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 .
Priority
This application is a national stage entry of PCT/CN2019/124575 filed on 12/11/2019. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 12/19/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s amendment filed on November 15, 2024, amending claim 1 and canceling claim 2 has been entered. Claims 10-12, 14 and 15 are withdrawn.
Claims 1, 3-9 and 13 are currently presented for examination and being examined as they read on the elected species.
Response to Arguments
Applicant's arguments filed November 15, 2024 have been fully considered but they are not persuasive.
Applicant argues that at the position corresponding to the G of the claimed compound (i.e., the para-position of N atom of the pyridine ring), Coates teaches that this position is a hydrogen atom, which is fixed as a hydrogen atom and is not a modified/alterable position. Applicant argues that claim 1 has been amended to recite “-G-J-L-” is selected from the group consisting of -NH-CH2-CH2-, -O-CH2-CH2-, -NH-C(=O)-CH2-, and -C(=O)-NH-CH2-,” which is completely different from the hydrogen atom taught by Coates. Applicant argues that Mallison does not cure this deficiency since Mallison teaches macrocyclization and further teaches common linking groups for macrocyclization in Table 23. Applicant argues that even if those skilled in the art would consider combining the macrocyclization teaching of Mallison, they will not obtain the compound containing the specific linking group “-G-J-L-“ as presently claimed because Coates teaches that the para-position of N atom of the pyridine ring is a hydrogen atom, not an amino group, a hydroxyl group, or a carbonyl group. Applicant argues that even if Coates’s compounds were macrocyclized at this position, the linking group is only other linking groups different from the amide group and amino group given in Table 23 of Mallison. Applicant further argues that one of ordinary skill would be unable to expect the activity of the claimed compound based on the cited references. Applicant argues that they have surprisingly found the claimed compound of formula (I) containing a particular linking group “-G-J-L-” is a class of compounds having excellent CDK inhibitory activity and these excellent technical effects cannot be expected from the disclosures of the cited references.
These arguments are found not persuasive because while Mallison teaches in certain sections that macrocyclization can be achieved by combining certain portions of the parent molecule, the rejection of record is based on the teachings of Mallison which teaches that a common design strategy in the synthesis of macrocycles is to join the functionalized termini of otherwise liner pharmacophores with simple linkers
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(page 1430). Thus, Mallison teaches that a series of chemical reactions are performed in order to attach the simple linker to the parent molecule and thus the simple linker is not a part of the original parent compound. In the instant case, the amide linker taught in Mallison in Table 23 on page 1427 would not be a part of the original parent compound of Coates, rather as taught in Mallison the amide group is a part of the linker that is attached to the compound of Coates through a series of chemical reactions. Thus, as detailed in the rejection of record, since Mallison teaches that conformational restriction, including cyclization of drug-like molecules is commonly used to improve potency towards a target such as CDK; and that macrocyclization could stabilize the bioactive conformation thus increasing binding affinity; as well as the potency of inhibitors can be retained or improved upon appropriate macrocyclization, it would have been obvious to a person of ordinary skill in the art to prepare macrocycles of the CDK4/6 inhibitors of Coates based on techniques known in the art as taught by Mallison including using a common amide linking group known in the art to form the macrocycle compound, with a reasonable expectation of improving the properties of the compound.
With respect to Applicant’s argument that one of ordinary skill would be unable to expect the activity of the claimed compound based on the cited references and that they have surprisingly found the claimed compound of formula (I) containing a particular linking group “-G-J-L-” is a class of compounds having excellent CDK inhibitory activity, it is noted that Coates specifically teaches that the compounds of formula (I) are useful as cyclin dependent kinase (CDK) 4/6 inhibitors for the treatment of cancer (column 4 lines 60-64). Furthermore, Mallison et al. teaches that conformational restriction, including cyclization of drug-like molecules is commonly used to improve potency towards a target such as CDK (pages 1412-1415). Thus Applicant’s finding that the claimed compounds have excellent CDK inhibitory activity would not be considered surprising nor unexpected given that Coates teaches that the parent compound has the same property of inhibition of CDK and Mallison teaches that cyclization of molecules is commonly used to improve potency towards a target such as CDK. It is Applicant’s burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989) (Claims at issue were directed to a process of sterilizing a polyolefinic composition which contains an antioxidant with high-energy radiation. Although evidence was presented in appellant’s specification showing that particular antioxidants are effective, the Board concluded that these beneficial results would have been expected because one of the references taught a claimed antioxidant is very efficient and provides better results compared with other prior art antioxidants.).
Thus, for reasons of record, and for the reasons detailed above, the previous rejection under 35 USC 103 is hereby maintained and reproduced below. This action is FINAL.
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.
Claims 1, 3-9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Coates et al. U.S. Patent No. 7,855,211 B2 in view of Mallison et al. (Future Med. Chem. (2012) 4(11), pages 1409-1438 Provided on IDS).
Claims 1, 3-9 and 13 of the instant application claim a compound of formula (I) such as
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as well as a pharmaceutical composition comprising a therapeutically effective amount of said compound and a pharmaceutically acceptable carrier, diluent or excipient.
Coates teaches compounds of formula (I)
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useful as cyclin dependent kinase 4/6 inhibitors for the treatment of cancer (abstract and column 2 lines 1-67). Coates et al. further teaches a pharmaceutical formulation for treating cancer comprising a compound of formula (I) and a pharmaceutically acceptable carrier (column 7 lines 9-50). Coates et al. specifically teaches example 1
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and a composition comprising said compound (column 27 lines 1-20, claims 12 and 19).
Coates et al. does not teach macrocyclization of said compound to form a compound as claimed in the instant claims.
Mallison et al. demonstrates that macrocyclization of compounds were known in the art prior to the effective filing date of the instant claims. Mallison et al. teaches that conformational restriction, including cyclization of drug-like molecules is commonly used to improve potency towards a target such as CDK (pages 1412-1413). Mallison et al. teaches that macrocyclization could stabilize the bioactive conformation thus increasing binding affinity (page 1415). Mallison et al. teaches the potency of inhibitors can be retained or improved upon appropriate macrocyclization (page 1417). Mallison et al. further teaches common linking groups for macrocyclization including an amide linking group (page 1427 Table 23).
Accordingly, prior to the effective filing date of the instant invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Coates et al. which teaches the CDK4/6 inhibitor
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with the teachings of Mallison et al. which teaches that conformational restriction, including cyclization of drug-like molecules is commonly used to improve potency towards a target such as CDK and that macrocyclization could stabilize the bioactive conformation thus increasing binding affinity as well as the potency of inhibitors can be retained or improved upon appropriate macrocyclization. Therefore, a person of ordinary skill in the art would have been motivated to apply macrocyclization technology to the compounds of Coates et al. based on the teachings of Mallison et al. using a common linking group such as an amide linking group known in the art with a reasonable expectation of improving the properties of the compound. Therefore, a compound of formula (I) as claimed is rendered obvious in view of Coates et al. and Mallison et al. since a person of ordinary skill in the art would have been motivated to use a common linker motif as taught in Mallison et al. to prepare a cyclic compound of the CDK inhibitor of Coates with a reasonable expectation of predictable results leading to improved potency of the compound towards CDK.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1, 3-9 and 13 are rejected. Claim 2 is canceled. Claims 10-12, 14 and 15 are withdrawn. No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM