRAS-mutants (page 3, column 2, paragraph 3). Sriskandarajah teaches that the KRAS-resistant cell line, MM.1S, was sensitive to GSK2334470 and that GSK2334470 is associated with suppression of the PI3K-mTOR pathway and enhanced apoptosis (page 9, column 1, paragraph 1).Sriskandarajah teaches that IGF-1 (insulin growth factor-1) plays a critical role in driving myeloma cell survival through activation of distinct downstream signaling pathways independent of IL-6 (page 9, column 1, paragraph 2). Sriskandarajah teaches that IGF-1 has recently been shown to mediate cancer cell survival through direct modulation of the PDK1 pathway, with enhanced phosphorylation of PDK1 observed following IGF-1 stimulation (page 9, column 1, paragraph 2). Sriskandarajah teaches that IGF-1 has also been shown to mediate drug resistance, including to dexamethasone, which could be reversed when cells are treated with either a PI3K inhibitor or a mTOR inhibitor (page 9, column 1, paragraph 2). Sriskandarajah teaches that IGF-1 protected cancer cells from the anti-proliferative effects of GSK2334470 and dexamethasone but the response to trametinib was not significantly affected (page 9, column 1, paragraph 2). Sriskandarajah teaches that IGF-1 conferred resistance to combined treatment with trametinib/dexamethasone in MM.1S cells (page 9, column 1, paragraph 2; page 9, column 2, paragraph 1). Sriskandarajah teaches that IGF-1 is able to blunt the antiproliferative effect of combined trametinib and dexamethasone treatment, potentially through reactivation of the PDK1 pathway (page 11, column 2, paragraph 3). Accordingly, Sriskandarajah suggests the combination of the PDK1 inhibitor, GSK2334470, and trametinib to overcome the reactivation of the PDK1 pathway (page 11, column 2, paragraph 3).
Regarding claim 18, Sriskandarajah fails to teach administering both GSK2334470 and trametinib to kill melanoma cells.
Lee teaches that the inherent ability of a cell to undergo apoptosis governs a number of developmental processes essential to proper mammalian development and that cancer is often associated with loss of an apoptotic response (abstract). Lee further teaches that avoidance of apoptosis not only prevents programmed cell death in an array of cell types but also promotes chemotherapeutic resistance during anticancer regimens (abstract). Lee teaches that IGF-1 originates from the IGF-1 receptor but is not expressed in melanoma cells (page 1358, column 3, paragraph 2; page 1359, column 1, paragraph 2). However, Lee teaches that IGF-1R expression is correlated with melanoma progression and that fibroblast-derived IGF-1 promotes growth and survival of early-stage melanoma cells (page 1359, column 1, paragraph 2). Lee suggests that IGF-1 mediates resistance to apoptosis in melanoma resulting in a chemoresistance phenotype associated with most advanced-stage melanomas (page 1359, column 1, paragraph 2).
Scortegagna teaches that PDK1 expression is significantly higher in primary melanoma and is further increased in metastatic melanoma (abstract). Scortegagna teaches PDK1 is implicated in enhanced tumor cell proliferation, reduced apoptosis, and angiogenesis (page 4330, column 1, paragraph 2). Scortegagna teaches that PDK1 inactivation effectively attenuated the development of Kras oncogene-driven pancreatic cancer (page 4330, column 2, paragraph 1). Scortegagna teaches that genetic data supporting an important role for PDK1 in melanoma development and metastasis are supported by the use of PDK1 inhibitor, specifically GSK2334470 (page 4335, column 2, paragraph 2). Scortegagna teaches genetic inactivation of Pdk1 delayed the onset of melanomas and almost completely abolished metastases in both the systemic and local BrafV600E::Pten-/- mouse melanoma models (page 4335, column 2, paragraph 2). Additionally, Scortegagna teaches that neither the tissue-specific genetic inactivation nor the general pharmacological inhibition of PDK1 results in toxicity, implying that higher doses and more potent PDK1 inhibitors can be tolerated (page 4335, column 2, paragraph 2). Scortegagna further suggests the combined treatment of a PDK1 inhibitor (such as GSK2334470) and a MEK inhibitor (page 4336, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify the method of Sriskandarajah to treat melanoma as taught by Lee and Scortegagna to arrive at the instant invention, because:
-Sriskandarajah teaches treating RAS-mutant multiple myeloma with trametinib and dexamethasone (a corticosteroid),
-Sriskandarajah teaches that the RAS oncogene in particular has gained significant interest, because it is one of the most frequently mutated genes in human cancers,
-Sriskandarajah teaches that corticosteroids are currently recommended to counteract the side effects of trametinib for the management of toxicities associated with BRAF and MEK inhibitors in melanoma patients,
-Sriskandarajah teaches that in acute lymphoblastic leukemia, RAS-MAPK signaling drives resistance to dexamethasone but can be overcome when steroids are combined with a MEK inhibitor,
-Sriskandarajah examined both KRAS and NRAS-resistant cell lines but focused on KRAS-mutants,
-Sriskandarajah teaches that the KRAS-resistant cell line, MM.1S, was sensitive to GSK2334470 and that GSK2334470 is associated with suppression of the PI3K-mTOR pathway and enhanced apoptosis,
-Sriskandarajah teaches that IGF-1 (insulin growth factor-1) plays a critical role in driving myeloma cell survival through activation of distinct downstream signaling pathways independent of IL-6,
-Sriskandarajah teaches that IGF-1 has recently been shown to mediate cancer cell survival through direct modulation of the PDK1 pathway, with enhanced phosphorylation of PDK1 observed following IGF-1 stimulation,
-Sriskandarajah teaches that IGF-1 has also been shown to mediate drug resistance, including to dexamethasone, which could be reversed when cells are treated with either a PI3K inhibitor or a mTOR inhibitor,
-Sriskandarajah teaches that IGF-1 protected cancer cells from the anti-proliferative effects of GSK2334470 and dexamethasone but the response to trametinib was not significantly affected,
-Sriskandarajah teaches that IGF-1 conferred resistance to combined treatment with trametinib/dexamethasone in MM.1S cells,
-Sriskandarajah teaches that IGF-1 is able to blunt the antiproliferative effect of combined trametinib and dexamethasone treatment, potentially through reactivation of the PDK1 pathway,
-Sriskandarajah suggests the combination of the PDK1 inhibitor, GSK2334470, and trametinib to overcome the reactivation of the PDK1 pathway,
-Lee teaches that the inherent ability of a cell to undergo apoptosis governs a number of developmental processes essential to proper mammalian development and that cancer is often associated with loss of an apoptotic response,
-Lee further teaches that avoidance of apoptosis not only prevents programmed cell death in an array of cell types but also promotes chemotherapeutic resistance during anticancer regimens,
-Lee teaches that IGF-1 originates from the IGF-1 receptor but is not expressed in melanoma cells,
-However, Lee teaches that IGF-1R expression is correlated with melanoma progression and that fibroblast-derived IGF-1 promotes growth and survival of early-stage melanoma cells,
-Lee suggests that IGF-1 mediates resistance to apoptosis in melanoma resulting in a chemoresistance phenotype associated with most advanced-stage melanomas,
-Scortegagna teaches that PDK1 expression is significantly higher in primary melanoma and is further increased in metastatic melanoma,
-Scortegagna teaches PDK1 is implicated in enhanced tumor cell proliferation, reduced apoptosis, and angiogenesis,
-Scortegagna teaches that PDK1 inactivation effectively attenuated the development of Kras oncogene-driven pancreatic cancer,
-Scortegagna teaches that genetic data supporting an important role for PDK1 in melanoma development and metastasis are supported by the use of PDK1 inhibitor, specifically GSK2334470,
-Scortegagna teaches genetic inactivation of Pdk1 delayed the onset of melanomas and almost completely abolished metastases in both the systemic and local BrafV600E::Pten-/- mouse melanoma models,
-Scortegagna teaches that neither the tissue-specific genetic inactivation nor the general pharmacological inhibition of PDK1 results in toxicity, implying that higher doses and more potent PDK1 inhibitors can be tolerated, and
-Scortegagna further suggests the combined treatment of a PDK1 inhibitor (such as GSK2334470) and a MEK inhibitor.
As such, an artisan having ordinary skill in the art would have been motivated to modify one known element for another to predictably arrive at a method of killing melanoma via administration of trametinib (an MEK inhibitor) and GSK2334470 (a PDK1 inhibitor).
Regarding claim 19, Scortegagna teaches that melanoma harbors a mutation in the NRAS gene (page 4335, column 2, paragraph 2). Additionally, Sriskandarajah teaches cancer cell lines harboring NRAS mutations (page 2, column 2, paragraph 2).
Regarding claim 20, Lee teaches the melanoma cell is a cultured melanoma cell (page 1359, column 1, paragraph 3). Scortegagna also teaches the melanoma cell is cultured from mice (page 4331, column 2, paragraph 3).
Regarding claim 21, Scortegagna teaches the melanoma is a primary melanoma cell (page 4331, column 2, paragraph 3).
Regarding claim 22, Scortegagna teaches the melanoma cell is in a subject: mice (page 4331, column 1, paragraph 2).
Regarding claim 23, Scortegagna teaches the subject is a mouse (page 4331, column 1, paragraph 2). Additionally, Sriskandarajah teaches that the subject is a patient (human) (page 2, column 1, paragraph 3).
Regarding claim 25, Sriskandarajah teaches administration of trametinib (an MEK inhibitor) with the corticosteroid (dexamethasone) to treat multiple myeloma (page 9, column 1, paragraph 2). Sriskandarajah teaches that IGF-1 conferred resistance to combined treatment with trametinib/dexamethasone in MM.1S cells (page 9, column 1, paragraph 2; page 9, column 2, paragraph 1). Sriskandarajah teaches that IGF-1 is able to blunt the antiproliferative effect of combined trametinib and dexamethasone treatment, potentially through reactivation of the PDK1 pathway (page 11, column 2, paragraph 3). Accordingly, Sriskandarajah suggests the combination of the PDK1 inhibitor, GSK2334470, and trametinib to overcome the reactivation of the PDK1 pathway (page 11, column 2, paragraph 3). Lee teaches IGF-1 mediates resistance to apoptosis in melanoma resulting in a chemoresistance phenotype associated with most advanced-stage melanomas (page 1359, column 1, paragraph 2). Scortegagna teaches that genetic data supporting an important role for PDK1 in melanoma development and metastasis are supported by the use of PDK1 inhibitor, specifically GSK2334470 (page 4335, column 2, paragraph 2). Scortegagna suggests that the combined treatment of a PDK1 inhibitor (such as GSK2334470) and a MEK inhibitor (page 4336, column 1, paragraph 1). Thus, the combination of Sriskandarajah, Lee, and Scortegagna teaches the administration of trametinib and GSK2334470 to kill melanoma.
2. Claim(s) 18-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Sriskandarajah (BMC Cancer, 2020, 20(269), 1-14) in view of Lee (J. Investigative Dermatology, 2008, 128, 1358-1360) and Scortegagna (Oncogene, 2014, 33, 4330-4339) as applied to claim 18-23 and 25 above, and further in view of Ju (Front. Oncology, July 2021, 11(709077), 1-16).
Sriskandarajah (BMC Cancer, 2020, 20(269), 1-14) in view of Lee (J. Investigative Dermatology, 2008, 128, 1358-1360) and Scortegagna (Oncogene, 2014, 33, 4330-4339) are applied as discussed in the 35 U.S.C. 103 rejection above.
Regarding claim 19, while the combination of Sriskandarajah, Lee, and Scortegagna teaches a method of killing a melanoma cell via trametinib (an MEK inhibitor) and GSK2334470 (a PDK1 inhibitor), they differ from that of the instantly claimed invention in that they do not explicitly teach that the method causes pyroptosis in the melanoma cell.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective
filing date of the instantly claimed invention to exemplify the method of Sriskandarajah, Lee, and Scortegagna with the method of Ju to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to make such a selection, with
a reasonable expectation of success, because Ju teaches that pyroptosis-related gene signatures in skin cutaneous melanoma to predict prognosis (abstract). Ju teaches that skin cutaneous melanoma is a chronically malignant tumor with a high mortality rate due to lack of specific treatment other than early surgical resection, which leads to poor prognosis and extremely high mortality (page 1, paragraph 1). Ju teaches that pyroptosis is triggered by various pathological stimuli, such as cancer and is characterized by rapid rupture of the plasma membrane and release of pro-inflammatory intracellular contents (page 2, column 1, paragraphs 1-2). Ju teaches that pyroptosis plays a dual role in cancer progression and is a double-edged sword: 1) inducing pyroptosis may be a feasible method to kill tumor cells but 2) a type of pro-inflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth (page 2, column 1, paragraph 3). Ju teaches that melanoma-targeting drugs, including BRAF and MEK inhibitors, also affect the immune microenvironment through pyroptosis (page 12, column 2, paragraph 3). Ju suggests that patients will benefit from BRAF and MEK inhibitors that trigger pyroptosis and their curative efficacy can be monitored by risk scores to guide treatment (page 12, column 2, paragraph 2). Thus, Ju teaches that the method causes pyroptosis in the melanoma cell.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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