DETAILED ACTION
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 .
Claim Status and Action Summary
Claims 128-135, 138, 141, 145-151, 177-178, and 183 are currently pending and under examination. No other claims are pending in the present application.
Priority
The present application, filed on October 4, 2024, is a 371 of PCT/US2023/065549, filed April 7, 2023, which claims priority to U.S. Provisional Patent Application No. 63/329,080, filed April 8, 2022.
Information Disclosure Statement
The Information Disclosure Statements dated October 4, 2024 and August 31, 2026 have been considered (see form 1449).
Drawings
The drawings filed October 4, 2024 are acceptable.
Specification
The use of the terms “NanoString” and “nCounter”, which are each a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is reminded that no new matter may be added to the disclosure.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
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.
Claims 128-135, 138, 141, 145-151, 177-178, and 183 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 128 recites a method comprising steps of “a) determining that a subject is in need of an increase in a gene signature”… and “b) based on the determining, administering a therapeutically-effective amount of… 4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide…”.
It is unclear what subject or subjects are determined to be in need of an increase in what “gene signature” as recited by step a.
The specification provides no limiting definition of the claim term “gene signature”. This term is used in the art to mean “Information about the activity of a specific group of genes in a cell or tissue.” NCI Dictionary of Cancer Terms, “gene signature”, Wayback Archive, https://web.archive.org/web/20211202101312/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/gene-signature, 2 December, 2021.
It is unclear what “specific group of genes”, what “cell or tissue”, and what measure of “activity” is required by the claim in the “determining” step. Neither the claims nor the specification identify any group(s) of genes for which a subject needs an increase or any cell or tissue type in which a “determining” step is performed.
Furthermore, the claims and the specification do not provide any limiting definition of what “activity” or “activities” is/are determined for the unspecified group(s) of genes. It is unclear whether this claim term requires measuring and/or observing gene expression levels (RNA transcript or protein abundance), a number or presence of “active” or functional alleles of the unspecified gene(s), a copy number variation in the unspecified gene(s), some unspecified post-translational modification to said protein(s) (e.g. phosphorylation at some specific residue(s) required for “activity”), or something else entirely.
The claim term “immune response gene signature” is likewise not defined by the claims or the specification and does not find any specific definition in the art. It is unclear whether an “immune response gene signature” encompasses any particular combination presence/absence, mutation, expression, or some other metric, for any particular combination of genes or any particular single gene in a tissue sample, single cell(s), or something else.
Claim 130 recites the limitation, “wherein the tumor comprises a Y220C mutation”. It is unclear whether the claim is intended to encompass embodiments wherein any protein in any tumor comprises a Tyrosine [Wingdings font/0xE0] Cysteine amino acid variant at residue number 220 (numbered sequentially from the N terminus to the C terminus of the/an unspecified protein), or whether the claim is intended to be limited to tumors comprising a Y220C mutation in some specific protein or protein isoform (e.g. TP53).
The term “about” in claims 138, 141, and 183 is a relative term which renders the claim indefinite. The term “about” 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. The claims and the specification do not provide any definite limitations for this claim term. It is unclear if the applicant intends to cover embodiments of the claims wherein the required numerical values and or ranges vary by any particular margin (e.g. ±1%, ±5%, ±10%, ±20%, or some other bounds not specified).
Claim 141 recites the limitation “administering is for at least about 1 week”. It is unclear whether this limitation requires administering a single dose, multiple doses over the course of “at least about 1 week” at some unspecified frequency, continuous administration over that entire time period, or something else entirely.
The claims further recite the following “immune response gene signatures” without defining any gene(s) belonging to the recited “signatures” or any particular metrics constituting said “signature”: “a tumor inflammation signature”, “a CD45 cell signature”, “a T-cell signature”, “an exhausted CD8 signature”, “a check-point biomarker signature”, “a PD-1 signature”, and “a PDL1 signature”. It is unclear whether the “signatures” named for a particular protein or cell type require simply measuring some expression value, presence/absence of mRNA, a functional protein of the recited gene (e.g. any detection of PD-1 expression), or something else.
Claim 177 depends from independent claim 128 and recites a limitation to the method “further comprising administering a therapeutically-effective amount of an anti-cancer agent”. It is unclear whether this limitation is intended to require something more than administration of 4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide as required by claim 128, as this compound is referred to by the specification as having the function “restore the ability of the p53 mutant to bind DNA… allow[ing] for the activation of downstream effectors of p53 leading to inhibition of cancer progression” (Specification, paragraph 011) (i.e. the compound recited by claim 128 is an anti-cancer agent). It is unclear whether claim 177 is intended to require a combination of the compound recited by claim 128 with another, different anti-cancer agent, simply encompasses administering the anti-cancer agent already recited by claim 128, or encompasses a second administration of the anti-cancer agent recited by claim 128.
Claim 183 recites a “therapeutically-effective amount of the anti-cancer agent is from about 1 µg/kg to about 10 mg/kg”. It is unclear whether this limitation refers to the agent recited in claim 128, a second dose or second agent recited in claim 177, or something else. Furthermore, the recited range of 1 µg/kg to about 10 mg/kg spans a 10,000 fold concentration range relative to an unspecified total mass amount. It is unclear whether this concentration range is intended to recite 1 µg/kg to about 10 mg/kg of tumor mass, of total body mass, of a total mass of a solution of the agent, or something else.
Claims 129-135, 138, 141, 145-151, 177-178, and 183 are also indefinite because of their dependence from, and necessarily inclusion of, the indefinite limitation(s) of the claim(s) rejected as indefinite above.
Claim Interpretation
The claims have been given their broadest reasonable interpretation according to the plain language of the claims and any stated limiting definitions, as informed by the present specification.
The compound recited by claim 128, “4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide” has been identified as the following chemical structure: (specification paragraph 0104)
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Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 177 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends.
Claim 177 depends from independent claim 128 and recites a limitation to the method “further comprising administering a therapeutically-effective amount of an anti-cancer agent”. It is unclear whether this limitation is intended to require something more than administration of 4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide as required by claim 128, as this compound is referred to by the specification as having the function “restore the ability of the p53 mutant to bind DNA… allow[ing] for the activation of downstream effectors of p53 leading to inhibition of cancer progression” (Specification, paragraph 011) (i.e. the compound recited by claim 128 is an anti-cancer agent). It is unclear whether claim 177 is intended to require a combination of the compound recited by claim 128 with another, different anti-cancer agent, simply encompasses administering the anti-cancer agent already recited by claim 128, or encompasses a second administration of the anti-cancer agent recited by claim 128.
Because it is not clear if claim 177 requires anything in addition to the limitations recited in claim 128, the claim is also rejected as failing to further limit the claim upon which it depends under 35 U.S.C. 112(d).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claims 128-135, 138, 141, 145-151, 177-178, and 183 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Relevant to the lack of particular structural limitations in the rejected claims drawn to: “determining that a subject is in need of an increase in a gene signature, wherein the gene signature comprises an immune response gene signature, and based on the determining, administering…”… wherein the immune response signature is: “a tumor inflammation signature” (claim 145), “a CD45 cell signature” (claim 146), “a T-cell signature” (claim 147), “an exhausted CD8 signature” (claim 148), “a check-point biomarker signature” (claim 149), “a PDL1 signature” (claim 150), or “a PD-1 signature” (claim 151).
MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claims are broadly drawn to a method comprising steps of a) “determining that a subject is in need of an increase in a gene signature… compris[ing] an immune response gene signature” and b) “based on the determining, administering…” a particular compound.
In the case of the instant claims, the functionality of “an immune response gene signature” to determine that a subject is “in need of an increase in a gene signature comprising [the immune response gene signature] is a critical feature of the claimed methods.
The specification teaches: “Figure 4… show[s] changes in NanoString signature scores of CD45 cell signature analysis… T-cell signature analysis… exhausted CD8 signature analysis… tumor inflammation signature analysis… PD1 signature analysis… and PDL1 signature analysis… in mice treated with vehicle… or [Compound 1]” (paragraph 010).
However, the specification does not teach any gene or gene(s) constituting the “NanoString signature scores”, any identification of what (expression?) patterns constitute a “signature”, what degree or observation of “signature” accomplishes “determining that a subject is in need of an increase in a gene signature”, or any criteria for the claimed determination step. There is no teaching in the specification limiting what these assays are nor what they may or may not require measuring/analyzing to accomplish said “determining”.
While the skilled artisan may be capable of identifying, performing, and/or developing assays capable of “determining” which subjects would benefit from administration of the claimed compound having the function “binds a mutant p53 protein and increases wild-type p53 activity of the mutant p53 protein” (Specification, paragraph 004), possession of said method of “determining… and based on the determining, administering…” may not be shown by merely describing how to obtain possession of such assays. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
The claims encompass a genus of methods requiring structurally undefined assays capable of accomplishing a function “determining that a subject is in need of…” increase in an unspecified gene signature comprising measuring an unspecified (expression?) “signature” of an unspecified (panel?) of gene(s).
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Thus considering the breadth of the assays required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 128-135, 138, 141, 145-151, 177-178, and 183 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Vu et al., WO 2021/061643 A1 (published 01 April, 2021 and filed 22 September 2020) as evidenced by Levine, “P53 and The Immune Response: 40 Years of Exploration – A Plan for the Future” Int. J. Mol. Sci. 2020, 21(2), 541.
The 102 rejections address the implicit teachings of Vu et al. as evidenced by Levine regarding claims 145-151 reciting various “immune response gene signatures” and “gene signatures” (see 112(a) and 112(b) rejections above).
Regarding claims 128 and 145-151, Vu et al. teach “The present invention provides compounds and methods for restoring wild-type function to mutant p53. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. The restoration of the activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression. The invention further provides methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation.” (Vu et al., paragraph 014) and “disclosed herein is a method of treating a cancer, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the disclosure” (Vu et al., paragraph 013). As evidenced by Levine, loss-of-function p53 mutations “result in an innate immune response” (Levine, page 6, paragraph 1), which reads on the limitations “an/the immune response gene signature” recited in claims 128 and 145-151. Vu et al. therefore teach methods comprising determining a subject is in need of an increase in p53 activity (i.e. a “gene signature comprising an immune response gene signature” recited in claim 128). Vu et al. further teach one such compound suitable for such methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation is 4-((3-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide. (Vu et al., Example D130, paragraph 0929, structure reproduced below from page 490 of Vu et al. for clarity).
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Regarding claim 129, Vu et al. teach the subject has a tumor (Vu et al., paragraph 013-014).
Regarding claim 130, Vu et al. teach the mechanism of compounds of the invention comprises selective binding to the p53 Y220C mutant (i.e. the tumor comprises a Y220C mutation) (Vu et al., paragraph 024).
Regarding claims 131-134, Vu et al. teach non-limiting examples of cancer that can be treated by the disclosed compounds include: ovarian cancer, breast cancer, lung cancer, and endometrial cancer (Vu et al., paragraph 0116).
Regarding claim 135, Vu et al. teach administering the compounds orally (Vu et al., paragraph 0131).
Regarding claim 138, Vu et al. teach administering the compounds in a dose from about 950 mg to about 1000 mg (i.e. within the claimed range “about 1000 mg to about 3000 mg”) (Vu et al., paragraph 0158).
Regarding claim 141, Vu et al. teach administering the compound for about 2 weeks (i.e. encompassing at least about 1 week) (Vu et al., paragraph 0148).
Regarding claim 147, Vu as evidenced by Levine teach loss-of-function p53 mutations activate CD-4 Th-2 helper T-cells to activate an antibody response (Vu et al., page 7, paragraph 2) (i.e. loss-of-function p53 activity comprises a T-cell signature).
Regarding claim 177, Vu et al. teach administering the compound (i.e. an anti-cancer agent) in conjunction with chemotherapy (i.e. an anti-cancer agent) (Vu et al., paragraph 0150).
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.
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.
The following 103 rejections address the explicit teachings of Vu et al. as evidenced by Levine and in view of Hayashi et al. regarding claims 145-151 reciting various “immune response gene signatures” and “gene signatures” (see 112(a) and 112(b) rejections above).
Claim(s) 128-135, 138, 141, 145-151, 177-178, and 183 are rejected under 35 U.S.C. 103 as being unpatentable over Vu et al., WO 2021/061643 A1 as evidenced by Levine, “P53 and The Immune Response: 40 Years of Exploration – A Plan for the Future” Int. J. Mol. Sci. 2020, 21(2), 541, and in view of Hayashi et al., “Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia” Nature Communications (2019).
Regarding claims 128 and 145-151, Vu et al. teach “The present invention provides compounds and methods for restoring wild-type function to mutant p53. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. The restoration of the activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression. The invention further provides methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation.” (Vu et al., paragraph 014) and “disclosed herein is a method of treating a cancer, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the disclosure” (Vu et al., paragraph 013). As evidenced by Levine, loss-of-function p53 mutations “result in an innate immune response” (Levine, page 6, paragraph 1), which reads on the limitations “an/the immune response gene signature” recited in claims 128 and 145-151. Vu et al. therefore teach methods comprising determining a subject is in need of an increase in p53 activity (i.e. a “gene signature comprising an immune response gene signature” recited in claim 128). Vu et al. further teach one such compound suitable for such methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation is 4-((3-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide. (Vu et al., Example D130, paragraph 0929, structure reproduced below from page 490 of Vu et al. for clarity).
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Regarding claim 129, Vu et al. teach the subject has a tumor (Vu et al., paragraph 013-014).
Regarding claim 130, Vu et al. teach the mechanism of compounds of the invention comprises selective binding to the p53 Y220C mutant (i.e. the tumor comprises a Y220C mutation) (Vu et al., paragraph 024).
Regarding claims 131-134, Vu et al. teach non-limiting examples of cancer that can be treated by the disclosed compounds include: ovarian cancer, breast cancer, lung cancer, and endometrial cancer (Vu et al., paragraph 0116).
Regarding claim 135, Vu et al. teach administering the compounds orally (Vu et al., paragraph 0131).
Regarding claim 138, Vu et al. teach administering the compounds in a dose from about 950 mg to about 1000 mg (i.e. within the claimed range “about 1000 mg to about 3000 mg”) (Vu et al., paragraph 0158).
Regarding claim 141, Vu et al. teach administering the compound for about 2 weeks (i.e. encompassing at least about 1 week) (Vu et al., paragraph 0148).
Regarding claim 145, Hayashi et al. teach methods for treating cancers that comprise overexpression of the negative regulator of p53, MDM2 (Hayashi et al., abstract). Hayashi et al. teach that MDM2 binds and targets p53 for proteasomal degradation, and that inhibition of the MDM2-p53 interaction increases the expression of functional p53 and downstream p53 targets which were likewise inhibited by degradation of p53 (i.e. absence of functional p53) (Hayashi et al., abstract and page 2, column 1).
Hayashi et al. further teach that restoration of p53 function in AML cells and in mouse models induced immune-inflammatory responses (i.e. a tumor inflammation signature, an immune response gene signature) (Hayashi et al., abstract and page 2, column 2, paragraph 3-4).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to combine the methods taught by Vu et al. comprising determining subjects with loss-of-function mutations in p53 in need of p53 function restoration (i.e. an increase in a gene signature) and treating said subjects with 4-((3-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide with the methods taught by Hayashi et al. comprising determining immune response gene signatures induced by restoration of functional p53 in tumors having an orthogonal p53 loss-of-function phenotype.
The ordinary artisan would have been motivated to combine the diagnostic and treatment methods taught by Vu et al. with the additional diagnostic markers of p53 loss-of-function taught by Hayashi et al. because of the teaching of Hayashi et al. that restoration of p53 function in tumors with a loss-of-function phenotype triggers an immune-inflammatory response that leads to cancer regression (Hayashi et al., page 2, column 2, paragraph 3).
Regarding claim 146, Hayashi et al. teach restoration of p53 function is accompanied by a change in a CD45 cell signature “%AML cells in bone marrow (BM)” (Hayashi et al., figure 6c, reproduced below for clarity) “DS-5272” refers to a different drug that restores p53 function in cancers having a different mechanism of loss-of-function than p53 mutation.
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Regarding claim 147, Vu as evidenced by Levine teach loss-of-function p53 mutations activate CD-4 Th-2 helper T-cells to activate an antibody response (Vu et al., page 7, paragraph 2) (i.e. loss-of-function p53 activity comprises a T-cell signature).
Regarding claims 149-151, Hayashi et al. teach restoration of p53 function is accompanied by a change in expression of the immune check-point molecules PD-1 and PDL1 (Hayashi et al., page 8, column 2, paragraph 3 and Fig. 3(b) and (c), reproduced below for clarity)
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Regarding claim 177, Vu et al. teach administering the compound (i.e. an anti-cancer agent) in conjunction with chemotherapy (i.e. an anti-cancer agent) (Vu et al., paragraph 0150).
Regarding claims 177-178, Hayashi et al. teach “Our study also provides a rationale for combining p53-activating drugs with Hif1 and/or immune checkpoint inhibitors in the treatment of AML (i.e. a cancer) (Hayashi et al., page 8, column 2, paragraph 3). Hayashi et al. further teach significant survival benefit of combination therapy comprising restoring p53 function and anti-PD1/PD-L1 therapy (i.e. the anti-cancer agent is an immune checkpoint inhibitor) (Hayashi et al., figure 8e, see below).
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Regarding claim 183, Hayashi et al. teach the therapeutically-effective amount of the anti-cancer agent (the anti-PD-1 and anti-PD-L1 antibodies) is 10 mg/kg (Hayashi et al., page 9, column 2).
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.
Claim 128 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,419,880 B2 (herein referred to as ‘880). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of ‘880 anticipates claim 128 of the present application as currently recited:
Claim 1 of ‘880 reads:
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Claim 1 of ‘880 recites “the subject has been previously determined to have the p53-deactivating mutation” (i.e. determining the subject is in need of an increase in (p53 function), an immune response gene signature) and “administering… a therapeutically effective amount of compound… wherein the compound is “4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide”.
Therefore, claim 1 of ‘880 encompasses all of the limitations of the present claim 1.
Claim 128 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 20 of U.S. Patent No. 11,938,124 B2 (herein referred to as ‘124). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 2, and 20 of ‘124 recite:
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Claim 20 of ‘124 (which depends from claim 1) recites a method of treating a cancer in a subject in need thereof comprising administering the same compound currently claimed to the subject. Claim 2 (which depends from claim 1) recites that the cancer expresses a mutant p53 protein (i.e. “an immune response gene signature”).
The present claim 1 is obvious over claims 1, 2, and 20 of ‘124 because claims 1, 2, and 20 are each preferred embodiments of the claims of ‘124 and the limitations of these claims, taken together, are identical in scope with claim 128 of the present claims as currently recited.
Claim 128 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 70 and 81 of copending Application No. 19/373,216 (herein referred to as ‘216). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 70 of ‘216 recites a method of treating cancer in a subject, comprising administering the same compound as presently required by the instant claim 128 (reproduced below)
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Claim 81 of ‘216 (which depends from claim 70), further recites that the cancer expresses a mutant p53 protein (i.e. a gene signature comprising an immune response gene signature) (reproduced below).
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Therefore, the present claim 128 is not patentably distinct from the claims of ‘216 because the claim is obvious over claims 70 and 81 of ‘216, as claims 70 and 81 are each preferred embodiments of the invention claimed by ‘216 and together encompass all of the limitations of the presently claimed method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 128 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69 and 103 of copending Application No. 18/865,464 (herein referred to as ‘464). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 69 and 103 (which depends from 69) of ‘464 recite a method of treating a condition in a subject comprising administering the same compound as presently claimed, wherein the condition is a cancer expressing a mutant p53 (i.e. “a gene signature comprising an immune response gene signature”)(reproduced below):
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Dumble et al., “Abstract LB006: PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development” Cancer Res (2021) 81 (13_Supplement): LB006.
Conference presentation by inventor April 10, 2021; abstract publication date unclear. (102(a)(1) eligibility date with applied 102(b)(1)(A) exception applied: April 7, 2021).
Tan et al., “A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma” J Clin Invest. 2021; 131(1):e137186.
Teaches pro-tumorigenic secretory pathway (i.e. “gene signatures”) induced by p53 deletion or loss-of-function mutation(s).
Wei et al., “Fundamental Mechanisms of Immune Checkpoint Blockade Therapy” Cancer Discov; 8(9): 1069-86.
Teaches various “immune checkpoint inhibitors” known in the art.
Zhao et al., “Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors” Annals of Oncology 28: 2002-2008, 2017.
Teaches therapeutically effective amount(s) of an exemplary immune checkpoint inhibitor (Nivolumab, an anti-PD-1 monoclonal antibody).
No claim is allowed.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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