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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 48-75, drawn to a method of treating cancer in a patient, and the following species:
(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid or a tautomer, pharmaceutically acceptable salt or solvate thereof as the elected species of an MDM2 antagonist;
CDKN2A depleted as the elected cancer species;
1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b ]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one ("ASTX660") or a tautomer or a solvate or a pharmaceutically acceptable salt thereof as the second therapeutic agent; and
step (i) the expression levels of CDKN2A is determined; in step (ii) selecting patients with decreased levels of CDKN2A; and in step (iii) the MDM2 antagonist (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid or a tautomer, pharmaceutically acceptable salt or solvate thereof is administered as the elected method species
in the reply filed on September 30, 2025 is acknowledged.
Please note Applicant indicates the elected species are encompassed by claims 48-75; However, the Examiner noted that claims 49-52, 54, 56, 58, 65, 67, 70, 72, 74 and 76 are drawn to a species non-elected. For instance, claim 60 is drawn to a non-elected cancer species (“the cancer has BAP1 present at a normal or high level”); claim 70 is drawn to interferon(s) as the second therapeutic agent, and that is a second therapeutic agent species non-elected; and claim 72 is drawn to normal or high levels of CDKN2A within the biological sample, and that not a CDKN2A depleted cancer nor a patient with decreased levels of CDKN2A.
Claims 49-52, 54, 56, 58, 60, 65, 67, 70, 72, 74 and 76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 30, 2025.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Chessari et al. that renders obvious the claimed invention, wherein the prior art teaches IAP antagonist LCL-161 as the second therapeutic agent; However, it is noted that the prior art does not teach the elected species of second therapeutic agent (ASTX660). In light of this discovery, the search is expanded to the subject matter of the second therapeutic agent to include IAP antagonist LCL-161 in addition to the elected species of second therapeutic agent (ASTX660) such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on October 16, 2023, claims 1-47 are cancelled; and claims 48-76 are newly added.
Claims 48-76 are pending. Claims 49-52, 54, 56, 58, 60, 65, 67, 70, 72, 74 and 76 are withdrawn.
Claims 48, 53, 55, 57, 59, 61-64, 66, 68-69, 71, 73, and 75 are under examination in accordance with the elected species along with the expanded species set forth the Expansion of Election of Species Requirement section above.
Priority
The instant application 17/757,843 filed on June 22, 2022 is a 371 of PCT/IB2020/062366 filed
on December 23, 2020, which claims priority to, and the benefits of Foreign Application No.
GB1919219.4 filed on December 23, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/16/2023 and 9/30/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
The chemical structures of ALRN-6924 (see page 33, line 1), ATSP-7041, SAH-p53-8, and PM-2 (see page 39) are blurry and unreadable.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. For instance, on page 81, line 1; page 184, line 12 and 27; and page 185, line2-3 of the specification, the disclosure contains an embedded hyperlink.
Appropriate correction is required.
Claim Interpretation
The claimed term “depleted” in the phrase of “CDKN2A depleted”, when construed in light of page 3, line 9-13 of the specification shown below:
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, is taken to include loss or complete loss of CDKN2A, mutation of CDKN2A and loss of function, and low CDKN2A expression and low protein expression of CDKN2A and function.
The limitations followed after the phrase of “optionally wherein” in claim 62 shown below:
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, is reasonably construed by the Examiner such that these limitations (see boxes above) are not required feature(s) of the claim.
Claim Objections
Claim 71 is objected to because of the following informalities:
Regarding claim 71, the phrase of step (ii) and the phrase of step (iii) in the last three lines of the claim is missing a coordinating conjunction “and” in between. Please note that the coordinating conjunction should be used to indicate the relationship between the clauses in the sentence.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 53, 59, 63, 69 and 71 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 53, the claim recites several MDM2 antagonist that does not have a chemical structure associate with the name, such as “CTX-50-CTX-1” and “ADO-21”. For instance, the specification discloses “CTX-50-CTX-1 is a small molecule MDM2 antagonist being developed by MiRx Pharmaceuticals, CRC” on page 37, line 8; However, the Examiner cannot determine the chemical structure of CTX-50-CTX-1. It is not clear what compound is being referred to by the Applicant. Therefore, the claim recites MDM2 antagonist that is indefinite, because the specification does not clearly point out the chemical structure of the MDM2 antagonists. In addition, the claim recites multiple conjunctions (“and” and “or”) that renders the claim indefinite, because it can lead to various interpretations. For instance, the recitation of “K-178, MMRi-64 and
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, or a tautomer” can be interpretated that the MDM2 antagonist is (a) K-178, the combination of (MMRi-64 and
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), or a tautomer thereof; or (b) the combination of (K-178, MMRi-64 and
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), or a tautomer thereof. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Regarding claim 59, the phrase “e.g., “ in the recitation of “e.g., 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b ]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one ("ASTX660"), or a tautomer or a solvate or a pharmaceutically acceptable salt thereof” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In addition, the phrase “an MDM2 antagonist” in the recitation of “induces sensitivity to an MDM2 antagonist” renders the claim indefinite, because it is not clear if applicant is referring to the same MDM2 antagonist set forth in claim 48 or another MDM2 antagonist that is structurally distinct. Please note the article “an” is used to refer something that is not previously mentioned.
Regarding claim 63, the recitation of “detecting expression level of biomarkers…wherein the biomarkers are (i)… and/or (ii) … and/or (iii)…” renders the claim indefinite. First, the claim recites the term “biomarkers” that is the plural form of the singular noun biomarker; and further recites said biomarkers are (i) and/or (ii) and/or (iii). If the biomarker is one of these three recited options, then the “biomarkers” should be in singular form rather than plural form. Therefore, it is not clear if applicant is intending to select more than one biomarkers recite therein as the “biomarkers”. In order to advance prosecution, the Examiner examining the claim to the extent the “biomarkers” includes a single biomarker.
Regarding claim 69, the phrase "such as" in the recitation of “optionally a p53 wild type cancer such as mesothelioma” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In addition, the recitation of “an MDM2 antagonist” renders the claim indefinite, because it is not clear if applicant is referring to the same MDM2 antagonist set forth in claim 68 or another MDM2 antagonist that is structurally distinct. To the extent that applicant is referring to the same MDM2 antagonist, it is not clear if the administration step (c) (“treating the patient with a therapeutically effective amount of an MDM2 antagonist”) is referring to the same administration step set forth in claim 68 or an additional administration step. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In order to advance prosecution, the Examiner is examining the claim to the extent that step (c) is an additional step that administer a therapeutically effective amount of the same MDM2 antagonist, which is the elected MDM2 antagonist.
Regarding claim 71, the recitation of “an MDM2 antagonist” in the context of “followed by administering a therapeutically effective amount of an MDM2 antagonist to said patient selected in step (ii)” renders the claim indefinite, because it is not clear if applicant is referring to the same MDM2 antagonist set forth in claim 68 or another MDM2 antagonist that is structurally distinct. Please note the article “an” is used to refer something that is not previously mentioned. To the extent that applicant is referring to the same MDM2 antagonist, it is not clear if the administration step (iii) (“followed by administering a therapeutically effective amount of an MDM2 antagonist to said patient selected in step (ii)”) is referring to the same administration step set forth in claim 68 or an additional administration step. The lack of clarity renders the claim indefinite as one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In order to advance prosecution, the Examiner is examining the claim to the extent that step (iii) is an additional step that administer a therapeutically effective amount of the same MDM2 antagonist, which is the elected MDM2 antagonist.
Claims 53 and 66 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature for the following reasons:
Claims 53 and 66 recite “the MDM2 antagonist is selected from the group consisting of idasanutlin (RG-7388), HDM-201, KRT-232 (AMG-232), ALRN-6924, MI-773 (SAR405838), CGM-097, milademetan tosylate, APG-115, BI-907828, LE-004, DS-5272, SJ-0211, BI-0252, AM-7209, SP-141, SCH-1450206, NXN-6, ADO-21, CTX-50 - CTX-1, ISA-27, RO-8994, RO-6839921, ATSP-7041, SAH-p53-8, PM-2, K-178, MMRi-64 and
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, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof; or is a compound of formula (I°)”.
The Markush grouping of MDM2 antagonist includes alternatives that do not share any single structure similarity. For instance, the Markush grouping includes the species, such as APG-115 having the structure of:
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(see e.g., p. 34, line 1 of the specification) and K-178 having the structure of:
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(see e.g., p. 40, line 1 of the specification), that do not share any single structure similarity. According to the instant specification, APG-115 is a small molecule antagonist of MDM2; and K-178 is a small molecule antagonist of MDM4 (see e.g., p. 33, last 4 lines; and p. 39, last 2 lines). In other words, the members of Markush grouping also do not share a common use.
Each of these findings demonstrates that not all members recited in this Markush grouping share a single structure similarity and a common use that flows from the substantial structural feature.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
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.
Claims 48, 53, 55, 57, 59, 61-64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1; cited in the IDS filed on 10/16/2023).
Chessari et al. teaches a method for the treatment of cancer comprising the steps of administering to a patient a medicament comprising at least one compound of formula (I) (see e.g., claim 31; p. 109, line 17-18). Chessari et al. further teaches a compound of Example 124, (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid, having the structure of:
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(referred to herein as “Compound 124”) is a compound of formula (I) useful for inhibiting MDM2-p53 interaction and the growth of MDM2 amplified cell lines, which are an isogenic matched pair of p53 wild-type and mutated osteosarcoma (SJSA-1 and SN40R2, respectively) shown below:
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(see e.g., p. 259, Example 124; Table 1, Patent Example 124). Chessari et al. further teaches the compounds of formula (I) will typically be administered in amounts that are therapeutically useful and which generally are non-toxic (see e.g., p. 119, line 30-31); and a typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight (see e.g., p. 120, line 3-4). Chessari et al. further teaches the compound can be used in the treatment of cancer in a patient possessing loss of a MDM2 negative regulator such as p14ARF (see e.g., p. 112, line 10-11). Chessari et al. further teaches loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2 and, therefore, loss of p53 function and cell cycle control (see e.g., p. 2, line 22-24). Chessari et al. further teaches the compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer (see e.g., p. 121, line 28-30). Chessari et al. further teaches particular examples of anti-cancer agents or adjuvants (or salts thereof) includes, inter alia, regulators of cell death (apoptosis) including IAP antagonists such as LCL-161 (see e.g., p. 125, (xlviii). Chessari et al. further teaches it may be beneficial to use the compound of formula (I) as a single agent or to combine the compound of formula (I) with another agent which acts via a different mechanism to regulate cell growth thus treating two of the characteristic features of cancer development (see e.g., p. 121, line 22-24). Chessari et al. further teaches prior to administration of the compound of formula (I), a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound which inhibits MDM2/p53 (see e.g., p. 109, line 20-22); For example, a biological sample taken from a patient may be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterized by a genetic abnormality or abnormal protein expression which leads to up-regulation of the levels of MDM2 or to upregulation of a biochemical pathway downstream of MDM2/p53; for example, deletion of its negative regulator such as p14ARF has been identified in a range of cancers (see e.g., p. 109, line 24-27). Chessari et al. further teaches the patient may be subjected to a diagnostic test to detect a marker characteristic of up-regulation of MDM2; and marker includes genetic markers including, for example, the measurement of DNA composition to identify presence of mutations in p53 or amplification MDM2 or deletion (loss) of p14ARF (see e.g., p. 110, line 3-6). Chessari et al. further teaches the diagnostic tests and screens are typically conducted on a biological sample (i.e. body tissue or body fluids) selected from tumor biopsy samples, blood samples (isolation and enrichment of shed tumor cells) (see e.g., p. 110, line 10-11).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer a therapeutically useful amount of the compound 124 of Chessari et al. as the compound of formula (I) for treating cancer in a patient possessing loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene. One would have been motivated to do so, because Chessari et al. teaches the compound 124 is a compound of formula (I) useful for the treatment of cancer by inhibiting MDM2-p53 interaction and the growth of MDM2 amplified cells in a patient possessing loss of a MDM2 negative regulator such as p14ARF; and teaches loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering the compound 124 of Chessari et al. at a therapeutically useful amount to a patient possessing loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene would successfully treat cancer by inhibiting MDM2-p53 interaction. Please note the compound 124 of Chessari et al. is the elected species of MDM2 antagonist, and a compound of formula (I°) instantly claimed. Please also note the homozygous mutation of CDKN2A that leads to loss of p14ARF protein taught by Chessari et al. is a mutation of CDKN2A with low protein expression of CDKN2A (p14ARF), and that is CDKN2A depleted. Please also note the therapeutically useful amount of the compound of formula (I) taught by Chessari et al. is a therapeutically effective amount.
Regarding the limitation of “further comprising administering a second therapeutic agent” in claim 57, and the limitation of “wherein the second therapeutic agent is an agent that: induces sensitivity to an MDM2 antagonist, e.g., 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b ]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one ("ASTX660"), or a tautomer or a solvate or a pharmaceutically acceptable salt thereof” in claim 59, to the extent that the second therapeutic agent is an agent induces sensitivity to an MDM2 antagonist, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to further administer IAP antagonist, such as LCL-161, for treatment of cancer. One would have been motivated to do so, because Chessari et al. teaches the compound of formula (I) can be combined with another agent which acts via a different mechanism to regulate cell growth for the treatment of cancer; and examples of anti-cancer agents or adjuvants includes IAP antagonist, such as LCL-161. Please note the IAP antagonist taught by Chessari et al. is an agent that induces sensitivity according to page 111, line 20-22 of the specification. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 124 of Chessari et al. combined with an IAP antagonist, such as LCL-161, would successfully treat the cancer through different mechanism.
Regarding the limitation of “comprising, prior to the treatment step: (i) determining that a sample from the patient… is CDKN2A depleted” in claim 61, the limitation of “comprising, prior to the treatment step, testing a sample of patient tissue to determine a cancer expression profile, wherein the patient is selected for treatment based on a determined expression profile” in claim 62, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to test a biological sample of body tissue from the cancer patient to determine that said patient is suffering from loss of p14ARF protein due to homozygous mutation of CDKN2A. One would have been motivated to do so, because Chessari et al. teaches that prior to administration of the compound of formula (I), a biological sample of the body tissue, such as tumor biopsy, taken from the patient may be analyzed to determine whether the cancer is characterized by a genetic abnormality or abnormal protein expression which leads to up-regulation of MDM2 levels. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by analyzing the tumor biopsy as the sample of patient tissue would successfully determine the protein expression of CDKN2A (a loss of p14ARF due to homozygous mutation in the CDKN2A) for the treatment of cancer, and that is a cancer expression profile.
Regarding the limitation of “comprising, prior to the treatment step, detecting expression level of biomarkers in a sample of cancer cells from said patient, wherein the biomarkers are… (ii) CDKN2A” in claim 63, and the limitation of “wherein said detecting expression level of biomarkers in a sample is carried out using an in vitro detection assay” in claim 64, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to detect homozygous mutation in the CDKN2A (INK4A) gene in the sample of cancer cells from the patient. One would have been motivated to do so, because Chessari et al. teaches the patient may be subjected to a diagnostic test to detect a marker characteristic of up-regulation of MDM2, including identifying the loss of p14ARF such as a homozygous mutation in the CDKN2A (INK4A) gene; and the diagnostic tests are typically conducted on a biological sample selected from tumor biopsy samples and blood samples (isolation and enrichment of shed tumor cells). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by detecting the expression level of CDKN2A in a sample of cancer cells prior to the admisnritation of Compound 124 would successfully identify patient with homozygous mutation of CDKN2A for the treatment of cancer, and that detecting said level in a sample of cancer cells is an in vitro detection assay.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 48, 53, 55, 57, 59, 61-64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1; cited in the IDS filed on 10/16/2023) as applied to claims 48, 53, 55, 57, 59, 61-64 and 66 above, and further in view of Chessari et al. (WO 2015/092420 A1; referred to herein as “Chessari#2”).
To the extent that the second therapeutic agent is the elected second therapeutic agent species (“1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one ("ASTX660") or a tautomer or a solvate or a pharmaceutically acceptable salt thereof”), then the following 35 U.S.C. 103 rejection applies.
The teachings of Chessari et al. are set forth above and applied as before.
Chessari et al. does not teach the elected second therapeutic agent species in claim 59.
Chessari#2 teaches a compound of Example 38, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one (referred to herein as “Compound 38”) is an antagonist of inhibitor of apoptosis protein (IAP) that will be useful in treating diseases or condition mediated by IAP, such as cancer (see e.g., p. 147, Example 38; claim 19; p. 70, line 1-7).
The difference between the method of Chessari et al. and the claimed method is that Chessari et al. does not expressly teach the elected second therapeutic agent species in the combination therapy. It would have been prima facie obvious to one of ordinary skill in the art to modify the method of Chessari et al. set forth above by substituting one art recognized equivalent IAP antagonist for another, in this case, substituting LCL-161 of Chessari et al. with compound 38 of Chessari#2 in the combination therapy. One would have been motivated to do so, because Chessari#2 teaches compound 38 is an IAP antagonist useful for treating cancer. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 38 of Chessari#2 would exerts the same or substantially similar IAP antagonistic effect as the IAP antagonist taught by Chessari et al., and therefore, by substituting LCL-161 of Chessari et al. with compound 38 of Chessari#2 would successfully treat the cancer.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 68, 73 and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1; cited in the IDS filed on 10/16/2023).
Chessari et al. teaches a method for the treatment of cancer comprising the steps of administering to a patient a medicament comprising at least one compound of formula (I), which is an antagonist capable of binding to MDM2 and exhibiting potency for MDM2 (see e.g., claim 31; p. 109, line 17-18; p. 104, line 32-33). Chessari et al. further teaches the compound can be used in the treatment of cancer in a patient possessing loss of a MDM2 negative regulator such as p14ARF (see e.g., p. 112, line 10-11). Chessari et al. further teaches the cancer may be cancers which are p53 wild-type; and particulars cancers include those cancer cells with wild-type p53, particularly but not exclusively, if MDM2 is highly expressed (see e.g., p. 107, line 30 and 33-34). Chessari et al. further teaches a compound of Example 124, (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid, having the structure of:
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246
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(referred to herein as “Compound 124”) is a compound of formula (I) useful for inhibiting MDM2-p53 interaction and the growth of MDM2 amplified cell lines, which are an isogenic matched pair of p53 wild-type and mutated osteosarcoma (SJSA-1 and SN40R2, respectively) shown below:
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147
631
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(see e.g., p. 259, Example 124; Table 1, Patent Example 124). Chessari et al. further teaches the compounds of formula (I) will typically be administered in amounts that are therapeutically useful and which generally are non-toxic (see e.g., p. 119, line 30-31); and a typical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight (see e.g., p. 120, line 3-4). Chessari et al. further teaches loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2 and, therefore, loss of p53 function and cell cycle control (see e.g., p. 2, line 22-24). Chessari et al. further teaches the compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example a neoplastic disease such as a cancer (see e.g., p. 121, line 28-30). Chessari et al. further teaches particular examples of anti-cancer agents or adjuvants (or salts thereof) includes, inter alia, regulators of cell death (apoptosis) including IAP antagonists such as LCL-161 (see e.g., p. 125, (xlviii)).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the compound 124 of Chessari et al. as the MDM2 antagonist for the treatment of cancer in a patient possessing loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene. Please note the compound 124 of Chessari et al. is the elected species of MDM2 antagonist, and a compound of formula (I°) instantly claimed. Please also note the homozygous mutation of CDKN2A that leads to loss of p14ARF protein taught by Chessari et al. is a mutation of CDKN2A with low protein expression of CDKN2A (p14ARF), and that is CDKN2A depleted. One would have been motivated to do so, because Chessari et al. teaches the compound 124 is useful for the treatment of cancer by inhibiting MDM2-p53 interaction and the growth of MDM2 amplified cells in a patient possessing loss of a MDM2 negative regulator such as p14ARF; and teaches loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering the compound 124 of Chessari et al. to a patient possessing loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene would successfully treat cancer by inhibiting MDM2-p53 interaction.
Regarding the limitation of “wherein said cancer is a p53 wild type cancer” in claim 73, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. to incorporate the p53 wild type cancer. One would have been motivated to do so, because Chessari et al. also teaches the compound of formula (I) is useful for the treatment of cancer with wild-type p53 if MDM2 is highly expressed. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 124 of Chessari et al. would successfully treat cancer with wild-type p53.
Regarding the limitation of “additionally comprising administering another anticancer agent to the patient” in claim 75, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to further administer another anticancer agent. One would have been motivated to do so, because Chessari et al. teaches the compound of formula (I) can be combined with another agent which acts via a different mechanism to regulate cell growth for the treatment of cancer; and examples of anti-cancer agents or adjuvants includes IAP antagonist, such as LCL-161. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 124 of Chessari et al. combined with an IAP antagonist, such as LCL-161, as the anticancer agent would successfully treat the cancer through different mechanism.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 68-69, 71, 73 and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1; cited in the IDS filed on 10/16/2023) as applied to claims 68, 73 and 75 above, and further in view of Chen et al. (WO 2015/000945 A1; cited in the IDS filed on 10/16/2023).
The teachings of Chessari et al. are set forth above and applied as before.
In addition to the teachings set forth above, Chessari et al. further teaches prior to administration of the compound of formula (I), a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound which inhibits MDM2/p53 (see e.g., p. 109, line 20-22); For example, a biological sample taken from a patient may be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterized by a genetic abnormality or abnormal protein expression which leads to up-regulation of the levels of MDM2 or to upregulation of a biochemical pathway downstream of MDM2/p53; for example, deletion of its negative regulator such as p14ARF has been identified in a range of cancers (see e.g., p. 109, line 24-27). Chessari et al. further teaches the patient may be subjected to a diagnostic test to detect a marker characteristic of up-regulation of MDM2; and marker includes genetic markers including, for example, the measurement of DNA composition to identify presence of mutations in p53 or amplification MDM2 or deletion (loss) of p14ARF (see e.g., p. 110, line 3-6). Chessari et al. further teaches the diagnostic tests and screens are typically conducted on a biological sample (i.e. body tissue or body fluids) selected from tumor biopsy samples, blood samples (isolation and enrichment of shed tumor cells) (see e.g., p. 110, line 10-11). Chessari et al. further teaches in screening by RT-PCR, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art (see e.g., p. 11, line 21-23).
Chessari et al. does not teach decreased CDKN2A expression as claimed in claims 69 and 71.
Chen et al. teaches the use of a gene expression (mRNA) signature to predict a patient response to treatment with an MDM2 inhibitor (antagonist); and the gene expression signature is a 4-gene mRNA signature consisting of MDM2, XPC, and BBC3 elevated expression as well as low expression of CDKN2A when measured at baseline, i.e., prior to treatment with an MDM2 inhibitor (antagonist) (see e.g., p. 57, line 11- 15). Chen et al. further teaches measuring the mRNA expression level of CDKN2A in a sample obtained from that patient prior to treatment (see e.g., [0069]). Chen et al. further teaches for the most sensitive cell lines, MDM2, XPC and BBC3 show high expression, and CDKN2A shows low expression (see e.g., p. 6, line 20-21).
The difference between the -method of Chessari et al. and the claimed method is that the prior art teaches detecting a loss of p14ARF by a homozygous mutation of CDKN2A in the biological sample of the patient rather than having decreased CDKN2A expression. Regarding the limitation of “(a) identifying a patient in need of treatment for cancer… (b) determining that the patient has… decreased CDKN2A expression within a biological sample obtained from said patient…(c) treating the patient with a therapeutically effective amount of an MDM2 antagonist” in claim 69, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to identify the patient in need of treatment for cancer, determine that the patient has decreased CDKN2A expression within the biological sample obtained from said patient, and administer a therapeutically useful amount of the compound 124 of Chessari et al. One would have been motivated to do so, because Chen et al. teaches the gene expression (mRNA) signature, including low expression of CDKN2A, can predict a patient response to treatment with an MDM2 antagonist; and the mRNA expression level of CDKN2A can be measured in a sample obtained from that patient prior to treatment. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by determining decreased CDKN2A expression within a biological sample obtained from the cancer patient prior to treatment would successfully predict treatment response to MDM2 antagonist, and therefore, by administering a therapeutically effective amount of the compound 124 of Chessari et al. would successfully treat the cancer.
Regarding the limitation of “comprising: (i) contacting a sample from the patient with a primer, antibody, substrate or probe, to determine the expression levels of… CDKN2A… (ii) selecting a patient having decreased levels of… CDKN2A… (iii) followed by administering a therapeutically effective amount of an MDM2 antagonist to said patient selected in step (ii)” in claim 71, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Chessari et al. set forth above to contact a sample from the patient with a primer to determine the expression levels of CDKN2A, select a patient having decreased levels of CDKN2A, and administer a therapeutically useful amount of the compound 124 of Chessari et al. One would have been motivated to do so, because Chen et al. teaches sensitive cell lines has low expression of CDKN2A, and said expression can be measured in a sample obtained from the patient prior to administering an MDM2 antagonist to predict the treatment response; and Chessari et al. teaches the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR, and the selection of primers for PCR amplification are known to a person skilled in the art. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by contacting the tumor sample obtained from the patient with a primer in the process of PCR amplification would successfully determine the expression level of CDKN2A, and the patient with decreased level of CDKN2A would response to MDM2 antagonist, and therefore, by administering a therapeutically effective amount of the compound 124 of Chessari et al. would successfully treat the cancer.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
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.
Claims 48, 53, 55, 57, 59, 61-64, 66, 68-69, 71, 73, and 75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 58, 63-65, 67-70, 73, and 75 of copending Application No. 18/548,522 (reference application).
Although the claims at issue are not identical, they are not patentably district from each other because the claims of the reference application is also drawn to administering a therapeutically effective amount of the elected MDM2 antagonist for the treatment of cancer with decreased expression of CDKN2A as the gene in one or more DNA damage repair pathway, assessing said expression in a sample from the cancer patient prior to the administration step, and further combine the elected MDM2 antagonist with ASTX600 as the additional therapeutic agent.
Specifically, the claims of the reference application is drawn to a method of treating cancer in a patient, comprising a treatment step that comprises administering to the patient a therapeutically effective amount of an MDM2 antagonist, wherein the cancer is depleted of one or more genes or gene products in one or more DNA damage repair (DDR) pathways (see claim 58); wherein the cancer is P53 wild-type (see claim 64); wherein the cancers shows decreased expression of CDKN2A (see claim 65); wherein the MDM2 antagonist is a compound of formula (I°), for example, (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof (see claim 67); comprising administering to the patient an additional therapeutic agent, e.g., ASTX600 or a tautomer or a solvate or a pharmaceutically acceptable salt thereof (see claim 75). The claims of the reference application is further drawn to testing a sample of patient tissue to determine the cancer expression profile prior to treatment (see claim 63); and prognosing or assessing the responsiveness of a human cancer patient to treatment with an MDM2 antagonist, comprising assessing the expression or activity level in a sample from a cancer patient of one or more DDR pathway genes, and the patient is identified for treatment with the MDM2 antagonist when decreased expression of one or DDR pathway genes is detected; wherein the step of detecting t