Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application claims priority to the applications, CN 202111020912.1 and PCT/CN2022/116085, with the effective filing dates of 1 Sept 2021 and 31 Aug 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Response to Restriction Requirement filed, 1 June 2026.
Applicant’s election with traverse of Group I and Compound 1:
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in the reply filed 1 June 2026 is acknowledged. The traversal is on the ground(s) that because the claimed subject matter of Groups I-V are sufficiently related such that an undue burden would not be presented to the Examiner and that claims 1-18 and 21-22 fall within the recitation of 37 CFR 1.475(b)(3). Applicant further submits that the claimed compounds of claim 1 are different from the prior art (Chari (WO 2020/219287, filed 9 Jul 2020; of record, see PTO-892 mailed 13 Apr 2026) and Masuda (US 10,195,288, issued 5 Feb 2019; of record, see PTO-892 mailed 13 Apr 2026) and that R7 of the R5 group of claim 1 exhibits proliferation inhibitory activity against at least one MCF-7, MDA-MB-231, and MDA-MB-435s cells that are superior to that of Compound 6a (Chari).
However, this is not found persuasive. The Examiner notes that the application is a National Phase (371) application, and thus Applicant applies a different standard to traverse the restriction requirement, which is irrelevant to National Phase (371) applications. In regard to Applicant’s assertion that the compounds of claim 1 exhibit superior activity than Compound 6a of Chari (Table 4 of the specification, [1084]; Tables 1-4), Compound 1 does not exhibit an unexpected effect over Terasawa (U.S. Patent No. 5,834,476, issued 10 Nov 1998) in view of Li (ACS Med. Chem. Lett.¸2019, 10, 1386-1392) and Schonherr (ACIE, 2013, 52, 12256-12267).
Terasawa teaches derivatives of camptothecin that are water-soluble with excellent antitumor activity and a high degree of safety:
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(abstract). Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47).
Terasawa fails to teach a compound of Formula (I).
Li teaches camptothecin derivatives and antibody-drug conjugates and structure-activity relationships (SAR) therein (abstract; Figure 1, page 1836; page 1387, column 1, paragraphs 1-3; page 1387, paragraph 1). Li teaches that camptothecin and its derivatives bind to topisomerase I/DNA complex to prevent reannealing, which can cause cell death due to partially cleaved DNA (page 1386, column 1, paragraph 2). Li teaches that camptothecin and its derivatives have at least five rings (A-E) and that the E-ring is in equilibrium between the closed and open forms:
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(page 1386, column 1, paragraph 2; page 1386, Figure 1). Li teaches that the E-ring when open is reported to be far less active, because it’s charge inhibits diffusion into cells and >99% of it is bound by human serum albumin in plasma (page 1386, column 2, paragraph 1). Li teaches that the fluorine substituent on the A ring at the C11 position typically increase cytotoxicity several fold and that the selectivity at C20, must be in the (S) configuration ((9S) in Terasawa; page 1386, column 2, paragraph 1; page 1387, column 2, paragraph 1). Li teaches that exatecan bears an additional F ring (“F-ring”) and was found to be less prone to hydrolysis in human plasma (~30% remaining in the E-ring) and attributed the lactone stability to the C11 fluorine and F-ring (page 1387, column 1, paragraph 1). Li teaches that the F-ring is not required for E-ring stabilization and that the F-ring complicates synthetic efforts and SAR studies (page 1387, column 1, paragraph 3; page 1387, column 2, paragraph 1; page 1391, column 1, paragraph 2). Li teaches Compound 10:
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(Scheme 1, page 1387). Additionally, Li teaches that more hydrophobic analogs had higher potencies against the two cancer cell lines tested (page 1389, column 2, paragraph 2).
Schonherr teaches the phenomenon characterized in medicinal chemistry as the magic methyl effect on potency (abstract). Schonherr teaches that the methyl group is one of the most prevalent functionalities in biologically active molecules, which are commonly installed to improve a molecule’s biological activity and physical properties (page 12257, column 1, paragraph 1). Schonherr teaches that methylation is used to optimize many properties of a drug candidate, such as methylating next to a metabolic hot spot to sterically block metabolism and lengthen half-life (page 12257, column 1, paragraph 2). Schonherr teaches that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 2, paragraph 1). Schonherr teaches the improvements in binding affinity observed upon introducing a methyl group have been attributed to desolvation effects (page 12257, column 2, paragraph 2). Schonherr teaches that methylation energetically favors binding and lowers the IC50 value (page 12257, column 2, paragraph 2). Schonherr teaches that estimates place the value for ΔΔG_transfer upon a proton for methyl replacement at about 0.8 kcal/mol for transfer from water to a protein and that this corresponds to an approximate 3.5-fold boost in potency from methylation based on ΔΔG_transfer alone (page 12257, column 2, paragraph 2). However, Schonherr teaches that the effect may even be greater in that a single methyl group may boost potency approximately 10-fold if the new methyl group sits nicely in a hydrophobic pocket of the active site (page 12257, column 2, paragraph 2; page 12258, column 1, paragraph 1). Schonherr teaches that installing a methyl group will not always lead to an increase in potency but that they must be space in the active site to accommodate the methyl group (page 12258, column 1, paragraph 2; page 12258, column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the (1R,9S) isomer of Terasawa and substitute the F-ring for a methylated alkylamine as taught by Li and Schonherr to increase potency, stabilize the E-ring to maintain good solubility, and simplify the structure for easier derivatization for SAR purposes to arrive at instant claim 1 (Compound 1). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: Terasawa teaches that camptothecin is a pentacyclic alkaloid with antitumor activity due to inhibition of nucleic acid synthesis (column 1, lines 25-29); Terasawa teaches that camptothecin is scarcely soluble in water, which is a problem for administration to a patient (column 1, lines 40-41); Terasawa teaches that opening of the lactone and converting to sodium carbonate provides a water-soluble camptothecin derivative but that derivation exhibits greatly reduced antitumor activity (column 1, lines 42-46); Terasawa teaches camptothecin derivatives that retain the lactone for activity whilst increasing solubility (column 1, lines 51-58); Terasawa teaches Example 50:
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, which has an unspecified amine stereocenter and both diastereomers are obtained:
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(1S,9S) and
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47); accordingly, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47); Li teaches camptothecin derivatives and antibody-drug conjugates and structure-activity relationships (SAR) therein; Li teaches that camptothecin and its derivatives bind to topisomerase I/DNA complex to prevent reannealing, which can cause cell death due to partially cleaved DNA; Li teaches that camptothecin and its derivatives have at least five rings (A-E) and that the E-ring is in equilibrium between the closed and open forms:
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; Li teaches that the E-ring when open is reported to be far less active, because it’s charge inhibits diffusion into cells and >99% of it is bound by human serum albumin in plasma; Li teaches that the fluorine substituent on the A ring at the C11 position typically increase cytotoxicity several fold and that the selectivity at C20, must be in the (S) configuration ((9S) in Terasawa); Li teaches that exatecan bears an additional F ring (“F-ring”) and was found to be less prone to hydrolysis in human plasma (~30% remaining in the E-ring) and attributed the lactone stability to the C11 fluorine and F-ring; Li teaches that the F-ring is not required for E-ring stabilization and that the F-ring complicates synthetic efforts and SAR studies; Li teaches Compound 10:
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; additionally, Li teaches that more hydrophobic analogs had higher potencies against the two cancer cell lines tested; Schonherr teaches that the phenomenon characterized in medicinal chemistry as the magic methyl effect on potency; Schonherr teaches that the methyl group is one of the most prevalent functionalities in biologically active molecules, which are commonly installed to improve a molecule’s biological activity and physical properties; Schonherr teaches that methylation is used to optimize many properties of a drug candidate, such as methylating next to a metabolic hot spot to sterically block metabolism and lengthen half-life; Schonherr teaches that methylation also has a favorable effect on solubility and selectivity against off-targets; Schonherr teaches the improvements in binding affinity observed upon introducing a methyl group have been attributed to desolvation effects; Schonherr teaches that methylation energetically favors binding and lowers the IC50 value; Schonherr teaches that estimates place the value for ΔΔG_transfer upon a proton for methyl replacement at about 0.8 kcal/mol for transfer from water to a protein and that this corresponds to an approximate 3.5-fold boost in potency from methylation based on ΔΔG_transfer alone; however, Schonherr teaches that the effect may even be greater in that a single methyl group may boost potency approximately 10-fold if the new methyl group sits nicely in a hydrophobic pocket of the active site; and Schonherr teaches that installing a methyl group will not always lead to an increase in potency but that they must be space in the active site to accommodate the methyl group.
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at Compound 1:
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, which is a compound of Formula (I).
Claims 1-18 and 21-22 are pending.
Claims 12 and 14-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group (Group II: claim 12; Group III: claims 14-15; Group IV: claim 16; Group V: claim 17), there being no allowable generic or linking claim. Claims 19-20 were canceled.
Claims 1-11, 13, 18, and 21-22 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statements filed 19 August 2024 and 14 Mar 2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claim(s) 1-11, 13, 18, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Terasawa (U.S. Patent No. 5,834,476, issued 10 Nov 1998) in view of Li (ACS Med. Chem. Lett.¸2019, 10, 1386-1392) and Schonherr (ACIE, 2013, 52, 12256-12267) as evidenced by American Pharmaceutical Review (“Diluent Excipient,” American Pharmaceutical Review, 2026, <americanpharmaceuticalreview.com/pfu/7964385/soids/1402534/Excipient_Search/Diluent>, accessed 17 June 2026) and DC Fine Chemicals (“Excipients: what they are and their importance in the pharmaceutical industry,” DC Fine Chemicals, 16 Sept 2024, <www.dcfinechemicals.com/en/blog/excipients-their-importance-pharmaceutical-industry/>, accessed 17 June 2026).
Terasawa teaches derivatives of camptothecin that are water-soluble with excellent antitumor activity and a high degree of safety:
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(abstract). Terasawa teaches that camptothecin is a pentacyclic alkaloid with antitumor activity due to inhibition of nucleic acid synthesis (column 1, lines 25-29). Terasawa teaches that camptothecin is scarcely soluble in water, which is a problem for administration to a patient (column 1, lines 40-41). Terasawa teaches that opening of the lactone and converting to sodium carbonate provides a water-soluble camptothecin derivative but that derivation exhibits greatly reduced antitumor activity (column 1, lines 42-46). Terasawa teaches camptothecin derivatives that retain the lactone for activity whilst increasing solubility (column 1, lines 51-58). Terasawa teaches Example 50:
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, which has an unspecified amine stereocenter and both diastereomers are obtained:
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(1S,9S) and
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47). Accordingly, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47).
Regarding claim 1, Terasawa fails to teach a compound wherein R4 and R5 are not linked together to form the F-ring.
Li teaches camptothecin derivatives and antibody-drug conjugates and structure-activity relationships (SAR) therein (abstract; Figure 1, page 1836; page 1387, column 1, paragraphs 1-3; page 1387, paragraph 1). Li teaches that camptothecin and its derivatives bind to topisomerase I/DNA complex to prevent reannealing, which can cause cell death due to partially cleaved DNA (page 1386, column 1, paragraph 2). Li teaches that camptothecin and its derivatives have at least five rings (A-E) and that the E-ring is in equilibrium between the closed and open forms:
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(page 1386, column 1, paragraph 2; page 1386, Figure 1). Li teaches that the E-ring when open is reported to be far less active, because it’s charge inhibits diffusion into cells and >99% of it is bound by human serum albumin in plasma (page 1386, column 2, paragraph 1). Li teaches that the fluorine substituent on the A ring at the C11 position typically increase cytotoxicity several fold and that the selectivity at C20, must be in the (S) configuration ((9S) in Terasawa); page 1386, column 2, paragraph 1; page 1387, column 2, paragraph 1). Li teaches that exatecan bears an additional F ring (“F-ring”) and was found to be less prone to hydrolysis in human plasma (~30% remaining in the E-ring) and attributed the lactone stability to the C11 fluorine and F-ring (page 1387, column 1, paragraph 1). Li teaches that the F-ring is not required for E-ring stabilization and that the F-ring complicates synthetic efforts and SAR studies (page 1387, column 1, paragraph 3; page 1387, column 2, paragraph 1; page 1391, column 1, paragraph 2). Li teaches Compound 10:
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(Scheme 1, page 1387). Additionally, Li teaches that more hydrophobic analogs had higher potencies against the two cancer cell lines tested (page 1389, column 2, paragraph 2).
Schonherr teaches the phenomenon characterized in medicinal chemistry as the magic methyl effect on potency (abstract). Schonherr teaches that the methyl group is one of the most prevalent functionalities in biologically active molecules, which are commonly installed to improve a molecule’s biological activity and physical properties (page 12257, column 1, paragraph 1). Schonherr teaches that methylation is used to optimize many properties of a drug candidate, such as methylating next to a metabolic hot spot to sterically block metabolism and lengthen half-life (page 12257, column 1, paragraph 2). Schonherr teaches that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 2, paragraph 1). Schonherr teaches the improvements in binding affinity observed upon introducing a methyl group have been attributed to desolvation effects (page 12257, column 2, paragraph 2). Schonherr teaches that methylation energetically favors binding and lowers the IC50 value (page 12257, column 2, paragraph 2). Schonherr teaches that estimates place the value for ΔΔG_transfer upon a proton for methyl replacement at about 0.8 kcal/mol for transfer from water to a protein and that this corresponds to an approximate 3.5-fold boost in potency from methylation based on ΔΔG_transfer alone (page 12257, column 2, paragraph 2). However, Schonherr teaches that the effect may even be greater in that a single methyl group may boost potency approximately 10-fold if the new methyl group sits nicely in a hydrophobic pocket of the active site (page 12257, column 2, paragraph 2; page 12258, column 1, paragraph 1). Schonherr teaches that installing a methyl group will not always lead to an increase in potency because there must be space in the active site to accommodate the methyl group (page 12258, column 1, paragraph 2; page 12258, column 2, paragraph 1), which Terasawa shows that there is space for incorporation of a methyl (column 65, lines 1-15; column 67, lines 45-47).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the (1R,9S) isomer of Terasawa and substitute the F-ring for a methylated alkylamine as taught by Li and Schonherr to increase potency, stabilize the E-ring to maintain good solubility, and simplify the structure for easier derivatization for SAR purposes to arrive at instant claim 1 (Compound 1). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Terasawa teaches derivatives of camptothecin that are water-soluble with excellent antitumor activity and a high degree of safety:
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,
-Terasawa teaches that camptothecin is a pentacyclic alkaloid with antitumor activity due to inhibition of nucleic acid synthesis,
-Terasawa teaches that camptothecin is scarcely soluble in water, which is a problem for administration to a patient,
-Terasawa teaches that opening of the lactone and converting to sodium carbonate provides a water-soluble camptothecin derivative but that derivation exhibits greatly reduced antitumor activity,
-Terasawa teaches camptothecin derivatives that retain the lactone for activity whilst increasing solubility,
-Terasawa teaches Example 50:
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, which has an unspecified amine stereocenter and both diastereomers are obtained:
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(1S,9S) and
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(1R,9S),
-Li teaches camptothecin derivatives and antibody-drug conjugates and structure-activity relationships (SAR) therein,
-Li teaches that camptothecin and its derivatives bind to topisomerase I/DNA complex to prevent reannealing, which can cause cell death due to partially cleaved DNA,
-Li teaches that camptothecin and its derivatives have at least five rings (A-E) and that the E-ring is in equilibrium between the closed and open forms:
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,
-Li teaches that the E-ring when open is reported to be far less active, because it’s charge inhibits diffusion into cells and >99% of it is bound by human serum albumin in plasma,
-Li teaches that the fluorine substituent on the A ring at the C11 position typically increase cytotoxicity several fold and that the selectivity at C20, must be in the (S) configuration ((9S) in Terasawa),
-Li teaches that exatecan bears an additional F ring (“F-ring”) and was found to be less prone to hydrolysis in human plasma (~30% remaining in the E-ring) and attributed the lactone stability to the C11 fluorine and F-ring,
-Li teaches that the F-ring is not required for E-ring stabilization and that the F-ring complicates synthetic efforts and SAR studies,
-Li teaches Compound 10:
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,
-Li teaches that more hydrophobic analogs had higher potencies against the two cancer cell lines tested,
-Schonherr teaches that the phenomenon characterized in medicinal chemistry as the magic methyl effect on potency,
-Schonherr teaches that the methyl group is one of the most prevalent functionalities in biologically active molecules, which are commonly installed to improve a molecule’s biological activity and physical properties,
-Schonherr teaches that methylation is used to optimize many properties of a drug candidate, such as methylating next to a metabolic hot spot to sterically block metabolism and lengthen half-life,
-Schonherr teaches that methylation also has a favorable effect on solubility and selectivity against off-targets,
-Schonherr teaches the improvements in binding affinity observed upon introducing a methyl group have been attributed to desolvation effects,
-Schonherr teaches that methylation energetically favors binding and lowers the IC50 value,
-Schonherr teaches that estimates place the value for ΔΔG_transfer upon a proton for methyl replacement at about 0.8 kcal/mol for transfer from water to a protein and that this corresponds to an approximate 3.5-fold boost in potency from methylation based on ΔΔG_transfer alone,
-Schonherr teaches that the effect may even be greater in that a single methyl group may boost potency approximately 10-fold if the new methyl group sits nicely in a hydrophobic pocket of the active site, and
-Schonherr teaches that installing a methyl group will not always lead to an increase in potency but that they must be space in the active site to accommodate the methyl group.
Thus, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at Compound 1:
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.
Regarding claim 2, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R0 is C1-4 alkyl (ethyl), R1 is H, R2 is halogen (F), R3 is alkyl (methyl), and R4 is H. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is H, R8 is H, and R9 is H. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is alkyl (methyl). Accordingly, the combination of Terasawa, Li, and Schonherr teaches R0 is C1-4 alkyl (ethyl), R1 is H, R2 is halogen (F), R3 is alkyl (methyl), R4 is H, R6 is H, R7 is alkyl (methyl), R8 is H, and R9 is H.
Regarding claim 3, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is halogen (F), R3 is alkyl (methyl), and R4 is H.
Regarding claim 4, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47) with stereochemistry (R) at R5. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is H. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches R5 is
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.
Regarding claim 5, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R0 is ethyl, R1 is hydrogen, R2 is fluorine, R3 is methyl, R4 is hydrogen, A is oxygen, Z is a hydroxyl, and m is 0. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, R9 is hydrogen, m is 0, and x is 0. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches R0 is ethyl, R1 is hydrogen, R2 is F, R3 is methyl, R4 is hydrogen, R5 is
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, R6 is hydrogen, R7 is methyl, R8 is hydrogen, R9 is hydrogen, A is oxygen, m is 0, and Z is a hydroxyl.
Regarding claim 6, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R1 is hydrogen, R2 is fluorine, R3 is methyl, and R4 is hydrogen. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, and R9 is hydrogen. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches a compound of Formula (II):
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.
Regarding claim 7, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is fluorine, R3 is methyl, and R4 is hydrogen. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, and R9 is hydrogen. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches a compound of Formula (III):
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, wherein R2 is halogen (F), R3 is alkyl (methyl), R4 is hydrogen, R5 is
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, R6 is hydrogen, R7 is alkyl (methyl), R8 is hydrogen, and R9 is hydrogen.
Regarding claim 8, Terasawa teaches the isomer,
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(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is fluorine and R3 is methyl. Li teaches Compound 10:
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(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, R9 is hydrogen, m is 0, and x is 0. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches a compound of Formula (IV):
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199
media_image12.png
Greyscale
, wherein R2 is halogen (F), R3 is alkyl (methyl), R5 is
PNG
media_image8.png
76
69
media_image8.png
Greyscale
, R6 is hydrogen, R7 is alkyl (methyl), R8 is hydrogen, R9 is hydrogen, and x is 0.
Regarding claim 9, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is fluorine, R3 is methyl, and R4 is hydrogen. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, and R9 is hydrogen. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches a compound of Formula (I-1):
PNG
media_image13.png
136
198
media_image13.png
Greyscale
, wherein R2 is F, R3 is methyl, R4 is H, R5 is
PNG
media_image8.png
76
69
media_image8.png
Greyscale
, R6 is hydrogen, R7 is alkyl (methyl), R8 is hydrogen, and R9 is hydrogen.
Regarding claim 10, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is fluorine and R3 is methyl. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, and R9 is hydrogen. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches a compound of Formula (V):
PNG
media_image14.png
130
196
media_image14.png
Greyscale
, wherein R2 is F, R3 is methyl, R4 is H, and R5 is
PNG
media_image15.png
41
46
media_image15.png
Greyscale
, R6 is hydrogen, R7 is methyl, R8 is hydrogen, and R9 is hydrogen.
Regarding claim 11, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47), wherein R2 is fluorine and R3 is methyl. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, and R9 is hydrogen. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches the compound,
PNG
media_image16.png
83
106
media_image16.png
Greyscale
.
Regarding claim 13, Terasawa teaching a pharmaceutical preparation as an oral tablet and injections which include auxiliary ingredients such as stabilizers and preservatives (column 70, lines 1-8), which are excipients, as evidenced by American Pharmaceutical Review (page 2, paragraph 1) and DC Fine Chemicals (page 2, paragraph 6).
Regarding claim 18, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47) with stereochemistry (R) at R5. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, R9 is hydrogen, and x is 0. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches that R5 is
PNG
media_image17.png
56
57
media_image17.png
Greyscale
Regarding claim 21, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47) with stereochemistry (R) at R5. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, R9 is hydrogen, and x is 0. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches that R5 is
PNG
media_image18.png
72
74
media_image18.png
Greyscale
.
Regarding claim 22, Terasawa teaches the isomer,
PNG
media_image3.png
210
469
media_image3.png
Greyscale
(1R,9S) (column 65, lines 1-15; column 67, lines 45-47) with stereochemistry (R) at R5. Li teaches Compound 10:
PNG
media_image5.png
61
113
media_image5.png
Greyscale
(Scheme 1, page 1387), wherein R6 is hydrogen, R8 is hydrogen, R9 is hydrogen, and x is 0. Schonherr teaches that methylation to optimize many properties of a drug candidate and that methylation also has a favorable effect on solubility and selectivity against off-targets (page 12257, column 1, paragraph 2; page 12257, column 2, paragraph 1), wherein R7 is methyl. Accordingly, the combination of Terasawa, Li, and Schonherr teaches that R5 is
PNG
media_image15.png
41
46
media_image15.png
Greyscale
.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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