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 with traverse of Group I, claims 1-12, drawn to a compound represented by formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, and a pharmaceutical composition; and the compound having the structure of:
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as the elected species of compound represented by formula (I) are maintained.
Claims 13-15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking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.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on July 6, 2026, wherein claims 1 and 3-8 are amended; claims 2 and 9-15 are unchanged; and claims 16-20 are newly added.
Claims 1-20 are pending.
Claims 13-15 are withdrawn.
Claims 1-12 and 16-20 are under examination in accordance with the elected species.
Priority
The instant application 18/282,082 filed on September 14, 2023 is a 371 of PCT/CN2022/081599 filed on March 18, 2022, which claims priority to, and the benefits of Foreign Application No.
CN202110296394.X filed on March 19, 2021.
Action Summary
Applicant’s amendment to the claims filed on July 6, 2026 overcome each and every objection previously set forth in the Non-Final Office Action mailed on April 3, 2026.
Claims 3-6 and 8 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in view of the claim amendments.
Claims 1-12 rejected and claims 16-20 are under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 101824029 A) are maintained, but revisited and modified in view 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 1-12 remain rejected and claims 16-20 are under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 101824029 A) (partially newly applied as necessitated by amendments).
Please note Zhang et al. is in written in Chinese and a machine translation has been provided, the specific portions cited in this instant office action will refer to the sections of the machine translation.
Zhang et al. teaches a compound having the structure of:
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, wherein R6 is methoxy (referred to herein as Compound 1) is an exemplary tyrosine kinase irreversible inhibitor of general formula (I) (see e.g., claims 1 and 7). Zhang et al. further teaches a drug composition for the treatment or prevention of cell proliferation disorders, including therapeutic effective amounts of the above-mentioned tyrosine kinase irreversible inhibitors and pharmaceutically available carriers (see e.g., p. 10, line 12-15 of machine translation). Zhang et al. further teaches the tyrosine kinase irreversible inhibitors of general formula (I):
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, wherein R7 is H or C1-6 alkyl groups (see e.g., claim 1). Zhang et al. further teaches C1-6 alkyl groups represent linear or branched-chain alkyl groups, such as methyl or ethyl (see e.g., p. 12, last 2 lines). Zhang et al. further teaches the compound can be combined with conventional cancer treatments such as chemotherapy or radiotherapy (see e.g., p. 11, line 26-27).
Zhang et al. does not teach the elected species of compound represented by formula (I).
According to MPEP 2144.09, “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)”. According to MPEP 2144.09 (II) and (III), ”[c]ompounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977) … Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979)”. In the present case, the difference between the compound 1 of Zhang et al. and the elected compound species instantly claimed is that the prior art compound has methyl at R7 rather than ethyl, and the methoxy is at the 7-position rather than 5-position of the quinazoline ring (
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) shown below (see shaded):
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. 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 selecting compound 1 of Zhang et al., and then modify said compound by substituting methyl with ethyl as C1-6 alkyl groups at R7, and then make the instantly claimed derivatives by changing the point of attachment for the methoxy. The claimed compound and the prior art compound are common derivatives known as isomers. One would have been motivated to do so, because Zhang et al. teaches methyl and ethyl can be interchanged as the C1-6 alkyl groups at R7 to arrive at a tyrosine kinase irreversible inhibitor. One would have also been motivated to do so in order to prepare similar compounds that are pharmacologically active compounds useful for inhibiting tyrosine kinase. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the position isomers (compounds having the same radicals in physically different positions on the same nucleus) of the modified compound 1 of Zhang et al., which substitutes methyl with ethyl at R7, would have exerted the same or substantially similar tyrosine kinase irreversible inhibiting affect; and therefore, said modified compound 1 can successfully be combine with a pharmaceutically acceptable carrier to arrive at a drug composition. Please note the fact that Zhang et al. teaches racemic mixture of compound 1, it renders obvious the limitation of “
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” recites in claim 10.
Regarding the limitation of “wherein the pharmaceutical composition also contains one or more other therapeutic agents” in claim 12, 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 drug composition set forth above by combining said drug composition with a chemotherapy as the conventional cancer treatments. One would have been motivated to do so, because Zhang et al. teaches the tyrosine kinase irreversible inhibitor can be combined with conventional cancer treatments, such as chemotherapy. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the drug composition comprising the modified compound 1 of Zhang et al. set forth above and a pharmaceutically acceptable carrier and chemotherapy can successfully be combined without any appreciable loss of activity, and that renders obvious the limitation of “contains one or more other therapeutic agents”.
Please note the modified compound 1 of Zhang et al. set forth above is a compound represent by instant formula (I):
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, wherein Z is -NH-; T1 is –(CH2)1-; R1 is
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(i.e., 2-ethylpyrrolidin-2-yl); L is O; R2 is -CH3; R4 is -Cl (i.e., halogen); T2 is -O-CH2-; and R3 is
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(i.e., pyridyin-2-yl).
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 July 6, 2026 with respect to the rejection of claims 1-12 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 101824029 A) have been fully considered but they are not persuasive.
Applicant newly added claims 16-20.
In Summary, Applicant argues the compounds of Zhang et al. has substituent added to the 7-position of the quinazoline core rather than the 5-position instantly claimed, and it is conventional in the art to introduce substituents at the 7-position in developing TKI inhibitors; and therefore, there is no motivation for a person to substitute at the 5-position of the quinazoline core, and said substitution is beyond the scope of the Markush formula taught by Zhang et al. and would not have led to predictable results. Applicant further argues the claimed invention demonstrates unexpected properties by directing attention to Table 11-1 of the specification. Specifically, applicant argues the Compound of Example 29 disclosed therein exhibits excellent ability to penetrate the blood-brain barrier (Brain tissue/blood ratio: 0.360) when comparing to control compound 2 having the structure of:
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(lacking substituents at both the 5- and 7-positions) and pyrotinib having the structure of:
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(bearing a substituent at the 7-position).
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, with respect to applicant’s argument that there is no teaching, suggestion, or motivation to arrive at the isomers of Zhang et al. because its general formula (I) does not explicitly teach attaching R6 substituent at the 5 position of quinazoline core (
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), such arguments are not found persuasive. The examiner recognizes that obviousness may be established by modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the obviousness-type rejection is form on the basis that chemical compounds with close structural similarities and function entails the motivation of one skilled in the art to arrive at the claimed invention in the expectation that compounds similar in structure will have similar properties of inhibiting tyrosine kinase enzymes. See In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979) and In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) cited in the rejection of record. Particularly, the Examiner has established that the compounds having the same radical in physically different position on the same nucleus are position isomer that are sufficiently close in structural and there is a presumed expectation that such compounds would possess similar properties inhibiting tyrosine kinase enzymes. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977) and In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) cited in the rejection of record. Given that applicant has not provided any factual evidence supporting that the position isomers of Zhang et al. provides a substantial degree of unpredictability, for example, possessed the opposite utility or abolished the properties of inhibiting tyrosine kinase enzymes, applicant’s assertion that changing the position of methoxy of compound 1 of Zhang et al. from the 7-position to the 5-position of quinazoline ring leads to unpredictable result appears to be mere argument without supporting evidence.
Second, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
The unexpected results which applicant relies upon (i.e., better ability to penetrate the blood-brain barrier) are demonstrated using Compound of Example 13 and Compound of Example 29 in Table 11-1 (see e.g., p. 60 of the specification), in which Example 13 has the structure of:
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with a brain tissue/blood ratio of 0.465 (see e.g., [00163]; Table 11-1); and Example 29 has the structure of:
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with a brain tissue/blood ratio of 0.360 (see e.g., [00195]; Table 11-1).
In contrast, instant claims broadly recite a compound represented by formula (I)
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, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof; and the structure formula includes a wide variety of L, T1-T2, Z, and R1-R4 combinations. However, it is respectfully noted that Applicant only exemplified the results using a finite species of compound represented by formula (I), which contains substituted pyrrolidinyl ring at R1, L is -O-, and R2 is alkyl; R3 is pyridinyl; T2 is -O-CH2-; and T1 is absent. For instance, instant claims encompass a wide variety of R1, including a genus of -NRaRb, and a genus of unsubstituted or substituted 4- to 7-memebred group containing 1-2 heteroatoms selected from N, O and S; and a wide variety of R2, including alkyl substituted with cycloalkyl or 4- to 6-membered heteroalicyclic group. In other words, the disclosed data are limited to selected compounds and does not provide adequate basis to establish that structurally diverse alternatives encompassed by instant formula (I) would possess the asserted results of enhancing penetration to the blood-brain barrier.
Lastly, the comparison data recited in Table 11-1 of the specification does not appear to be a true comparison between the claimed invention with the closest prior art to establish that interchanging the position of R6 substituent (i.e., methoxy of Compound 1 of Zhang et al.) from the 7-position to the 5-position of quinazoline ring alone lead to unexpected results. In this case, applicant specifically compares the compound of Example 29 with pyratinib and control compound 2, respectively, to establish said compound with a substituent added to the 5-position of quinazoline ring has comparatively better ability to penetrate the blood-brain barrier; However, when comparing these compounds side-by-side shown below (see shaded):
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. As illustrated above, the difference between the control compound 2 and the claimed compound (i.e., compound of Example 29) is that the control compound 2 contains (i) a methyl substituent rather than ethyl on the pynolidinyl ring; (ii) has different stereochemistry, (2S)-1-methyl-2-pyrrolidinyl-(2E)- propenamide rather than (2R)-1-ethyl-2-pyrrolidinyl-(2E)-2-propenamide; and (iii) has no additional substituent(s) added to the quinazoline core whereas the claimed compound has methoxy added to the 5-position of the quinazoline core. While the specification demonstrates the compound of Example 29 has a brain tissue/blood ratio of 0.360 whereas the control compound 2 has a value that is too low to be counted, it is not clear whether control compound 2’s poor brain tissue/blood ratio is attributable to the change in stereochemistry, the lack of additional substituent(s) added to the quinazoline core, the methyl substituent added to the pynolidinyl ring, or all of them together. Furthermore, the difference between the pyrotinib and the claimed compound (i.e., compound of Example 29) is that the pyrotinib contains (i) quinoline core
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rather than the quinazoline instantly claimed
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; (ii) has ethoxy substituent rather than methoxy added to the 7- position rather than the 5-position of the core; (iii) a methyl substituent rather than ethyl on the pynolidinyl ring; and (iv) has a cyano (-CN) added to the 3-position of the quinoline core. While the specification demonstrates the compound of Example 29 has a brain tissue/blood ratio of 0.360, which is better than pyratinib’s brain tissue/blood ratio of 0.0291, it is also not clear whether pyratinib’s poor brain tissue/blood ratio is attributable to the change in quinoline core, the addition of cyano substituent at the 3-position of the quinoline core, the addition of methoxyethyl substituent at the 7-position of the quinoline core, the methyl substituent on the pynolidinyl ring, the ethyl on the ethoxy group attached to the 7-position of the quinoline core, or all of them together. In view of the foregoing, the comparison group applicant relies upon has more than once difference when compared to the claimed compound; and therefore, it is apparent that changing the position of the R6 substituents where it attaches to the quinazoline core alone can enhance the ability of penetrating the blood-brain barrier.
In view of all the foregoing, applicant’s arguments are not found persuasive; therefore, the rejection of record has been revisited and modified in view of the claim amendments.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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