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, 63/213,301, 63/257,907, and PCT/US2022/034574, with effective filing dates of 22 June 2021, 20 October 2021, and 22 June 2022.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 31 August 2026.
Applicant’s election of Group I (claims 1-2, 4, 10, 14-15, 18, 21, 23, 27, 29-30, 32, 38, 58-59, 71, and 93-94 and glioblastoma multiforme and Compound I (
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) as the species in the reply filed on 31 August 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 50 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected group (Group II: claim 50), there being no allowable generic or linking claim.
Claims 14, 21, 27, 58-59, 71, and 93-94 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species, there being no allowable generic or linking claim.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 14 recites treating an astrocytoma, which does not read on the elected species. Claim 21 recites R15 is selected from C1-6 alkyl and C1-6 haloalkyl, which does not read on the elected species. Claim 27 recites R11 is C1-4 alkyl, R12 is H or C1-6 alkyl, and R13 is C2-6 alkenyl, which does not read on the elected species. Claim 58 recites Compound 2, which does not read on the elected species. Claim 59 recites Compound 2, which does not read on the elected species. Claim 71 recites Compound 2, which does not read on the elected species. Claim 93 recites a method of treating a metastatic brain tumor, which does not read on the elected species. Claim 94 recites a method of treating a metastatic brain tumor, which does not read on the elected species.
Claims 1-2, 4, 10, 15, 18, 23, 29-30, 32, and 38 are under consideration in the instant office action.
Claim Interpretation
For clarity, the Examiner notes that Compound 1 (
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) has the following mapping into Formula (I):
18/573,473 Formula (I) components
18/573,473 Formula (I)
Compound 1
Z1
N
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64
90
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Z2
N
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64
90
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Z3
CR8, R8 = H
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64
90
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R1
H
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64
90
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R2
H
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64
90
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R3
C1-4 alkoxy = OMe
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50
27
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R4
NR9R10
R9 = C1-4 alkyl = Me
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55
106
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R10 = (C1-4 alkyl)-N-(C1-4 alkyl)2
R5
NR12C(O)R13
R12 = H
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R13 = C2-6 alkenyl
R6, R7
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; X1, X2, X4, X5, X6 = CH; X3 = N
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Accordingly, Compound 1 falls into Formula (I).
Information Disclosure Statement
The Information Disclosure Statement filed 18 July 2024 and 31 August 2026 and the references cited therein have been considered, unless indicated otherwise.
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) 1-2, 4, 10, 15, 18, 23, 29-30, 32, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Gray (U.S. Patent No. 10,266,517, issued 23 Apr 2019, see IDS filed 18 Jul 2024) in view of Abousaud (J. Cancer Sci. Clin. Therap., 2021, 5(2), 210-220) as evidenced by Mayo Clinic (“Glioma vs. glioblastoma: what’s the difference,” Mayo Clinic, 2026, <mayoclinic.org/diseases-conditions/glioma/expert-answers/glioma-vs-glioblastoma/faq-20593852>, accessed 15 Sept 2026) and as evidenced by Wikipedia (“Osimertinib,” Wikipedia, 2026, <en.wikipedia.org/wiki/Osimertinib>, accessed 15 Sept 2026).
Gray teaches compounds that modulate the activity of EGFR and methods of treating EGFR-related diseases (abstract). Gray teaches that EGFR is involved in the proliferation of normal and malignant cells and that overexpression of EGFR is present in at least 70% of human cancers, in particular, non-small cell lung carcinoma, breast cancer, glioma, squamous cell carcinoma of the head and neck, and prostate cancer (column 1, lines 17-22). Gray teaches that EGFR-TK is a widely recognized attractive target for compound design and development for specifically binding and inhibiting the tyrosine kinase activity and its signal transduction pathway in cancer cells (column 1, lines 28-32). Gray teaches that EGFR TKIs (tyrosine kinase inhibitors) are effective clinical therapies for EGFR mutant non-small cell lung cancer in randomized clinical trials as measured by response rate and progression free survival as compared to chemotherapy (column 1, lines 39-50). However, Gray teaches that a vast majority of patients will develop disease progression following successful treatment with an EGFR TKI and that the most common mechanism of acquired resistance (detected in 60% of patients) is a secondary mutation in EGFR at position T790M, which makes it more difficult for reversible EGFR TKIs to bind to the EGFR TKI domain (column 1, lines 56-64). Gray teaches that covalent EGFR inhibitors have emerged as strategies to inhibit EGFR T790M containing cancers and that current covalent inhibitors (afatinib) are only effective in EGFR TKI naïve EGFR mutant cancers and has a response rate of <10% in patients with non-small cell lung cancer resistant to gefitinib or erlotinib (column 1, lines 66-67; column 2, lines 1-8). Gray teaches that afatinib inhibits both mutant and wild type EGFR and that wild type EGFR inhibition leads to toxicities, including skin rash and diarrhea, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M (column 2, lines 9-15). Gray teaches that irreversible pyrimidine EGFR inhibitors, such as AZD9291, overcome many of the limitations of afatinib such as increased clinical efficacy and less toxicity (column 2, lines 13-22). Gray teaches that despite the success of AZD9291, it is expected that patients will ultimately develop acquired resistance and thus novel irreversible pyrimidine EGFR inhibitors are needed (column 2, lines 24-32). Gray teaches treating glioblastoma multiforme and glioblastoma (column 30, line 56; column 45, lines 1-5; column 46, lines 14-19), which are synonymous as evidenced by Mayo Clinic (page 1, paragraph 2). Gray teaches Compound I-1:
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, which is Compound 1 (column 13). Gray teaches administering 100 mg/day to a human (column 56, lines 18-21; column 56, lines 27-31).
Regarding claim 1, Gray fails to teach administering at least 100 mg/day of Compound I-1 to a patient in one embodiment.
Abousaud teaches EGFR alterations are commonly observed in malignant gliomas and that Osimertinib (AZD9291) is an irreversible EGFR-tyrosine kinase inhibitor that effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue (abstract). Wikipedia evidences that Osimertinib has the structure:
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(page 1, side box). Abousaud teaches that finding effective treatments for primary malignant brain tumors has been challenging due to their chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier, which limits entry of systemically administered therapeutics (page 211, column 2, paragraph 1). Abousaud teaches that the EGFR signaling pathway has garnered a great deal of attention due to its role in cancer pathogenesis and the availability of novel therapies that specifically and effectively target this pathway (page 211, column 2, paragraph 2). Abousaud teaches that there is the suggestion that EGFR alteration/mutations are correlated with glioma tumor growth, survival, invasion, and angiogenesis (page 211, column 2, paragraph 2). Abousaud teaches that previous EGFR TKI first- and second-generation TKIs have been studied in EGFR-altered glioma but have yielded minimal to no clinical benefit and short durations of response (page 212, column 1, paragraph 2). Abousaud teaches that osimertinib is a third-generation irreversible EGFR TKI that is more tolerable agent in comparison to other first- and second-generation EGFR TKIs (page 212, column 1, paragraph 2). Abousaud teaches that there are in vitro and in vivo studies supporting the preclinical activity of Osimertinib in EGFR expression glioblastoma, particularly glioblastomas that express EGFR vIII (page 212, column 1, paragraph 2). Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib in addition to other drugs and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death (page 212, column 2, paragraphs 2-3; page 217, Table 2). Abousaud teaches that although the sample size is small due to challenges in obtaining Osimertinib for off-label use in glioma/glioblastoma, the heavily pretreated brain tumor population tolerated Osimertinib therapy and half of the patients were able to achieve either partial response or stable disease ranging from 77 to 294 days (page 218, column 2, paragraphs 1 and 3).
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 Gray with the method of Abousaud to treat patients with glioblastoma, which is challenging due to chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier as taught by Abousaud. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Gray teaches compounds that modulate the activity of EGFR and methods of treating EGFR-related diseases,
-Gray teaches that EGFR is involved in the proliferation of normal and malignant cells and that overexpression of EGFR is present in at least 70% of human cancers, in particular, non-small cell lung carcinoma, breast cancer, glioma, squamous cell carcinoma of the head and neck, and prostate cancer,
-Gray teaches that EGFR-TK is a widely recognized attractive target for compound design and development for specifically binding and inhibiting the tyrosine kinase activity and its signal transduction pathway in cancer cells,
-Gray teaches that EGFR TKIs (tyrosine kinase inhibitors) are effective clinical therapies for EGFR mutant non-small cell lung cancer in randomized clinical trials as measured by response rate and progression free survival as compared to chemotherapy,
-However, Gray teaches that a vast majority of patients will develop disease progression following successful treatment with an EGFR TKI and that the most common mechanism of acquired resistance (detected in 60% of patients) is a secondary mutation in EGFR at position T790M, which makes it more difficult for reversible EGFR TKIs to bind to the EGFR TKI domain,
-Gray teaches that covalent EGFR inhibitors have emerged as strategies to inhibit EGFR T790M containing cancers and that current covalent inhibitors (afatinib) are only effective in EGFR TKI naïve EGFR mutant cancers and has a response rate of <10% in patients with non-small cell lung cancer resistant to gefitinib or erlotinib,
-Gray teaches that afatinib inhibits both mutant and wild type EGFR and that wild type EGFR inhibition leads to toxicities, including skin rash and diarrhea, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M,
-Gray teaches that irreversible pyrimidine EGFR inhibitors, such as AZD9291, overcome many of the limitations of afatinib such as increased clinical efficacy and less toxicity (column 2, lines 13-22). Gray teaches that despite the success of AZD9291, it is expected that patients will ultimately develop acquired resistance and thus novel irreversible pyrimidine EGFR inhibitors are needed,
-Gray teaches treating glioblastoma multiforme and glioblastoma, which are synonymous as evidenced by Mayo Clinic,
-Gray teaches Compound I-1:
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, which is Compound 1,
-Gray teaches administering 100 mg/day to a human,
-Abousaud teaches EGFR alterations are commonly observed in malignant gliomas and that Osimertinib (AZD9291) is an irreversible EGFR-tyrosine kinase inhibitor that effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue,
-Wikipedia teaches that Osimertinib has structure:
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,
-Abousaud teaches that finding effective treatments for primary malignant brain tumors has been challenging due to their chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier, which limits entry of systemically administered therapeutics,
-Abousaud teaches that the EGFR signaling pathway has garnered a great deal of attention due to its role in cancer pathogenesis and the availability of novel therapies that specifically and effectively target this pathway,
-Abousaud teaches that there is the suggestion that EGFR alteration/mutations are correlated with glioma tumor growth, survival, invasion, and angiogenesis,
-Abousaud teaches that previous EGFR TKI first- and second-generation TKIs have been studied in EGFR-altered glioma but have yielded minimal to no clinical benefit and short durations of response,
-Abousaud teaches that osimertinib is a third-generation irreversible EGFR TKI that is more tolerable agent in comparison to other first- and second-generation EGFR TKIs,
-Abousaud teaches that there is in vitro and in vivo studies supporting the preclinical activity of Osimertinib in EGFR expression glioblastoma, particularly glioblastomas that express EGFR vIII,
-Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib in addition to other drugs and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death, and
-Abousaud teaches that although the sample size is small due to challenges in obtaining Osimertinib for off-label use in glioma/glioblastoma, the heavily pretreated brain tumor population tolerated Osimertinib therapy and half of the patients were able to achieve either partial response or stable disease ranging from 77 to 294 days.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05(II)(A). Gray specifically teaches administering Compound 1 from about 10 mg to about 1000 mg per day in single or multiple doses (column 56, lines 27-31) and administering 100 mg/day of Compound 1 to a human (column 56, lines 18-21; column 56, lines 27-31). Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib in addition to other drugs and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death in order to treat glioblastoma (page 212, column 2, paragraphs 2-3; page 217, Table 2). Gray teaches that afatinib (the second-generation EGFR TKI) inhibits both mutant and wild type EGFR and that wild type EGFR inhibition leads to adverse effects, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M (column 2, lines 9-15). Accordingly, an artisan having ordinary skill in the art would recognize that optimizing the dosing protocol when dosing only Compound 1 (a derivative of Osimertinib) would limit the rise of resistance as taught by Gray and ensure penetrance of the blood brain barrier as taught by Abousaud. Accordingly, the combination of Gray and Abousaud teaches treating glioblastoma via administering at least 100 mg of Compound 1.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a method of treating glioblastoma multiform in patients via administering at least 100 mg/day of Compound 1:
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.
Regarding claim 2, Gray teaches Compound I-1, which is Compound 1 (column 13). As Applicant does not further recite a certain concentration responsible for the subject to not lose more than 10% of its body weight within 1 month after administration, claim 2 does not specify an additional step but does specify an additional effect. Thus, claim 2 merely recites an additional effect of a claimed composition. Further, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Where Applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the Examiner may make a rejection under both 35 U.S.C. 102 and 103. This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. See MPEP § 2112(II) and (III). Consequently, Gray teaches the subject to not lose more than 10% of its body weight within 1 month after administration.
Regarding claim 4, Gray teaches administering Compound 1 from about 10 mg to about 1000 mg per day in single or multiple doses (column 56, lines 27-31). Gray also teaches that the therapeutic amount of dose of the compound may range from about 0.1 mg/kg to about 500 mg/kg or alternatively from about 1 to about 50 mg/kg (column 56, lines 24-27).
Regarding claim 10, Gray teaches a method of treating glioblastoma multiforme (column 30, line 56; column 45, lines 1-5; column 46, lines 14-19).
Regarding claim 15, Gray teaches Compound I-1, which is Compound 1 (column 13), wherein Z1 and Z2 are N, Z3 is CR8, R1 is H, and R2 is H.
Regarding claim 18, Gray teaches Compound I-1, which is Compound 1 (column 13), wherein R3 is C1-4 alkoxy, R4 is NR9R10, and R5 is NR12C(O)R13.
Regarding claim 23, Gray teaches Compound I-1, which is Compound 1 (column 13), wherein R8 is H, R9 is C1-4 alkyl, and R10 is (C1-4 alkyl)-N-(C1-4 alkyl)2.
Regarding claim 29, Gray teaches Compound I-1, which is Compound 1 (column 13), wherein X1, X2, X4, X5, and X6 are CH, R91 is C1-4 alkyl, and R101 is (C1-4 alkyl)-N-(C1-4 alkyl)2.
Regarding claim 30, Gray teaches Compound I-1, which is Compound 1 (column 13), which is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Regarding claim 32, Gray teaches administering Compound 1 from about 10 mg to about 1000 mg per day in single or multiple doses (column 56, lines 27-31). Additionally, Gray teaches administration in divided doses up to four times a day (column 56, lines 18-21).
Regarding claim 38, Gray teaches a method of treating glioblastoma and inhibiting EGFR in a subject suffering from glioblastoma via administering Compound 1 (abstract; column 30, line 56; column 45, lines 1-5; column 46, lines 14-19;column 13).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
2. Claim 1-2, 10, 15, 18, 23, 29-30, 32, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 8-11, 14, and 16-18 of U.S. Patent No. 10,870,636 in view of Abousaud (J. Cancer Sci. Clin. Therap., 2021, 5(2), 210-220) as evidenced by Mayo Clinic (“Glioma vs. glioblastoma: what’s the difference,” Mayo Clinic, 2026, <mayoclinic.org/diseases-conditions/glioma/expert-answers/glioma-vs-glioblastoma/faq-20593852>, accessed 15 Sept 2026) and as evidenced by Wikipedia (“Osimertinib,” Wikipedia, 2026, <en.wikipedia.org/wiki/Osimertinib>, accessed 15 Sept 2026).
U.S. Patent No. 10,870,636 claims a method of treating non-small cell lung cancer in a subject via a compound of Formula (I):
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, and Compound 1 maps into Formula (I) of ‘656, wherein Z1 and Z2 are N, Z3 is CR8, R8 is H, R1 is H, R2 is H, R3 is C1-4 alkoxy (OMe), R4 is NR9R10 (N(Me)(ethylene-N-(methyl)2), R5 is NR12C(O)R13 (NHC(O)C2-6 alkenyl), and R6 and R7 form
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, wherein X3 is N and X1, X2, X4, X5, and X6 are CH (claim 1-6). ‘636 claims the compound, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide, which is Compound 1 (claim 17).
Regarding claim 1, ‘636 fails to teach administering at least 100 mg/day Compound 1 to a patient.v
Abousaud teaches EGFR alterations are commonly observed in malignant gliomas and that Osimertinib (AZD9291) is an irreversible EGFR-tyrosine kinase inhibitor that effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue (abstract). Wikipedia evidences that Osimertinib has the structure:
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(page 1, side box). Additionally, Mayo Clinic teaches that glioblastoma and glioblastoma multiforme are synonymous (page 1, paragraph 2). Abousaud teaches that finding effective treatments for primary malignant brain tumors has been challenging due to their chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier, which limits entry of systemically administered therapeutics (page 211, column 2, paragraph 1). Abousaud teaches that the EGFR signaling pathway has garnered a great deal of attention due to its role in cancer pathogenesis and the availability of novel therapies that specifically and effectively target this pathway (page 211, column 2, paragraph 2). Abousaud teaches that osimertinib is a third-generation irreversible EGFR TKI that is more tolerable agent in comparison to other first- and second-generation EGFR TKIs (page 212, column 1, paragraph 2). Abousaud teaches that there is in vitro and in vivo studies supporting the preclinical activity of Osimertinib in EGFR expression glioblastoma, particularly glioblastomas that express EGFR vIII (page 212, column 1, paragraph 2). Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death (page 212, column 2, paragraphs 2-3; page 217, Table 2). Abousaud teaches that although the sample size is small due to challenges in obtaining Osimertinib for off-label use in glioma/glioblastoma, the heavily pretreated brain tumor population tolerated Osimertinib therapy and half of the patients were able to achieve either partial response or stable disease ranging from 77 to 294 days (page 218, column 2, paragraphs 1 and 3).
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 ‘636 with the method of Abousaud to treat patients with glioblastoma, which is challenging due to chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier as taught by Abousaud. One or ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘636 claims a method of treating non-small cell lung cancer in a subject via a compound of Formula (I):
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, and Compound 1 maps into Formula (I) of ‘656, wherein Z1 and Z2 are N, Z3 is CR8, R8 is H, R1 is H, R2 is H, R3 is C1-4 alkoxy (OMe), R4 is NR9R10 (N(Me)(ethylene-N-(methyl)2), R5 is NR12C(O)R13 (NHC(O)C2-6 alkenyl), and R6 and R7 form
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, wherein X3 is N and X1, X2, X4, X5, and X6 are CH,
-‘636 claims the compound, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide, which is Compound 1,
-Abousaud teaches EGFR alterations are commonly observed in malignant gliomas and that Osimertinib (AZD9291) is an irreversible EGFR-tyrosine kinase inhibitor that effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue,
-Wikipedia evidences that Osimertinib has the structure:
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,
-Mayo Clinic teaches that glioblastoma and glioblastoma multiforme are synonymous,
-Abousaud teaches that finding effective treatments for primary malignant brain tumors has been challenging due to their chemo- and radio-resistant properties, paucity of targetable genomic aberrations, and the presence of the blood brain barrier, which limits entry of systemically administered therapeutics,
-Abousaud teaches that the EGFR signaling pathway has garnered a great deal of attention due to its role in cancer pathogenesis and the availability of novel therapies that specifically and effectively target this pathway,
-Abousaud teaches that osimertinib is a third-generation irreversible EGFR TKI that is more tolerable agent in comparison to other first- and second-generation EGFR TKIs,
-Abousaud teaches that there is in vitro and in vivo studies supporting the preclinical activity of Osimertinib in EGFR expression glioblastoma, particularly glioblastomas that express EGFR vIII,
-Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death, and
-Abousaud teaches that although the sample size is small due to challenges in obtaining Osimertinib for off-label use in glioma/glioblastoma, the heavily pretreated brain tumor population tolerated Osimertinib therapy and half of the patients were able to achieve either partial response or stable disease ranging from 77 to 294 days.
A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.). See MPEP 2144.05(I)-(II)(A). Abousaud teaches treating glioblastoma in patients via administering 80 mg per day of Osimertinib in addition to other drugs and continuing treatment until disease progression, the development of unacceptable side effects, medical complications, or death (page 212, column 2, paragraphs 2-3; page 217, Table 2). ‘636 claims treating non-small cell lung cancer that is characterized by EGFR mutation, such as T790M (claim 18). Abousaud teaches that finding effective treatments for primary malignant brain tumors has been challenging due to chemo- and radio-resistant properties and the presence of the blood brain barrier, which limits entry of systemically administered therapeutics (page 211, column 1, paragraph 1). Additionally, Abousaud teaches that there is the suggestion that EGFR alteration/mutations are correlated with glioma tumor growth, survival, invasion, and angiogenesis (page 211, column 2, paragraph 2). Abousaud teaches that previous EGFR TKI first- and second-generation TKIs have been studied in EGFR-altered glioma but have yielded minimal to no clinical benefit and short durations of response (page 212, column 1, paragraph 2). Accordingly, an artisan having ordinary skill in the art would recognize that optimizing the dosing protocol when dosing only Compound 1 (a derivative of Osimertinib) would limit the rise of resistance and ensure penetrance of the blood brain barrier as taught by Abousaud. Accordingly, the combination of ‘636 and Abousaud teaches treating glioblastoma via administering at least 100 mg of Compound 1.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive a method of treating glioblastoma multiform in patients via administering at least 100 mg/day of Compound 1:
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Regarding claim 2, ‘636 claims Compound 1 (claim 17). As Applicant does not further recite a certain concentration responsible for the subject to not lose more than 10% of its body weight within 1 month after administration, claim 2 does not specify an additional step but does specify an additional effect. Thus, claim 2 merely recites an additional effect of a claimed composition. Further, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Where Applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the Examiner may make a rejection under both 35 U.S.C. 102 and 103. This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. See MPEP § 2112(II) and (III). Consequently, Gray teaches the subject to not lose more than 10% of its body weight within 1 month after administration.
Regarding claim 10, Abousaud teaches treating glioblastoma multiforme (page 217, Table 2).
Regarding claim 15, ‘636 claims Compound 1 (claim 17), wherein Z1 and Z2 are N, Z3 is CR8, R1 is H, and R2 is H.
Regarding claim 18, ‘636 claims Compound 1 (claim 17), wherein R3 is C1-4 alkoxy, R4 is NR9R10, and R5 is NR12C(O)R13.
Regarding claim 23, ‘636 claims Compound 1 (claim 17), wherein R8 is H, R9 is C1-4 alkyl, and R10 is (C1-4 alkyl)-N-(C1-4 alkyl)2.
Regarding claim 29, ‘636 claims Compound 1 (claim 17), wherein X1, X2, X4, X5, and X6 are CH, R91 is C1-4 alkyl, and R101 is (C1-4 alkyl)-N-(C1-4 alkyl)2.
Regarding claim 30, ‘636 claims Compound 1 (claim 17), which is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Regarding claim 32, Abousaud teaches treating glioblastoma via Osimertinib once daily (page 212, column 2, paragraph 3).
Regarding claim 38, ‘636 claims a method of treating non-small cell lung cancer and inhibiting EGFR in a subject via administering Compound 1 (a derivative of Osimertinib; claims 1-6, 8-11, 14, and 16-18). Abousaud teaches treating glioblastoma via Osimertinib once daily (page 212, column 2, paragraph 3). Accordingly, the combination of ‘636 and Abousaud teaches a method of treating glioblastoma and inhibiting EGFR in a subject via administering Compound 1.
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
