DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
1. The Amendment filed March 2, 2026 in response to the Office Action of September 2, 2025, is acknowledged and has been entered. Claims 23-28, 31-33 and 35 are pending and being examined. Claim 23 is amended and altered in scope to require administering the treatment regimen comprising drugs targeting EGFR tyrosine kinase activity to the breast cancer patient regardless of the observed changes in biomarker levels before and during treatment.
Maintained Rejections
(addressing amendments)
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
2. Claims 23, 24, 31, and 35 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2011/0071042, Kim et al, published March 2011; in view of Gao et al (Bio-Rad 2007 Bulletin); Gao et al (ACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA, abstract #2824); LoPiccolo et al (Drug Resistance Updates, 2008, 11:32-50); Lin et al (British J of Cancer, 2005, 93:1372-1381); Han et al (PLoS ONE, 2011, 6:e18691, internet pages 1-8); Dong et al (Cancer Chemother Pharmacol, 2012, 70:707-716); and Corkery et al (Annals of Oncology, 2009, 20:862-867).
Kim teaches a method of monitoring response to a cancer treatment in a breast cancer patient, the method comprising:
(a) measuring a plurality of biomarkers comprising phosphorylated forms (activation states) of Akt, MEK, mTOR, and GSK3beta in a breast cancer patient’s test samples ([110-111]; [124-126]; [137]; [270]; [282-285]; Tables 1 and 2; [307-317]; [491-493]);
(b) wherein measuring the activation states of the biomarkers in patient test samples occurs at periodic time intervals before (baseline), during (interim), and after (interim) cancer treatment ([37-41]; [110-111]; [250-254]; [282]; [491]; [505]; Figure 10);
(c) comparing biomarker levels measured at baseline and interim, therefore a comparison is received;
(d) identifying changes in the compared biomarker levels to evaluate efficacy of the treatment and to identify treatment response or resistance ([24-29]; [41]; [118-120]; [250-254]; [303-305]; [505]; Figure 10); and
(e) continuing to administer treatment until the patient becomes refractory and administering alternative therapy ([41]; [254]; [267]; [505]).
Kim teaches:
[0110] In many cases, the activity of particular signal transduction pathways, and components thereof, may serve as molecular signatures for a given type of cancer. Such activated components may further provide useful targets for therapeutic intervention. Accordingly, knowledge of the activity level of a particular signal transduction system within a cancer cell prior to, during, and after treatment provides a physician with highly relevant information that may be used to select an appropriate course of treatment to adopt. Furthermore, the continued monitoring of signal transduction pathways that are active in cancer cells as treatment progresses can provide the physician with additional information on the efficacy of treatment, prompting the physician to either continue a particular course of treatment or to switch to another line of treatment, when, for example, cancer cells have become resistant to treatment through further aberrations that activate either the same or another signal transduction pathway.
[0111] Accordingly, the present invention provides methods and compositions for detecting the expression and/or activation states of a plurality of deregulated signal transduction molecules in tumor tissue or extratumoral cells such as rare circulating cells of a solid tumor in a specific, multiplex, high-throughput assay. The invention also provides methods and compositions for the selection of appropriate therapy (single drugs or combinations of drugs) to down-regulate or shut down a deregulated signaling pathway. Thus, the invention may be used to facilitate the design of personalized therapies for cancer patients.
[0118] In contrast to currently available breast cancer testing options, the methods of the present invention enable the monitoring of breast cancer patients through all stages of the disease by providing a “real-time biopsy” of solid breast tumors using samples such as circulating tumor cells (CTCs) from blood and/or fine needle aspirates (FNAs). As a non-limiting example, the breast cancer assays described herein can be used in the initial diagnosis of breast cancer in a patient at an early stage of the disease. Selection of a suitable cancer therapy is guided by profiling the expression and/or activation states of specific signaling pathways with and without anticancer drugs using the assays described herein. Advantageously, the methods of the present invention can also be used to monitor the progression or regression of the disease because therapeutic intervention may be based on samples taken at any stage of the disease and analyzed using the assays described herein. As such, selection of suitable cancer therapies for the early and metastatic stages of breast cancer is guided by real-time diagnosis and an analysis of the expression and/or activation status of specific signaling pathway molecules.
[0120] In sum, the compositions and methods of the present invention advantageously provide accurate prediction, selection, and monitoring of cancer patients (e.g., breast cancer patients) most likely to benefit from targeted therapy by performing pathway profiling on easily accessible tumor cells using multiplexed, antibody-based proximity assays.
[0304] wherein the presence of a substantially decreased activation level of one or more of the signal transduction molecules in the cellular extract compared to the reference activation level of the one or more signal transduction molecules indicates that the anticancer drug is suitable for the treatment of the breast tumor.
[505] A subject can also be monitored at periodic time intervals to assess the efficacy of a certain therapeutic regimen. For example, the activation states of certain signal transduction molecules may change based on the therapeutic effect of treatment with one or more of the anticancer drugs described herein. The subject can be monitored to assess response and understand the effects of certain drugs or treatments in an individualized approach. Additionally, subjects who initially respond to a specific anticancer drug or combination of anticancer drugs may become refractory to the drug or drug combination, indicating that these subjects have developed acquired drug resistance. These subjects can be discontinued on their current therapy and an alternative treatment prescribed in accordance with the methods of the present invention.
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Kim teaches their method is used to decide if treatment should be continued or adjusted (e.g., maintaining the current dose of the compound, changing a subsequent dose of the compound, or selecting an alternative anticancer drug) (abstract; [41]; [250-254]; [528]; [536]).
Kim teaches the biomarkers are measured by an immunoassay for testing a single sample which comprises a multiplexed high-throughput antibody array that comprises contacting the patient sample with a solid support coated with capture antibodies for immobilizing the biomarkers proteins, and adding detection antibodies that are specific for the activation state (phosphorylation) of the biomarker and have a detectable label/signal ([135-138]; [375-385]; [396-397]; [412-419]; [432-434]; [446]);
wherein the detectable label/signal is chemiluminescent such as luminol or isoluminol ([442-443]);
wherein the immunoassay comprises calibrator proteins or controls, and in compartments on the assay ([569]; Figure 23); and
wherein the labeled detection antibodies are comprised in a kit ([395]; [447]).
Kim teaches the biomarkers can be used to determine a prognosis or monitor the progression of the breast cancer ([47]; [118]; [326]).
Kim demonstrates conducting an immunoassay on slides to detect a plurality of biomarker protein activation states, wherein the slides comprise a plurality of domains or “pads”, wherein each pad comprises a plurality of assay domains that comprise reagents for measuring different biomarkers (Figures 23, 29, 37-46, and 48a).
Kim teaches the anticancer treatment administered in their method of monitoring of responsiveness includes gefitinib that interferes with the function of EGFR ([160]; [232]; [260]; [281]; Table 1; [309]; [493]).
Kim does not teach:
The comparison of baseline levels consists of phosphorylated isoforms Akt, MEK, mTOR, and GSK3beta (claim 23);
Identifying the patient as responsive to the anticancer treatment when levels of phosphorylated Akt, MEK, mTOR, and GSK3beta are decreased after treatment and administering the treatment until unacceptable toxicity occurs (claim 23 and 35).
Gao et al (Bio-Rad bulletin) teach the signaling relationship between EGFR, MEK, Akt, and GSK3β, wherein MEK, Akt, and GSK3β are downstream targets of EGFR (Figure 1). Gao et al (Bio-Rad bulletin) teach and demonstrate it is known that phosphorylated Akt, MEK, and GSK3β levels change in response to anti-EGFR gefitinb treatment, wherein decreased levels of the phosphorylated proteins after treatment are indicative of responsiveness (see bar graphs). Gao et al utilized a multiplex phosphoprotein assay to measure the response (Figure 2). Gao et al teach the known relationship between gefitinib inhibition of EGFR and cell signaling to MEK, Akt, and GSK3β to associated with cell proliferation (Figure 1).
Gao et al (Meeting abstract) summarize the data in the Gao et al Bio-Rad Bulletin and state that the phosphorylation of their six tested downstream targets, including Akt, MEK and GSK3β, were unaffected by gefitinib in the resistant cancer cell lines. Therefore, Gao et al establish that unchanged levels of MEK, Akt, and GSK3β phosphorylation before and after treatment indicate unresponsiveness to gefitinib.
LoPiccolo et al teach many clinical observations support targeting the PI3K/Akt/mTOR pathway in human cancer, and that Akt is phosphorylated in many cancers including breast cancer (section 1.3, p. 34, col. 1). LoPiccolo et al teach the known pathway relationships between activation of EGFR or receptor tyrosine kinase (RTK) signaling, and activation of PI3K, Akt, mTOR and MEK, and teach known EGFR/RTK inhibitor gefitinib (Figure 2).
Lin et al teach it is known mTOR is a downstream target of Akt (p. 1373, col. 1), and demonstrate that breast cancer cells have activated and increased phosphorylated mTOR and Akt (p. 1375, col. 2 to p. 1377, col. 2; Figures 1-3). Lin et al teach EGFR is considered an upstream regular of Akt pathway and demonstrate EGFR was phosphorylated in 75% of primary breast tumors and associated with invasive breast tumors (p. 1378, col. 1; Table 1).
Han et al demonstrate that gefitinib significantly reduces levels of phosphorylated Akt and mTOR after treatment in A549 and H1299 cancer cells and the cells are reduced in viability in response to gefitinib even when the cells are “relatively resistant to EGFR-receptor tyrosine kinase inhibitors” (Figure 4; p. 4, col. 2). Han et al teach that gefitinib, an EGFR tyrosine kinase inhibitor (TKI), inhibits the PI3K/Akt/mTOR pathway signaling (abstract).
Dong et al also teach that EGFR and mTOR control cross-linked signaling pathways and assess changes in cancer cell signaling in response to gefitinib (EGFR inhibitor) and/or everolimus (mTOR inhibitor). Dong et al demonstrated that even in relatively gefitinib-resistant cells A549, H1650 and PC-9GR, gefitinib treatment still reduced cell proliferation simultaneously with reduction in p-mTOR and p-Akt, particularly at higher doses (Figures 1, 2, 5), while the addition of an mTOR inhibitor with gefitinib provided increased inhibition of cell proliferation and reduction in p-mTOR and p-Akt levels (Figures 1, 2, and 6).
Corkery et al demonstrate the same correlation in breast cancer cells, where gefitinib treatment results in decreasing levels of phosphorylated Akt (pAkt) over time in HER2+ sensitive breast cancer cells, and there is no change in pAkt levels during treatment of triple negative breast cancer cells that are resistant to gefitinib (p. 865, col. 1; Figure A). Corkery et al demonstrate that treatment of the resistant cells with gefitinib alone has limited effect on reducing cell proliferation (Figure 1). Corkery et al also demonstrate that adjusting gefitinib therapy by adding chemotherapy to gefitinib treatment increased breast cancer cell responsiveness to gefitinib, even in gefitinib-insensitive triple negative breast cancer cells (Figure 1B).
Panel of biomarkers consisting of phosphorylated isoforms of MEK, Akt, mTOR and GSK3β:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to utilize a panel of biomarkers consisting of phosphorylated isoforms of MEK, Akt, mTOR and GSK3β for gefitinib efficacy assessment in the method of Kim. One would have been motivated to, and have a reasonable expectation of success to, given: (1) Kim suggests their method assess known EGFR inhibitor gefitinib and suggests assessing known biomarkers of therapeutic responsiveness including phosphorylation levels of MEK, Akt, mTOR and GSK3β; (2) both Gao references, LoPiccolo, Lin, Han, Dong, and Corkery identify phosphorylation levels of MEK, Akt, mTOR and GSK3β as specifically indicative of therapeutic response to gefitinib, either separately or in subsets together, providing motivation and reasonable expectation of success to select these biomarkers disclosed in Kim for therapeutic response assessment. Further, according to the cited prior art, the biomarkers of phosphorylated MEK, Akt, mTOR and GSK3β would have predictably performed the same function in assessing response to gefitinib individually as they would have in various subsets or all together, providing a reasonable expectation of success for a panel of biomarkers consisting of phosphorylated MEK, Akt, mTOR and GSK3β to serve the same function taught by the cited prior art.
Identify the breast cancer patient as responsive when phosphorylation levels of MEK, Akt, mTOR and GSK3β are reduced during gefitinib treatment and administering more of the same effective gefitinib treatment until no longer beneficial or unacceptable toxicity occurs:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to identify the patient responsive to treatment when phosphorylation levels of MEK, Akt, mTOR and GSK3β decrease after treatment and to continue administering treatment until unacceptable toxicity and treatment is no longer beneficial, in the method of evaluating treatment response taught by Kim. One would have been motivated to given: (1) Kim teaches monitoring changes in phosphorylation levels of biomarkers MEK, Akt, mTOR and GSK3β in breast cancer patients to evaluate therapeutic efficacy of treatment, wherein treatment includes gefitinib, and teaches continuing to administer treatment until the patient becomes refractory; (2) both Gao et al references, LoPiccolo et al, and Lin et al teach signaling pathways of EGFR (inhibited by gefitinib) are known to include Akt, MEK, mTOR, and GSK3β that are interrelated, and LoPiccolo et al and Lin et al teach that EGFR, Akt and mTOR phosphorylation and signaling are increased in breast cancer, suggesting targeting the pathways for therapy; (3) both Gao et al references, Han et al, and Dong et al recognize that anticancer therapy, gefitinib, changes levels in phosphorylation of MEK, Akt, mTOR and GSK3β signaling proteins when cancer cells are responsive to gefitinib and have decreased proliferation, and no changes or no decreased levels in phosphorylation occur when cancer cells are resistant; (4) Corkery et al demonstrate the same correlation for the Akt pathway and gefitinib response in breast cancer cells.
One of ordinary skill in the art would have a reasonable expectation of success identifying a responsive patient in the method of Kim when phosphorylation levels of MEK, Akt, mTOR and GSK3β are reduced during gefitinib treatment, given the cited art establish the known correlation between a reduction in MEK, Akt, mTOR and GSK3β phosphorylation/signaling, inhibition of cancer cell growth, and cancer cell sensitivity to treatment.
Finally, one of ordinary skill in the art would have motivation and reasonable expectation of success to continue treatment to responsive patients, because: (1) Kim suggests continuing to administer treatment until the patient becomes refractory; and (2) all of the cited references teach monitoring biomarkers for the sake of administering cancer therapy beneficial to responsive patients.
3. Claims 26-28, 32, and 33 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2011/0071042, Kim et al, published March 2011; Gao et al (Bio-Rad 2007 Bulletin); Gao et al (ACR Annual Meeting—Apr 14-18, 2007; Los Angeles, CA, abstract #2824); LoPiccolo et al (Drug Resistance Updates, 2008, 11:32-50); Lin et al (British J of Cancer, 2005, 93:1372-1381); Han et al (PloS ONE, 2011, 6:e18691, internet pages 1-8); Dong et al (Cancer Chemother Pharmacol, 2012, 70:707-716); and Corkery et al (Annals of Oncology, 2009, 20:862-867); as applied to claims 23, 24, 31, and 35 above, and further in view of MSD® Technology Platform (July 2011); MSD® Toxicology Applications (October 2011); Meso Scale Discovery® Assays and Kits (March 2011); and WO 2010/127057, Glezer et al, published November 2010 (all references cited in IDS).
Kim; Gao et al Bio-Rad Bulletin; Gao et al abstract; LoPiccolo et al, Lin et al, Han et al; Dong et al, and Corkery et al (the combined references) teach a method of administering a treatment regimen to a patient in need thereof for treating breast cancer, comprising:
(a) measuring in a first test sample from a patient before said treatment regimen is initiated, baseline levels of a plurality of biomarkers comprising phosphorylated isoforms of Akt, MEK, mTOR, and GSK3beta,
(b) measuring in an interim test sample from said patient during said treatment regimen for breast cancer interim levels of said plurality of biomarkers in said interim test sample,
(c) comparing said interim levels to said baseline levels of said plurality of biomarkers,
(d) evaluating from said comparing step (c) whether said patient is responsive to said treatment regimen, wherein if said interim levels of phosphorylated isoforms of Akt, MEK, mTOR, and GSK3beta are decreased as compared to said baseline levels, then the patient is responsive to said treatment regimen;
wherein measuring is conducted by multiplex immunoassay comprising a plurality of assay binding domains comprising reagents for measuring different biomarkers; wherein the assay uses both capture antibodies and detection antibodies that are labeled with chemiluminescent label, as set forth above.
The combined references do not teach detecting the biomarkers using MSD® multi-spot multi-well assay that comprises:
a multi-well assay plate, each well comprising a plurality of assay domains that comprise reagents for measuring different biomarkers (claims 26-27);
assay domains positioned on an electrode within the wells (claim 28); and
detection antibodies with an ECL label and an ECL read buffer for their chemiluminescent immunoassay (claims 32 and 33).
MSD® Technology Platform teaches commercially available multiplexed 14hosphor14t cell signaling kits that can be customized and comprise 96-well plates with a 4-spot or 10-spot format in order to detect multiple analytes in a single well (p. 2), and provides a diagram for the multi-array plate and spots on the cover and pages 2, 3, and 6. MSD® Technology Platform teaches their system uses electrochemiluminescence antibody label detection (p. 2) and each binding domain or spot is positioned on an electrode within each well (p. 2). MSD® Technology Platform teaches on page 1: “MESO SCALE DISCOVERY offers a unique, multiplexed immunoassay platform for the quantification of proteins in biological samples. With over 400 convenient assay kits and assay customization capabilities, MSD has enabled scientists to make accurate and precise determinations of levels of cytokines, phosphoproteins, and other biomarkers in different matrices. High quality data can be obtained in less time on the MSD platform with minimal effort and low cost. MSD’s MULTI-ARRAY technology has been adopted by major pharmaceutical companies, clinical research organizations, biotech companies, personalized medicine companies, and academic and government institutions.” The MSD technology is used in oncology (p. 1), and provides custom surface coatings and patterns with custom panels of analytes, (p. 2, 3, 8, 9, 12). MSD® Technology Platform teaches that “If you are studying a special combination of analytes, we can provide a multiplex panel to meet your needs. We will work with you to prepare a custom kit according to your preferences and provide you with a protocol for the assay” (p. 8). MSD® Technology Platform teaches the advantages of using their rapid quantification of phosphoproteins is to reduce cost and time, gain sensitivity, reduce cell culture volume, analyze a wide range of matrices, gain with MSD multiplexing, gain in throughput (p. 6). MSD® Technology Platform lists advantages of using their system on p. 3 including large dynamic range, high sensitivity, high precision, low background, conserves sample volume, simple protocols, reduces matrix effects, eliminates multiple dilutions, multiple analytes in a single well, no compromise on performance or speed, catalog assay panels for rapid delivery, available custom panels.
MSD® Toxicology Applications also teaches the commercially available cell signaling kits can be customized and comprise 96-well plates with a 10-spot format (p. 2) and MSD® provides a diagram for the multi-array plate and spots on p. 2. MSD® Toxicology Applications teaches the kits can comprise antibodies to detect 15hosphor-Akt, 15hosphor-GSK3beta, and 15hosphor-mTor with signals >1500 and <106 (p. 17-18). MSD® provides a figure demonstrating the interrelated cell signaling for GSK3, Akt, mTOR, and MEK (p. 17). MSD® teaches the advantage of their kit is to measure multiple analytes in a single sample with ultra-low detection limits.
Meso Scale Discovery® Assays and Kits (March 2011) teach commercially available ECL kits to detect total and phosphorylated forms of any of: Akt, GSK3beta, MEK, and mTOR (last page).
Glezer et al teach using a multi-well, multi-spot MSD® electrochemiluminescent assay to measure the level of phosphorylated proteins in samples from a cancer patient undergoing therapy to determine efficacy of therapy or responsiveness of the patient, including comparing levels between baseline samples and subsequent samples taken during the course of therapy (pages 7-9, claims 1-30). Glezer et al teach successful use of a multi-well, multi-spot MSD® electrochemiluminescent assay for determining the total amount and phosphorylation of biomarker proteins including Akt, GSK3beta, and MEK in cell signaling for cancer. Glezer et al teach a multiplex immunoassay kit with either purified calibrator biomarker proteins or controlled cell lysates containing the biomarker proteins used to make a serial dilution for calibration curves to calculate the levels of protein biomarkers in samples in the electrochemiluminescent assay (Tables 1 and 2; Examples, p. 17-21).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to customize and use a Meso Scale Discovery® multiplexed multi-spot plate kit using ECL detection in the method of the combined references. One would have been motivated to in order to: (1) gain all of the advantages taught by MSD® Technology Platform and MSD® Toxicology Applications, and (2) apply the multiplexed multi-spot assay to measuring cell signaling in oncology as taught by the combined references, MSD® Technology Platform, MSD® Toxicology Applications, Meso Scale Discovery® Assays and Kits, and Glezer et al. One of ordinary skill in the art would have a reasonable expectation of success given the multiplexed multi-spot plate kit are commercially available, customizable, and Meso Scale Discovery® Assays and Kits teaches all of the capture and detection reagents for the analytes of the combined references are available for customizing plates. Further, one of ordinary skill in the art would have a reasonable expectation of success given Glezer et al teach successful use of a multi-well, multi-spot MSD® electrochemiluminescent assay for measuring the phosphorylation of biomarker proteins including at least Akt, GSK3beta, and MEK as correlated to cancer patient response to therapy.
4. Claim 25 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2011/0071042, Kim et al, published March 2011; Gao et al (Bio-Rad 2007 Bulletin); Gao et al (ACR Annual Meeting—Apr 14-18, 2007; Los Angeles, CA, abstract #2824); LoPiccolo et al (Drug Resistance Updates, 2008, 11:32-50); Lin et al (British J of Cancer, 2005, 93:1372-1381); Han et al (PloS ONE, 2011, 6:e18691, internet pages 1-8); Dong et al (Cancer Chemother Pharmacol, 2012, 70:707-716); and Corkery et al (Annals of Oncology, 2009, 20:862-867); as applied to claims 23, 24, 31, and 35 above, and further in view of Generali et al (Journal of Oncology, 2009, 27:227-234).
Kim; Gao et al Bio-Rad Bulletin; Gao et al abstract; LoPiccolo et al, Lin et al, Han et al; Dong et al, and Corkery et al (the combined references) teach a method of administering a treatment regimen to a patient in need thereof for treating breast cancer, as set forth above. Kim further suggests using their methods to monitor the progression of disease, particularly progression of cancer as a result of resistance to treatment, and teach activation or phosphorylation, of their biomarkers indicates cancer progression ([118]; [353]; [536]).
The combined references do not teach determining from the interim levels the disease progression of breast cancer by ROC curve analysis (claim 25).
Generali demonstrates correlating measured phosphorylation levels of biomarkers in breast cancer to treatment response/resistance using ROC curve analysis and commercially available software, including utilizing phosphorylated markers Akt and mTOR, and wherein disease progression is an indicator of treatment resistance (p. 228, col. 1; p. 229, col. 1; p. 230, col. 1; Table 1 and 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to determine from the interim phosphorylated biomarker levels the disease progression of breast cancer by ROC curve analysis. One would have been motivated to and have a reasonable expectation of success to because: (1) Kim suggests using their methods to monitor the progression of disease, particularly progression of cancer as a result of resistance to treatment, and teach activation or phosphorylation, of their biomarkers indicates cancer progression; and (2) Generali demonstrates successfully utilizing ROC curve analysis of phosphorylated biomarkers, by commercially available software, to monitor the progression and resistance of breast cancer to treatment.
Response to Arguments Under U.S.C. 103(a)
5. Applicants point to the 37 CFR 1.132 Mathew declaration and argue that Kim and Holmes do not provide motivation to arrive at the claimed method. Applicants argue that Kim discloses detecting expression and/or activation states of a plurality of signal transduction molecules in tumor tissues, extratumoral cells, and their lysates, and monitoring response to therapy with a compound that modulates HER2 signaling pathway by determining changes in expression and/or activity (phosphorylation) of one or more components of the HER2 signaling pathway, wherein a difference in expression/activity of the one or more components of the HER2 signaling pathway indicates the therapy should be continues or adjusted (e.g. maintaining the current dose, changing the subsequent dose, or selecting an alternative anticancer drug).
Applicants argue that Kim defines a “component of a HER2 signaling pathway” as including any one or more of an upstream ligand of HER2, binding partner of HER2, and/or downstream effector molecule that is modulated through HER2 and lists a multitude of non-limiting examples of such components. Applicants argue that Kim does not teach or suggest how gefitinib affects any of Akt, MEK, mTOR, or GSK3beta biomarkers in breast cancer cells and does not provide a correlation of decreased interim levels of the biomarkers to gefitinib response. Applicants argue that Kim does not provide motivation to identify a patient as responsive to gefitinib based on observing decreased interim levels of the biomarkers Akt, MEK, mTOR, and GSK3beta compared to baseline, and does not provide motivation to continue administering gefitinb until the patient is no longer clinically benefitting from it.
Applicants argue that Holmes discusses patient response to lapatinib and trastuzumab, but not gefitinib. Applicants argue that Holmes measured over 20 biomarkers that included Akt, MEK, mTOR, and GSK3beta. Applicants argue that Holmes also does not provide motivation to identify a patient as responsive to gefitinib based on observing decreased interim levels of the biomarkers Akt, MEK, mTOR, and GSK3beta compared to baseline, and does not provide motivation to continue administering gefitinb until the patient is no longer clinically benefitting from it.
Applicants argue that LoPiccolo and Lin do not remedy the deficiencies of Kim and Holmes discussed above. Applicants argue that LoPiccolo teaches Akt is phosphorylated in breast cancer but does not teach Akt phosphorylation is inhibited by gefitinib. Applicants argue that Lin teaches AKT, mTOR, as well as PDK-1, p20S6K, S6, and Stat3 have increased phosphorylation in breast cancer. Applicants argue that Lin does not teach the effects of gefitinib on Akt, MEK, mTOR, and GSK3beta phosphorylation levels or their correlation to treatment response.
Applicants argue that Corkey is silent with regards to Akt, MEK, mTOR, and GSK3beta and fails to remedy the deficiencies argued above.
Applicants argue that Gao Bio-Rad, Gao ACR han, and Dong are directed to Akt, MEK, mTOR, and GSK3beta signaling related to gefitinib response lung cancer cells and are not directed to breast cancer. Applicants state they believe these references would not be relied upon to understand or predict the behavior of signaling molecules in breast cancer.
Applicants argue that Han teaches phosphorylation levels of Akt and mTOR after treatment in responsive cancer cells. Applicants argue that while the office action states gefitinib treatment significantly reduced phosphorylation levels of Akt and mTOR after treatment in A549 and H1299 cancer cells, these cells are lung cancer cells and are not breast cancer cells as taught in the other cited references. Applicants argue that the claims require treating breast cancer and Han does not teach the effect of gefitinib on breast cancer cells or on a patient responsive to gefitinib. Applicants argue that the lung cancer cells tested by Han were relatively resistant to EGFR-TKIs and are not representative of responsive cancer cells.
Applicants state the remaining cited references address various assay elements in the dependent claims.
Applicants argue that the office used hindsight reasoning to arrive at the claimed invention. Applicants argue that even if all the cited references are combined, one skilled in the art would not arrive at the claimed method.
6. The arguments have been carefully considered but are not persuasive.
It is noted that Applicants argue a “Holmes” reference, but no such reference was cited in the rejections.
Claim 23 has been amended to require administering a treatment comprising “drugs targeting EGFR tyrosine kinase activity until the patient is no longer clinically benefitting from the treatment” regardless of the changes in phosphorylation of Akt, MEK, mTOR, and GSK3beta observed in the breast cancer patient. Although step (b) of claim 23 provides a wherein clause stating “wherein if interim levels of phosphorylation isoforms of Akt, MEK, mTOR, and GSK3beta are decreased as compared to said baseline levels, then the patient is responsive to said treatment regimen,” claim 23 does not require any patient to be positively identified as responsive to the treatment regimen. The wherein clause of claim 23 defines what changes in Akt, MEK, mTOR, and GSK3beta phosphorylation levels indicate a patient is responsive to treatment, however, claim 23 does not require a step of actually identifying any patients as responsive or non-responsive based on Akt, MEK, mTOR, and GSK3beta phosphorylation level changes. Claim 23 as amended recites in step (c) administering drugs targeting EGFR tyrosine kinase activity until the patient is no longer clinically benefitting to every patient tested, regardless of the resulting changes in Akt, MEK, mTOR, and GSK3beta phosphorylation levels. Therefore, with regards to claim 23 and arguments that the references do not teach identifying what changes in Akt, MEK, mTOR, and GSK3beta phosphorylation levels indicate a patient is responsive to gefitinib treatment, the arguments are not persuasive because such limitations are not recited or required in claim 23. Examiner maintains the cited combined reference provide both motivation and reasonable expectation of success to evaluate the claimed biomarkers before and during EGFR kinase inhibitor (gefitinib) treatment of breast cancer patients, and to continue administering treatment until patients no longer clinically benefit.
With regard to claim 35 that does require positively identifying the patient as being responsive and continuing to administer the treatment until unacceptable toxicity occurs, Examiner maintains the cited combined reference provide both motivation and reasonable expectation of success to evaluate the claimed biomarkers before and during EGFR kinase inhibitor (gefitinib) treatment, identify a patient as responsive to treatment when the levels of phosphorylated Akt, MEK, mTOR, and GSK3beta decrease after treatment, and to continue administering treatment until unacceptable toxicity occurs and the patient is no longer clinically benefitting.
With regard to Kim, Applicants admit that Kim does teach detecting expression and/or activation states of a plurality of HER2 signal transduction molecules including phosphorylated Akt, MEK, mTOR, and GSK3beta in a breast cancer patient’s test sample before and after treatment, and correlating changes to response to treatment. With regards to treatment, Kim teaches drugs that affect the HER2 signal transduction molecules:
[0160] Non-limiting examples of compounds that modulate HER2 activity include monoclonal antibodies, tyrosine kinase inhibitors, and combinations thereof. In preferred embodiments, the HER2-modulating compound inhibits HER2 activity and/or blocks HER2 signaling, e.g., is a HER2 inhibitor. Examples of HER2 inhibitors include, but are not limited to, monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (2C4); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327, and JNJ-26483327; and combinations thereof. In other embodiments, the HER2-modulating compound activates the HER2 pathway, e.g., is a HER2 activator.
[0309] Examples of anti-signaling agents suitable for use in the present invention include, without limitation, monoclonal antibodies such as trastuzumab (Herceptin®), pertuzumab (2C4), alemtuzumab (Campath®), bevacizumab (Avastin®), cetuximab (Erbitux®), gemtuzumab (Mylotarg®), panitumumab (Vectibix™), rituximab (Rituxan®), and tositumomab (BEXXAR®); tyrosine kinase inhibitors such as gefitinib (Iressa®), sunitinib (Sutent®), erlotinib (Tarceva®), lapatinib (GW-572016; Tykerb®), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006; Nexavar®), imatinib mesylate (Gleevec®), leflunomide (SU101), vandetanib (ZACTIMA™; ZD6474), pilitinib, CP-654577, CP-724714, HKI-272, PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327, and JNJ-26483327; and combinations thereof.
Also see paragraphs [0232]; [260]; [281]; [493]; claim 5; and Table 1.
Therefore, Kim identifies small molecule tyrosine kinase inhibitor gefitinib as a drug that affects the HER2 signal transduction molecules in breast cancer. Kim also identified erlotinib, pelitinib, lapatinib, HKI-272 (neratinib), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992 (afatinib), ARRY-334543 (varlitinib), JNJ-26483327, as drugs that affect the HER2 signal transduction molecules, all of which are EGFR tyrosine kinase inhibitors. Kim provides direct suggestion and motivation to assess the effects of the EGFR tyrosine kinase inhibitor gefitinib on their disclosed HER2 signal transduction molecules that include phosphorylated Akt, MEK, mTOR, and GSK3beta.
The secondary references provide motivation and reasonable expectation of success to specifically select and assay phosphorylation levels of Akt, MEK, mTOR, and GSK3beta suggested by Kim, in response to gefitinib, suggested by Kim, and to identify decreased levels as responsive. The secondary references: both Gao references, LoPiccolo, Lin, Han, Dong, and Corkery identify phosphorylation levels of MEK, Akt, mTOR and GSK3β as specifically indicative of therapeutic response to gefitinib, either separately or in subsets together, providing motivation and reasonable expectation of success to select these biomarkers disclosed in Kim for therapeutic response assessment. Further, according to the cited prior art, the biomarkers of phosphorylated MEK, Akt, mTOR and GSK3β would have predictably performed the same function in assessing response to gefitinib individually as they would have in various subsets or all together, providing a reasonable expectation of success for a panel of biomarkers consisting of phosphorylated MEK, Akt, mTOR and GSK3β to serve the same function taught by the cited prior art.
Although Applicants argue secondary references teach the effects of gefitinib on phosphorylated levels of Akt, MEK, mTOR, and GSK3beta in lung cancer, Kim already recognizes EGFR tyrosine kinase inhibitor gefitinib is also administered to treat lung cancer patients ([0005]-[0006]).
Applicants opine that one of ordinary skill in the art would not extrapolate the effects of gefitinib on phosphorylated levels of Akt, MEK, mTOR, and GSK3beta in lung cancer cells to the effects in breast cancer cells. MPEP 716.01(c) states:
I. TO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULD BE SUPPORTED BY ACTUAL PROOF
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." "[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument."). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
II. ARGUMENTS BY APPLICANT CANNOT TAKE THE PLACE OF EVIDENCE
Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
In the instant case, Applicants have presented no evidence as to why the effects of gefitinib would or could not be extrapolated to other cancers, or why it would not have the same effect on the same phosphorylated levels of Akt, MEK, mTOR, and GSK3beta in different cancers. None of the cited references teach that the EGFR, mTOR, Akt, MEK and GSK3β cell signaling relationship is different from cancer to cancer or is interpreted differently in response to EGFR inhibitor or cancer therapy treatment. Contrary to arguments, the cited secondary references teach that decreases (or changes) in all of these phosphorylated biomarkers in response to EGFR inhibitor treatment indicate positive response to EGFR inhibitor treatment, and the cited secondary references teach it is known that all of the four biomarkers are related in the EGFR signaling pathway and their phosphorylation is decreased by successful EGFR inhibition or unchanged when unresponsive to EGFR inhibition, providing motivation and reasonable expectation of success to utilize the phosphorylation levels in assessing breast cancer response to therapy and determining subsequent therapeutic action. Additionally, LoPiccolo et al, Lin et al, and Corkery et al teach that EGFR, Akt and mTOR phosphorylation and signaling pathways are increased in breast cancer, and suggest targeting the pathways for therapy, therefore the pathways are relevant to breast cancer, as taught by Kim.
Although Han teaches the lung cancer cells tested are “relatively resistant to RTKIs”, Han demonstrates that even these “relatively resistant” cells responded to treatment with gefitinib by demonstrating both a reduction in cell viability and reduction in phosphorylation of Akt and mTOR in response to treatment. Thus, Han provides a reasonable and predictable correlation between a reduction in phosphorylation of Akt and mTOR levels in response to gefitinib treatment, and reduction in cell viability. Dong et al further provide a predictable correlation between reducing phosphorylation of Akt and mTOR in cancer cells by treatment with gefitinib, and a reduction in cell proliferation. Dong demonstrates that adding a second inhibitor with gefitinib further reduced Akt and mTOR phosphorylation and reduced cell proliferation, providing motivation and reasonable expectation of success to interpret decreased phosphorylation of Akt and mTOR as indicative of successful cancer cell killing and treatment response.
Finally, 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 the instant case, it is clear in the rejection of record that the combined references teach not only the suggestion but also the means and motivation to make the claimed method that is to successfully receive a comparison of levels of phosphorylated Akt, MEK, mTOR, and GSK3beta from a breast cancer patient’s test samples before (baseline) and during (interim) gefitinib treatment, evaluate changes in levels, identify responsiveness, and administer the treatment until unacceptable toxicity occurs and treatment is no longer clinically beneficial.
7. Conclusion: No claim is allowed. The rejection under 35 U.S.C. 101 is withdrawn in view of amendments. The claim amendments alter the scope of the claimed method requiring administration of the drugs targeting EGFR tyrosine kinase activity to the patient regardless of their observed biomarker changes, therefore, the method practically applies a treatment targeting EGFR tyrosine kinase activity.
Conclusion
8. 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.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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