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 .
DETAILED ACTION
Election of Species and Status of the Claims
Applicant’s election without traverse of “CgA” as the single specific neuroendocrine marker or TRAIL signaling pathway marker, “small cell lung carcinoma” as the single specific neuroendocrine tumor, “ONC206” as the single specific imipridone compound, and “ex vivo” as the single specific method of determining biological marker expression levels in the response filed on June 11th 2026 is acknowledged. Claims 1-13 are pending. Claims 3, 5-6, 10, and 13 are withdrawn from further consideration as being directed towards nonelected species until a generic claim has been found allowable. Claims 1-2, 4, 7-9, and 11-12 are examined on their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 120 is acknowledged. Applicant has complied with all conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 based on the date of the provisional application 63/395,695 filed on August 5th 2022.
Claim Interpretation
The term “imipridone compound” is not defined by the specification. The term will be interpreted by its broadest reasonable interpretation, consistent with the art, as a compound containing a fused tetrahydropyridine—pyrimidinone—imidazoline core in an angular [3,4-e] arrangement, accounting for varying saturation in the rings.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-2, 4, 7-9, and 11-12 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.
The term “higher dose” in claim 1 is a relative term which renders the claim indefinite. The term “higher dose” 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. Specifically, no base dosage of imipridone compound is defined for the relative term “higher dose” to be compared to, and it is thus unclear what constitutes a “higher dose.”
Claim 1 and its dependent claims 2, 7-9, and 11-12 are indefinite for the phrase “neuroendocrine differentiation markers and/or TRAIL signaling pathway markers,” because one of ordinary skill in the art could not reasonably determine the metes and bounds of the claims from the phrase as written. The terms are defined in the specification as “genes, proteins, or antigens known to be associated with the differentiation of neuroendocrine cells” (specification, paragraph [0040]) and “genes and proteins involved in TRAIL signaling” (specification, paragraph [0041]). In each case, a plurality of examples are defined of each biomarker type. However, the full scope of all biomarkers encompassed by the terms is never defined by the specification.
Furthermore, one of ordinary skill in the art could not reasonably determine the scope of all “genes, proteins, or antigens” that are associated with the neuroendocrine differentiation process, as the term associated with is relative in nature. Similarly the scope of “genes and proteins involved in TRAIL signaling,” is unclear because the degree of involvement required to be included in the scope of the term is never defined nor implied.
Claim 1 and its dependent claims 2, 4, 7-9, and 11-12 are indefinite for reciting the term “if the level of expression of one or more markers is high.” The term “high” is a relative term which renders the claims indefinite. The term “high” is not defined by the claims, 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. In each case, the claim references “high” expression of neuroendocrine differentiation markers, but in neither case is the degree which constitutes a “high” expression defined, neither explicitly, nor implicitly. Consequently, there is no clear dividing line between a “neuroendocrine tumor wherein the expression of neuroendocrine differentiation markers and/or TRAIL signaling markers is high” and a “neuroendocrine tumor wherein the expression of neuroendocrine differentiation markers and/or TRAIL signaling markers is not high.”
This is in contrast to the standard in the art wherein such biomarkers are often used as a determining factor in treatment outcome. For example, see Yao (Yao et al., Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011 Dec;96(12):3741-9).
Yao measures the CgA neuroendocrine differentiation marker in patients with pancreatic neuroendocrine tumors, and uses such results as a predictor for the patient’s response to the drug everolimus (Yao, pg. 3741, results). Importantly, Yao establishes a baseline for elevated vs nonelevated CgA, as above/below 2 x 36.4 ng/ml (Yao, pg. 3743). Such a cutoff value allows the CgA assay to serve as a tool in predicting treatment outcome.
Without the establishment of such a cutoff value, one of ordinary skill in the art could not reasonably determine the difference between a patient with “high expression” of the described biomarkers, and a patient with “low expression” of the described biomarkers.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 11, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yao (Yao et al., Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011 Dec;96(12):3741-9).
Claim 1 recites a method of treating a neuroendocrine tumor in a subject, comprising determining the level of expression of neuroendocrine differentiation markers and/or TRAIL signaling pathway markers by the tumor and either:
Treating the subject with a therapeutically effective amount of imipridone compound if the level of expression of one or more markers is high
or
Treating the subject with a higher dose of imipridone compound
or
Treating the subject with a different neuroendocrine tumor treatment method
Yao teaches the measurement of the CgA neuroendocrine differentiation marker in patients with pancreatic neuroendocrine tumors, and uses such results as a predictor for the patient’s response to the drug everolimus (Yao, pg. 3741, results). Yao then treats such patients with everolimus (Yao, pg. 3741, results). Yao’s method thereby satisfies the limitations of both steps of the claim and anticipates claim 1.
Claim 4 requires that the neuroendocrine differentiation marker in claim 1 is CgA, and is anticipated by Yao for the same reasons as claim 1.
Claim 11 requires that the subject in claim 1 is human, and is anticipated by Yao for the same reasons as claim 1.
Claim 12 requires that the diagnostic step of claim 1 is performed ex vivo. Yao’s Cga measurement step was performed via enzyme-linked immunoabsorbent assay (Yao, pg. 3743), and Yao thereby anticipates claim 12.
Claims 1, 2, 9, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Anderson (Anderson et al., Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor. Clin Cancer Res. 2022 May 2;28(9):1773-1782).
Claim 1 is directed towards the treatment of a neuroendocrine tumor via the two-step process of
Determining the level of expression of TRAIL signaling pathway markers.
Treating the subject with a therapeutically effective amount of an imipridone compound if the level of expression is high.
Anderson teaches administration of the imipridone compound, ONC201 at a dose of 625 mg (Anderson, pg. 1773), to patients with pheochromocytoma-paraganglioma, a neuroendocrine tumor demonstrated to overexpress the TRAIL pathway marker, DRD2 (Anderson, pg. 1774). Anderson thereby anticipates claim 1.
Claim 2 limits the imipriodone compound of claim 1 to ONC201 and is anticipated by Anderson for the same reasons as claim 1.
Claim 9 requires that, in the method of claim 1, the subject is treated with an imipridone compound if the level of expression of one or more neuroendocrine differentiation markers is high. Anderson teaches administration of the imipridone compound ONC201 to treat tumors overexpressing DRD2 (Anderson, pg. 1774), a marker that one of ordinary skill in the art would recognize as a neuroendocrine differentiation marker due to its pathological involvement in the regulation of neuroendocrine cancers1. Anderson thereby anticipates claim 9.
Claim 11 requires that the subject of claim 1 is human and is anticipated by Anderson for the same reasons as claim 1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Anderson in view of Lee (Lee et al., Abstract 5260: Preclinical studies with ONC201 in combination with clinically approved chemotherapy as a novel treatment strategy against Small Cell Lung Cancer (SCLC). Cancer Res 15 August 2020; 80 (16_Supplement): 5260).
Claim 7 is directed towards the method of claim 1 wherein the tumor is a small cell lung carcinoma. For the teachings of Anderson as they relate to claim 1 see the above 102 rejection for claim 1. Regarding the treatment of small cell lung carcinoma (SCLC), one of ordinary skill in the art would have a reasonable expectation of success in applying Anderson’s method of treating neuroendocrine tumors with measured high levels of DRD2 with ONC201 to SCLC, because ONC201 is already known in the art for the treatment of SCLC (Lee, Abstract). Claim 7 is thereby prima facie obvious.
Claims 8 is rejected under 35 U.S.C. 103 as being unpatentable over Anderson in view of Kline (Kline et al., Role of Dopamine Receptors in the Anticancer Activity of ONC201. Neoplasia. 2018 Jan;20(1):80-91).
Claim 8 is directed towards the method of claim 1 wherein the subject is treated with an imipridone compound if the level of expression of a plurality of markers is high. For the teachings of Anderson as they are relevant to claim 1, see the above 102 rejection for claim 1.
Anderson does not explicitly teach the treatment of neuroendocrine tumors wherein more than one marker (DRD2). However, one of ordinary skill in the art would have a reasonable expectation of success in treating neuroendocrine tumors where additional markers are highly expressed with ONC201, because ONC201 is known as a selective antagonist of multiple markers, including both DRD2 (described in Anderson above) and DRD3 (Kline, Abstract). One of ordinary skill in the art would therefore have a reasonable expectation of success in treating neuroendocrine tumors wherein both DRD2 and DRD3 are highly expressed via administration of ONC201 and claim 8 is prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anthony Seitz whose telephone number is (703)756-4657. The examiner can normally be reached 7:30 AM ET - 5:00 PM ET M-F.
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/ANTHONY JOSEPH SEITZ/Examiner, Art Unit 1629
1 For evidentiary support, see Gatto (Federico Gatto, Leo J Hofland; The role of somatostatin and dopamine D2 receptors in endocrine tumors. Endocr Relat Cancer 1 December 2011; 18 (6): R233–R251)
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