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
are maintained.
Claims 49-52, 58, 60, 65, 70, 72, 74 and 76 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
Please note Applicant does not indicate claim 49 is being withdrawn in the amendments to claims filed on March 31, 2026, and said claim has been amended from “wherein the cancer is BAP1 depleted” to the recitation of “wherein the cancer is also BAP1 depleted”. Since applicant has received an action on the merits for the originally presented invention, amended claim 49 (drawn to cancer that is also BAP1 depleted) is still drawn to a non-elected cancer species, because the elected cancer species is not a BAP1 depletion cancer.
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 March 31, 2026, wherein claims 1-47, 53-56 and 66-67 are cancelled; claims 48-50, 58-59, 61, 63-64, 68-69 and 71 are amended; and claims 51-52, 57, 60, 62, 65, 70 and 72-76 are unchanged. In short, Applicant amends claim 48 by adding the new limitation that recites “and wherein the MDM2 antagonist is (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; and the MDM2 antagonist is administered orally at a dose of 2 to 800 mg daily or intermittently”, and that changes the scope of the claim(s).
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 48-52, 57-65 and 68-76 are pending.
Claims 49-52, 58, 60, 65, 70, 72, 74 and 76 remain withdrawn
Claims 48, 57, 59, 61-64, 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.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 31, 2026 and April 3, 2026 were filed after the mailing date of the Non-Final Office Action on October 31, 2025. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Action Summary
Acknowledgement is made of the receipt and entry of the amendment to the specification filed on March 31, 2026. Applicant’s amendment to the specification overcome each and every objection previously sets forth in the Non-Final Office Action mailed on October 31, 2025.
Applicant’s amendment to the claims filed on March 31, 2026 overcome each and every objection previously sets forth in the Non-Final Office Action mailed on October 31, 2025.
Claim 53 and 63 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 are withdrawn in light of the claim amendments. Claim 53 and 63 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 are withdrawn in light of the claim amendments.
Claims 59, 69 and 71 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 are maintained, but revisited and modified in light of the claim amendments.
Claims 53 and 66 rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives are withdrawn in light of the claim amendments that cancelled these claims.
Claims 48, 53, 55, 57, 59, 61-64 and 66 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) are withdrawn in light of the claim amendments that added new limitation(s); However, upon further consideration, the prior art has been reapplied for the reasons set forth herein.
Claims 48, 53, 55, 57, 59, 61-64 and 66 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”) are withdrawn in light of the claim amendments that added new limitation(s); However, upon further consideration, the prior art has been reapplied for the reasons set forth herein.
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) are withdrawn in light of the claim amendments that added new limitation(s); However, upon further consideration, the prior art has been reapplied for the reasons set forth herein.
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) are withdrawn in light of the claim amendments that added new limitation(s); However, upon further consideration, the prior art has been reapplied for the reasons set forth herein.
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) are withdrawn in light of the claim amendments that added new limitation(s); However, upon further consideration, the new ground of rejection has been applied for the reasons set forth herein.
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 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 59, 69 and 71 remain 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 59, 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 69, the recitation of “treating the patient with a therapeutically effective amount of the MDM2 antagonist” renders the claim indefinite, because it is not clear if the administration step (c) (“treating the patient with a therapeutically effective amount of the 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 “a therapeutically effective amount of the MDM2 antagonist to said patient selected in step (ii)” renders the claim indefinite, because it is not clear if the administration step (iii) (“followed by administering a therapeutically effective amount of the 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.
Response to Arguments
Applicant's arguments filed on March 31, 2026 with respect to all rejections pertaining to claims 53 and 66 are moot, because these claims were cancelled in light of the claim amendments.
Applicant’s arguments filed on March 31, 2026 with respect to the rejection of claim 63 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 are withdrawn in light of the claim amendments have been fully considered and are persuasive. The rejection of claim 63 has been withdrawn in light of the claim amendments.
Applicant's arguments filed on March 31, 2026 with respect to the rejection of 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 have been fully considered but they are not persuasive.
In Summary, Applicant argues the claim amendments overcome the rejection on the record.
In response, Applicant’s argument is not found persuasive. Amended claim 59 still recites “an MDM2 antagonist” inline 3 that 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. Additionally, although applicant amends claims 69 and 71 from the recitation of “a therapeutically effective amount of an MDM2 antagonist” to the recitation “a therapeutically effective amount of the MDM2 antagonist”, the claim(s) still recites an article “a” and that does not clearly set forth whether said step is referring back to the same administration step set forth in claim 68 or an additional administration step.
In view of the foregoing, the rejection of claims 48, 69 and 71 are maintained but revisited and modified in light of the claim amendments.
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, 57, 59 and 61-64 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)(newly reapplied as necessitated by amendment).
Chessari et al. teaches a method for 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), 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 the 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 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; p. 269, line 14-15). Chessari et al. further teaches the compounds of the invention may be administered orally in a range of doses, for example, 0.1 to 5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg; the compound may be administered once or more than once each day; the compound can be administered continuously (i.e., taken every day without a break for the duration of the treatment regimen) or intermittently (i.e., taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen) (see e.g., p. 120, line 18-25). 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); 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 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).
According to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by selectively choose to administer compound 124 of Chessari et al. as the compound of formula (I) orally at a dose of 2 to 800 mg every day or intermittently 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 the loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2; and the further teaches the compound may be administered orally in a range of doses, including 2 to 800 mg, and may be administered continuously (i.e., taken every day without a break for the duration of the treatment regimen) or intermittently. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by orally administering the compound 124 of Chessari et al. at a dose of 2 to 800 mg 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 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.
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” 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, in the method set forth above 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 incorporate testing 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 CDKN2A in a sample of cancer cells from said patient” in claim 63, and the limitation of “wherein said detecting expression level of CDKN2A 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 incorporate detecting 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 administration 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, 57, 59 and 61-64 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, 57, 59 and 61-64 above, and further in view of Chessari et al. (WO 2015/092420 A1; referred to herein as “Chessari#2”)(newly reapplied as necessitated by amendment).
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.
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. set forth above and the claimed method is that Chessari et al. does not expressly teach the elected second therapeutic agent species; However, Chessari et al. clealry teaches the compound can be administered in combination therapy with one of more other compounds (see e.g., p. 121, line 28-30), 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 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)(newly reapplied as necessitated by amendment).
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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(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). Chessari et al. further teaches the compounds of the invention may be administered orally in a range of doses, for example, 0.1 to
5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular
examples of doses including 10, 20, 50 and 80 mg; the compound may be administered once or more than once each day; the compound can be administered continuously (i.e., taken every day without a
break for the duration of the treatment regimen) or intermittently (i.e., taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen) (see e.g., p. 120, line 18-25). 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)).
Regarding claim 68, according to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by selectively choose to administer compound 124 of Chessari et al. as the compound of formula (I) at a dose of 2 to 800 mg every day or intermittently for treating cancer in a patient possessing loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene. Please 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 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 the loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2; and the further teaches the compound may be administered in a range of doses, including 2 to 800 mg, and may be administered continuously (i.e., taken every day without a break for the duration of the treatment regimen) or intermittently. 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 dose of 2 to 800 mg 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. set forth above to incorporate 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 in the method set forth above 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)(newly reapplied as necessitated by amendment).
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 fact that Chessari et al. teaches the administration of compound of formula (I), including the Compound 124, for treating cancer in a patient; the patient in need of treatment for cancer would necessarily be identified. The difference between the -method of Chessari et al. set forth above and the claimed method is that Chessari et al. 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 the 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 incorporate identifying the patient in need of treatment for cancer, determining that the patient has decreased CDKN2A expression within the biological sample obtained from said patient, and treating the patient 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 in said cancer patient.
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; and (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 incorporate contacting a sample from the patient with a primer to determine the expression levels of CDKN2A, selecting a patient having decreased levels of CDKN2A, and administering 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.
Response to Arguments
Applicant's arguments filed on March 31, 2026 with respect to the rejection of claims 48, 53, 55, 57, 59, 61-64 and 66 under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1); with respect to the rejection of claims 48, 53, 55, 57, 59, 61-64 and 66 under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1) 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”) have been fully considered but they are not persuasive.
Applicant's arguments filed on March 31, 2026 with respect the rejection of claims 68, 73 and 75 under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1); and with respect to the rejection of claims 68-69, 71, 73 and 75 under 35 U.S.C. 103 as being unpatentable over Chessari et al. (WO 2017/055860 A1) as applied to claims 68, 73 and 75 above, and further in view of Chen et al. (WO 2015/000945 A1) have been fully considered but they are not persuasive.
Applicant amends independent claims 48 by adding a new limitation that recites “and wherein the MDM2 antagonist is (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; and the MDM2 antagonist is administered orally at a dose of 2 to 800 mg daily or intermittently”. Applicant further amends independent claim 68 by adding a new limitation that recites “and wherein the MDM2 antagonist is (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; and the MDM2 antagonist is administered at a dose of 2 to 800 mg daily or intermittently”. Each of these findings demonstrate the claim amendments changes the scope of the claims, and necessitated a modification of the rejection on the record.
In Summary, Applicant argues the amendments to claims 48 and 68 introduces limitations that overcome the rejection on the record.
In response, applicant’s argument is not found persuasive. It may well be true that the claim amendments added new limitations that is not addressed in the previous rejection on the record; however, upon further consideration, the Examiner discovered the new limitation is also taught by Chessari et al. (WO 2017/055860 A1). Therefore, the rejection on the record has been revisited and modified in light of the claim amendments for the reasons set forth herein.
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.
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Claims 48, 57, 59, 61-64, 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), in view of Chessari et al. (WO 2017/055860 A1; cited in the IDS filed on 10/16/2023)(newly applied as necessitated by amendment).
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 method of treating cancer in a patient, comprising a treatment step that comprises 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 the expression or activity level of the biomarkers in a sample of cancer cells from said human patient, optionally wherein the detection is carried out using an in vitro detection assay (see claims 68-70). Please note the ASTX660 taught by the reference application is an agent that induces sensitivity to an MDM2 antagonist.
The reference application does not teach the MDM2 antagonist is administered orally at a dose of 2 to 800 mg daily or intermittently as claimed in claim 48. The reference application also does not teach the MDM2 antagonist is administered at a dose of 2 to 800 mg daily or intermittently as claimed in claim 68.
Chessari et al. teaches a method for 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), and the loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in MDM2 (see e.g., p. 2, line 22-24), 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); wherein the cancer may be cancers which are p53 wild-type (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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(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, including isogenic matched pair of p53 wild-type and mutated osteosarcoma (see e.g., p. 259, Example 124; Table 1, Patent Example 124). Chessari et al. further teaches the compounds of the invention may be administered orally in a range of doses, for example, 0.1 to 5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg; the compound may be administered once or more than once each day; the compound can be administered continuously (i.e., taken every day without a break for the duration of the treatment regimen) or intermittently (i.e., taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen) (see e.g., p. 120, line 18-25).
According to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the present case, the difference between the reference application and the claimed method is that the reference application does not expressly teach the therapeutically effective amount of an MDM2 antagonist, i.e., (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. 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 reference application by administering (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 orally at a dose of 2 to 800 mg every day or intermittently as taught by Chessari et al. One would have been motivated to do so, because Chessari et al. teaches compound 124 may be administered orally in a range of doses, including 2 to 800 mg, and may be administered continuously (i.e., taken every day without a break for the duration of the treatment regimen) or intermittently 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 the 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 orally administering the (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 at a dose of 2 to 800 mg in the method of reference application, the patient with cancer that is CDKN2A depleted would successfully be treated by inhibiting MDM2-p53 interaction.
Therefore, this is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed on March 31, 2026 with respect to the provisional rejection of claims 48, 53, 55, 57, 59, 61-64, 66, 68-69, 71, 73, and 75 are 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) have been fully considered.
Applicant amends independent claims 48 by adding a new limitation that recites “and wherein the MDM2 antagonist is (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; and the MDM2 antagonist is administered orally at a dose of 2 to 800 mg daily or intermittently”. Applicant further amends independent claim 68 by adding a new limitation that recites “and wherein the MDM2 antagonist is (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; and the MDM2 antagonist is administered at a dose of 2 to 800 mg daily or intermittently”. Each of these findings demonstrate the claim amendments changes the scope of the claims, and necessitated a modification of the rejection on the record.
Applicant requests the double patenting rejections be held in abeyance until the identification of allowable subject matter.
In response, since Applicant did not put forth any arguments specifically against this obviousness-type double patenting rejection. Given that the amendments change the scope of the claims by adding new limitation indicated above, the rejection on the record has been revisited and modified in light of the claim amendments for the reasons set forth herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHIHYI LEE/Examiner, Art Unit 1628
/JEAN P CORNET/Primary Examiner, Art Unit 1628
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