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: 63/210,925 and PCT/US2022/033168, with the effective filing dates of 15 June 2021 and 13 June 2022.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 26 June 2026.
Applicant’s election without traverse of Group I (claims 1-3, 5-9, 11-15, and 17-21) and species (lung cancer, rac-(E)-N-[4-(3-chloro-4-fluoro-anilino)-7-[rac-(3S)-tetrahydrofuran-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide (afatinib), and 1-(4-((4—((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidinyl-2-yl)amino)phenyl)-3-(4-(methylthio)phenyl)urea (IPA)) in the reply filed on 24 June 2026 is acknowledged.
Claims 23 and 27 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected group (Group II: claim 23; Group III: claim 27), there being no allowable generic or linking claim.
Claim 5 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species , there being no allowable generic or linking claim. Claim 5 recites a reversible inhibitor, which does not read on the elected species (afatinib: an irreversible inhibitor).
Claims 1-3, 6-9, 11-15, and 17-21 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed 24 April 2024 and the references cited therein have been considered, unless indicated otherwise.
Claim Interpretation
For clarity, the Examiner notes that the specification defines “treating” to be an approach for obtaining beneficial or desired clinical results ([0047]). The Examiner notes that the specification does not define beneficial or desired clinical results. Accordingly, the Examiner interprets beneficial clinical results to include alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, reduction of pathological consequence of lung cancer, and preventing initial onset of lung cancer in a patient.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claim 1-3, 6-9, 11-15, and 17-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating lung cancer in a subject via alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, and reduction of pathological consequence of lung cancer, does not reasonably provide enablement for treating lung cancer via preventing initial onset of lung cancer in a patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP § 2164.01(a), considers the
following factors:
Breadth of the Claims
The instant claims are directed to a method of treating cancer in an individual in need thereof via administering a therapeutically effective amount of a combination of (i) an EGFR inhibitor and (ii) a PERK activator. The specification defines “treating” to be an approach for obtaining beneficial or desired clinical results ([0047]). This includes alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, reduction of pathological consequence of lung cancer, and preventing initial onset of lung cancer in a patient.
As such, the breadth of the claims is great.
Level of Skill in the Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Art
Vilenchik (US 2017/0296541, published 19 Oct 2017, see IDS filed 24 Apr 2024) teaches a method of treating cancer in a subject via combination therapy with an EGFR inhibitor (abstract; [0095]; claim 1). Vilenchik teaches that cancer cell quiescence is a cell in a state of sleep, and is a major mechanism of cancer cell resistance to treatment and provides a pathway for disease recurrence ([0001]). Vilenchik teaches that treating is a mean to counteract a medical condition (e.g. cancer) to the extent that the medical condition is improved according to a clinically-acceptable standard ([0057]). Vilenchik further teaches reduced rate of tumor growth (tumor growth inhibition), tumor shrinkage (regression), remission (partial or total), reduction in metastases, prolonging progression free survival, and delay or elimination of recurrence ([0057]). Additionally, Vilenchik teaches a method of treating lung cancer (both small cell and non-small cell) with a DYRK1 inhibitor and an EGFR inhibitor ([0019]; [0087]; [0097]; [0105]).
Shokat (WO 2016/022839, published 11 Feb 2016) teaches small molecule PERK activators and methods of treating lung cancer for modulating the unfolded protein response (UPR; abstract; [0071]). Shokat teaches that IRE1 and PERK are two protein kinases that share homology of their luminal domain and are amenable to modulation by small molecule ATP-mimetics ([0003]-[0004]). Shokat teaches that treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being ([0061]).
Wu (Molecular Cancer¸ 2018, 17(38), 1-14) teaches resistance mechanisms of EGFR inhibitors, such as the second-generation molecule, afatinib, in non-small cell lung cancer (abstract). Wu teaches that preclinical data shows that the second-generation EGFR TKI (tyrosine kinase inhibitor) could overcome the resistance caused by the T790M mutation but that clinical trials have not yet revealed the effect due to toxicity limitations (page 2, column 1, paragraph 2). Additionally, Wu teaches that the discovery of driver mutations in lung cancer allows the creation of personalized targeted treatment, which is important for patients to receive matched targeted therapy (page 1, column 1, paragraph 2). Wu teaches that while EGFR TKIs have a favorable and durable treatment response, most patients will eventually develop progressive disease within about one year of treatment (page 1, column 2, paragraph 2). Wu teaches that acquired resistance develops and limits long-term efficacy of these EGFR TKIs and that there are a variety of acquired resistance mechanisms (page 1, column 2, paragraph 2; page 2, column 1, paragraph 1). Wu teaches that the most common resistance mechanism is the EGFR T790M mutation and that preclinical data showed that the second-generation EGFR TKI, afatinib, could overcome the resistance caused by the T790M mutation (page 2, column 1, paragraphs 1-2). Wu teaches that clinical trials, however, have not revealed the effect due to toxicity limitations and that the narrow therapeutic window of afatinib caused severe adverse effects (page 2, column 1, paragraph 2). Wu further teaches a third-generation EGFR TKI that is related to different acquired resistance mechanisms, Osimertinib (page 2, column 1, paragraph 2). Wu further teaches that different resistance mechanisms can be detected in disease progression to EGFR TKIs and that it is important to identify the tumor resistance mechanism (page 3, column 2, paragraph 2). Wu teaches that tumor heterogeneity appears in the primary tumor and in metastatic lesions and that intratumor and intermetastases may have diverse clones with different oncogenic driver mutations or resistance mechanisms (page 3, column 2, paragraph 3). Wu teaches that the resistant mutations may occur at a small clone of tumor cells and clonal evolution may develop during the treatment process, so molecular-based detection methods play an important role (page 3, column 2, paragraph 3). Additionally, Wu teaches next-generation sequencing to detect known and unknown mutations and genetic alterations (page 3, column 2, paragraph 3; page 4, column 1, paragraph 1). Further, Wu teaches the difficulties of re-biopsying tumor specimens due to patient fear and physical preference as it is an invasive diagnostic procedure (page 4, column 1, paragraph 2). Accordingly, Wu teaches that after acquiring resistance to first-line EGFR TKI therapy, it is important that the mechanisms of acquired resistance in all patients are explored and that subsequent treatment can be chosen (page 10, column 2, paragraph 2). Wu teaches that combination therapy may be effective for acquired resistance resulting from activation of the bypass signaling pathway and that advances in the detection method for different resistance mechanisms and the development of new drugs are both urgently needed for personalized therapy (page 10, column 2, paragraph 2).
Duruisseaux (Seminars in Cancer Biol., 2018, 51, 116-128) teaches that lung cancer is the leading cause of cancer death worldwide and that the high mortality observed in lung cancer patients is associated with a common diagnosis at advanced stage that hampers curative therapy and a poor five-year survival rate estimated at 15% of all stages combined (page 116, column 1, paragraph 1). Duruisseaux teaches that 80-90% of lung cancer cases occur in smokers and that smoking is a major risk factor for the disease (page 116, column 1, paragraph 1). Duruisseaux teaches that there are efforts to reduce lung cancer lethality and that tyrosine kinase inhibitors have markedly improved clinical outcomes for 15-20% of patients (page 116, column 1, paragraph 2; page 116, column 2, paragraph 1). Duruisseaux teaches that primary and secondary drug resistance eventually leads to targeted treatment failure in all patients (page 116, column 2, paragraph 1). Duruisseaux teaches that the foremost hypothesis to explain lung carcinogenesis posits tumor development occurs in a multistage stepwise fashion that leads to a sequential accumulation of genetic and epigenetic abnormalities (page 116, column 2, paragraph 2). Duruisseaux teaches that epigenetic disruptions promote the acquisition of a cancerous phenotype and aggressive behavior in lung cancer cells as well as primary or acquired resistance to treatment, introducing new avenues for epigenetic therapy and for the discovery of new therapeutic targets (page 116, column 2, paragraph 2; page 117, column 1, paragraph 1). Additionally, Duruisseaux teaches that targeting the epigenome is a fairly new approach in lung cancer treatment for addressing chemoresistance and reversing immune escape (page 122, column 1, paragraph 1).
Johns Hopkins (“Lung Cancer Prevention,” Johns Hopkins Medicine¸2020, < web.archive.org/web/20200925075149/https://www.hopkinsmedicine.org/health/conditions-and-diseases/lung-cancer/lung-cancer-prevention>, accessed 22 July 2026) teaches that lung cancer is the second most common cancer in the US and that cigarette smoking is the No. 1 risk factor for lung cancer, causing about 90% of lung cancer cancers (page 1, paragraph 1; page 1, paragraph 4). Johns Hopkins teaches that the best prevention for lung cancer is to stop smoking or to never start (page 2, paragraph 3). Additionally, Johns Hopkins teaches that limiting exposure to radon, exercising, and eating a healthy, balanced diet help reduce the risk of lung cancer (page 2, paragraphs 6-7). However, Johns Hopkins teaches that while these preventive measures may lower the risk of lung cancer, that there is no definitive way to prevent lung cancer (page 2, paragraph 8).
Thus, while the prior art teaches a method of treating lung cancer via alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, and reduction of pathological consequence of lung cancer, the prior art teaches that preventing initial onset of lung cancer in a patient is not yet possible.
Predictability in the Art
Vilenchik (US 2017/0296541, published 19 Oct 2017, see IDS filed 24 Apr 2024) teaches a method of treating cancer in a subject via combination therapy with an EGFR inhibitor (abstract; [0095]; claim 1). Vilenchik teaches that doses and duration of anticancer treatment are limited by toxicity and that lower effective doses and/or shorter treatment durations are highly desirable ([0004]). Vilenchik teaches a method of treating lung cancer (both small cell and non-small cell) with a DYRK1 inhibitor and an EGFR inhibitor ([0019]; [0087]; [0097]; [0105]).
Shokat (WO 2016/022839, published 11 Feb 2016) teaches small molecule PERK activators and methods of treating lung cancer for modulating the unfolded protein response (UPR; abstract; [0071]). Shokat teaches that IRE1 and PERK are two protein kinases that share homology of their luminal domain and are amenable to modulation by small molecule ATP-mimetics ([0003]-[0004]).
Wu (Molecular Cancer¸ 2018, 17(38), 1-14) teaches resistance mechanisms of EGFR inhibitors, such as the second-generation molecule, afatinib, in non-small cell lung cancer (abstract). Additionally, Wu teaches that the discovery of driver mutations in lung cancer allows the creation of personalized targeted treatment, which is important for patients to receive matched targeted therapy (page 1, column 1, paragraph 2). Wu teaches that acquired resistance develops and limits long-term efficacy of these EGFR TKIs and that there are a variety of acquired resistance mechanisms (page 1, column 2, paragraph 2; page 2, column 1, paragraph 1). Wu further teaches that different resistance mechanisms can be detected in disease progression to EGFR TKIs and that it is important to identify the tumor resistance mechanism (page 3, column 2, paragraph 2). Wu teaches that tumor heterogeneity appears in the primary tumor and in metastatic lesions and that intratumor and intermetastases may have diverse clones with different oncogenic driver mutations or resistance mechanisms (page 3, column 2, paragraph 3). Wu teaches that the resistant mutations may occur at a small clone of tumor cells and clonal evolution may develop during the treatment process, so molecular-based detection methods play an important role (page 3, column 2, paragraph 3). Additionally, Wu teaches next-generation sequencing to detect known and unknown mutations and genetic alterations (page 3, column 2, paragraph 3; page 4, column 1, paragraph 1). Further, Wu teaches the difficulties of re-biopsying tumor specimens due to patient fear and physical preference as it is an invasive diagnostic procedure (page 4, column 1, paragraph 2). Accordingly, Wu teaches that after acquiring resistance to first-line EGFR TKI therapy, it is important that the mechanisms of acquired resistance in all patients are explored and that subsequent treatment can be chosen (page 10, column 2, paragraph 2). Wu teaches that combination therapy may be effective for acquired resistance resulting from activation of the bypass signaling pathway and that advances in the detection method for different resistance mechanisms and the development of new drugs are both urgently needed for personalized therapy (page 10, column 2, paragraph 2).
Duruisseaux (Seminars in Cancer Biol., 2018, 51, 116-128) teaches that lung cancer is the leading cause of cancer death worldwide and that the high mortality observed in lung cancer patients is associated with a common diagnosis at advanced stage that hampers curative therapy and a poor five-year survival rate estimated at 15% of all stages combined (page 116, column 1, paragraph 1). Duruisseaux teaches that epigenetic disruptions promote the acquisition of a cancerous phenotype and aggressive behavior in lung cancer cells as well as primary or acquired resistance to treatment, introducing new avenues for epigenetic therapy and for the discovery of new therapeutic targets (page 116, column 2, paragraph 2; page 117, column 1, paragraph 1). Additionally, Duruisseaux teaches that targeting the epigenome is a fairly new approach in lung cancer treatment for addressing chemoresistance and reversing immune escape (page 122, column 1, paragraph 1), underscoring the unpredictability in the art.
Johns Hopkins (“Lung Cancer Prevention,” Johns Hopkins Medicine¸2020, < web.archive.org/web/20200925075149/https://www.hopkinsmedicine.org/health/conditions-and-diseases/lung-cancer/lung-cancer-prevention>, accessed 22 July 2026) teaches that lung cancer is the second most common cancer in the US and that cigarette smoking is the No. 1 risk factor for lung cancer, causing about 90% of lung cancer cancers (page 1, paragraph 1; page 1, paragraph 4). Johns Hopkins teaches that while these preventive measures may lower the risk of lung cancer, that there is no definitive way to prevent lung cancer (page 2, paragraph 8).
Thus, while the combination of Vilenchik, Shokat, Wu, and Duruisseaux teaches a method of treating lung cancer via alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, and reduction of pathological consequence of lung cancer, Johns Hopkins teaches that preventing initial onset of lung cancer in a patient is not yet possible.
Working Examples
The instant specification teaches the administration of the combination of an EGFR inhibitor and a PERK activator to PC9 cells, which is human lung cancer cell line ([0130]). However, the instant specification does not teach prevention of lung cancer.
Quantity of Experimentation
The amount of experimentation required to determine which compound, in what amounts, in what order, which type of lung cancer, would be astronomical. A skilled artisan would be required to start with proof-of-concept and proceed through all levels of lead identification and optimization, which is invention and not development; this is undue amount of experimentation.
As such, while the specification is enabling for a method of treating lung cancer in a subject via alleviation of one or more symptoms of lung cancer, diminishment of extent of lung cancer, preventing or delaying spread (e.g. metastasis) of lung cancer, preventing or delaying recurrence of lung cancer, delay or slowing of lung cancer progression, amelioration of lung cancer, and reduction of pathological consequence of lung cancer, it does not reasonably provide enablement for a method of treating lung cancer via preventing initial onset of lung cancer in a patient.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claim 1-3, 6-9, 11-15, and 17-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a method of treating cancer in an individual in need thereof via administering a therapeutically effective amount of a combination of (i) an EGFR inhibitor and (ii) a PERK activator. However, the specification defines “treating” to be an approach for obtaining beneficial or desired clinical results ([0047]). The term “desired clinical results” in claim 1 is a relative term which renders the claim indefinite. The term “desired clinical results” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, it is ambiguous as to the exact scope that Applicant considers part of the claim invention and what degree of similarity would infringe.
Dependent claims 2-3, 6-9, 11-15, and 17-21 are included for depending on a rejected claim and not reciting limitations that resolve the ambiguity.
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.
3. Claim(s) 1-3, 6-9, 11-15, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Vilenchik (US 2017/0296541, published 19 Oct 2017, see IDS filed 24 Apr 2024) in view of Shokat (WO 2016/022839, published 11 Feb 2016) and Wu (Molecular Cancer¸ 2018, 17(38), 1-14).
Vilenchik teaches a method of treating cancer in a subject via combination therapy with an EGFR inhibitor (abstract; [0095]; claim 1). Vilenchik teaches that cancer cell quiescence is a cell in a state of sleep, and is a major mechanism of cancer cell resistance to treatment and provides a pathway for disease recurrence ([0001]). Vilenchik teaches that cells may also be induced into the quiescent state by the action of a drug substance, as in pharmacological quiescence ([0002]). Vilenchik teaches that doses and duration of anticancer treatment are limited by toxicity and that lower effective doses and/or shorter treatment durations are highly desirable ([0004]). Vilenchik teaches a method of treating lung cancer (both small cell and non-small cell) with a DYRK1 inhibitor and an EGFR inhibitor ([0019]; [0087]; [0097]; [0105]). Vilenchik teaches that the EGFR inhibitor is afatinib (Example 4, [0110]).
Regarding claim 1, Vilenchik fails to teach a method of treating with the PERK activator, IPA.
Shokat teaches small molecules and methods of treating lung cancer for modulating the unfolded protein response (UPR; abstract; [0071]). Shokat teaches that 30% of all proteins encoded in eukaryotes pass through the endoplasmic reticulum (ER), where they are folded, modified, and assembled, before they are delivered to the plasma membrane, the outside of the cell, or to various way-stations in the secretory pathway ([0003]). Shokat teaches that IRE1 and PERK are two protein kinases that share homology of their luminal domain and are amenable to modulation by small molecule ATP-mimetics ([0003]-[0004]). Shokat teaches that PERK activation is driven through interactions of its luminal domain with unfolded polypeptides in the ER and that active PERK phosphorylate the alpha-subunit of eIF2α, thus trapping eIF2α and attenuating global protein synthesis ([0004]). Shokat teaches IPA:
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(page 73).
Wu teaches resistance mechanisms of EGFR inhibitors, such as the second-generation molecule, afatinib, in non-small cell lung cancer (abstract). Additionally, Wu teaches that acquired resistance develops and limits long-term efficacy of these EGFR TKIs and that there are a variety of acquired resistance mechanisms (page 1, column 2, paragraph 2; page 2, column 1, paragraph 1). Wu teaches that the most common resistance mechanism is the EGFR T790M mutation and that preclinical data showed that the second-generation EGFR TKI, afatinib, could overcome the resistance caused by the T790M mutation (page 2, column 1, paragraphs 1-2). Wu teaches that the narrow therapeutic window of afatinib caused severe adverse effects (page 2, column 1, paragraph 2).
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 substitute the DYRK1 inhibitor in the method of Vilenchik with the PERK activator of Shokat to overcome resistance and attenuate global protein synthesis whilst also lowering the required dosage of afatinib as suggested by Vilenchik and Wu. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Vilenchik teaches a method of treating cancer in a subject via combination therapy with an EGFR inhibitor,
-Vilenchik teaches that cancer cell quiescence is a cell in a state of sleep, and is a major mechanism of cancer cell resistance to treatment and provides a pathway for disease recurrence,
-Vilenchik teaches that cells may also be induced into the quiescent state by the action of a drug substance, as in pharmacological quiescence,
-Vilenchik teaches that doses and duration of anticancer treatment are limited by toxicity and that lower effective doses and/or shorter treatment durations are highly desirable,
-Vilenchik teaches a method of treating lung cancer (both small cell and non-small cell) with a DYRK1 inhibitor and an EGFR inhibitor,
-Vilenchik teaches that the EGFR inhibitor is afatinib,
-Shokat teaches small molecules and method of treating lung cancer for modulating the unfolded protein response,
-Shokat teaches that 30% of all proteins encoded in eukaryotes pass through the endoplasmic reticulum (ER), where they are folded, modified, and assembled, before they are delivered to the plasma membrane, the outside of the cell, or to various way-stations in the secretory pathway,
-Shokat teaches that IRE1 and PERK are two protein kinases that share homology of their luminal domain and are amendable to modulation by small molecule ATP-mimetics,
-Shokat teaches that PERK activation is driven through interactions of its luminal domain with unfolded polypeptides in the ER and that active PERK phosphorylate the alpha-subunit of eIF2α, thus trapping eIF2α and attenuating global protein synthesis,
-Shokat teaches IPA:
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,
-Wu teaches resistance mechanisms of EGFR inhibitors, such as the second-generation molecule, afatinib, in non-small cell lung cancer,
-Wu teaches that acquired resistance develops and limits long-term efficacy of these EGFR TKIs and that there are a variety of acquired resistance mechanisms,
-Wu teaches that preclinical data shows that the second-generation EGFR TKI (tyrosine kinase inhibitor) could overcome the resistance caused by the T790M mutation but that clinical trials have not yet revealed the effect due to toxicity limitations, and
-Wu teaches that the narrow therapeutic window of afatinib caused severe adverse effects.
Accordingly, the combination of Vilenchik, Shokat, and Wu teaches a method of treating lung cancer in an individual via administering to the individual a therapeutically effective amount of a combination of afatinib (an EGFR inhibitor) and IPA (
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, a PERK activator).
Regarding claim 2, Shokat teaches the PERK activator is IPA:
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(page 73).
Regarding claim 3, Wu teaches the EGFR inhibitor (afatinib) is a small molecule EGFR TKI (page 2, column 1, paragraph 2).
Regarding claim 6, Wu teaches afatinib is an irreversible EGFR TKI (Table 2, page 7).
Regarding claim 7, Wu teaches that afatinib is an inhibitor of both wild-type EGFR and mutant EGFR: T790M, exdel19, uncommon mutations, HER2 and HER4 (page 2, column 1, paragraph 2; Table 2, page 7).
Regarding claim 8, Vilenchik teaches that the EGFR inhibitor is afatinib (Example 4, [0110]).
Regarding claim 9, Vilenchik teaches a method of treating lung cancer (both small cell and non-small cell) with a DYRK1 inhibitor and an EGFR inhibitor ([0019]; [0087]; [0095]; [0097]; [0105]).
Regarding claim 11, Vilenchik teaches the individual is diagnosed with NSCLC ([0019]; [0087]; [0095]; [0097]; [0105]). Additionally, Wu teaches the individual is diagnosed with NSCLC (page 1, column 1, paragraph 2), and Shokat teaches that the cancer is NSCLC ([0073]).
Regarding claim 12, Vilenchik teaches the individual is diagnosed with NSCLC ([0019]; [0087]; [0095]; [0097]; [0105]). Additionally, Wu teaches the individual is diagnosed with NSCLC (page 1, column 1, paragraph 2), and Shokat teaches that the cancer is NSCLC ([0073]).
Regarding claim 13, Vilenchik teaches that the cancer is metastatic ([00871]; [0084]; [0095]). Additionally, Wu teaches that the cancer is locally advanced or metastatic NSCLC (page 9, column 1, paragraph 2).
Regarding claim 14, Wu teaches that the individual is diagnosed with EGFR exon 19 deletion positive NSCLC or exon 21 L858R mutation positive NSCLC (abstract; page 1, column 2, paragraph 1).
Regarding claim 15, Wu teaches that the individual is diagnosed with EGFR T790M mutation positive NSCLC (page 2, column 1, paragraph 2; Table 2, page 7).
Regarding claim 17, Vilenchik teaches that the administration is sequentially ([0093]). Additionally, Shokat teaches that the administration is sequentially ([0098]).
Regarding claim 18, Vilenchik teaches that the administration is concurrently (simultaneously; [0093]). Additionally, Shokat teaches that the administration is simultaneously ([0098]).
Regarding claim 19, Shokat teaches that the co-administration is co-formulated, i.e. preparing a single pharmaceutical composition involving both active agents ([0107]).
Regarding claim 20, Shokat teaches that the co-administration is separate compositions ([0107]).
Regarding claim 21, Vilenchik teaches administration of two or more EGFR inhibitors sequentially or concomitantly (i.e. a third anti-cancer therapy; [0008]). Shokat teaches administration of other therapies: chemotherapy ([0069]), radiation therapy ([0107]), surgery ([0107]), targeted therapy (wherein EGFR inhibitors are targeted therapy; [0070]), or an immunostimulant ([0070]). Thus, the combination of Vilenchik and Shokat teach a third anticancer therapy selected from chemotherapy, radiation therapy, surgery, targeted therapy, or an immunostimulant.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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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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