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 .
Status of Claims and Response to Amendments
The amendments filed January 24, 2025 have been acknowledged and entered. Claims 1-3, 6-20, 22-23 and 25-29 are pending.
Terminal Disclaimer
The terminal disclaimer filed on January 31, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Number 12,122,787 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Information Disclosure Statements
Acknowledgement is made of the Information Disclosure Statement filed on January 24, 2025. All references have been considered except where marked with a strikethrough.
Election/Restriction
The present examination is based on Applicant’s election with traverse of Group I, presently claims 1-3, 6-20, 22-23, 25 and 28-29 and species of Formula (I-B) in the reply filed June 17, 2024. Applicant traverses the restriction pursuant to section 803(I)(B) of the M.P.E.P., which states that a "requirement for restriction" is "proper" when "[t]here would be a serious burden on the examiner if restriction is not required." Applicant's traversal is based on its likelihood that a search relating to the claimed invention of one group will identify any references that are material to the claimed invention of the other groups. In the instant case, claims 26 and 27 are dependent, ultimately, from compound claim 1, and therefore incorporate all the limitations of claim 1. Therefore, it is respectfully submitted that a search for the two claim groups would not pose an undue burden on the Patent Office. The traversal is thus on the grounds that there is no undue burden. Examiner respectfully disagrees for at least the reason that method claims 26-27 require additional search limitations that are not required by the elected compound of Formula (I-B). Method claim 26, for instance, is so broad as to be drawn to a generic method of treating cancer and therefore has additional considerations that are not required by the elected group.
Therefore this restriction is considered proper and thus made FINAL.
Applicant amendments filed January 24, 2025 overcame the art rejection set forth in the previous office action. The search has been expanded to include the entire scope of Formula (I-B).
Priority
Examiner notes that Applicant acknowledges the provisions of 37 CFR 41. l 54(b) cited in the previous Office Action and will take appropriate action should the need for translations arise. Because no English translations of the priority documents have been provided, the effective filing date of the instant claims is September 21, 2020.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this Office Action has been withdrawn or rendered moot in view of Applicant’s amendments and/or
remarks.
Claims Objections
Claim 3 is objected to because of the following informalities:
Claim 3 are objected to as for having extraneous text. The phrase “X1, X2, R1, R2…ring A and n are as defined in claim 1” is extraneous because the definitions of each of these variables carry over from claim 1. The extraneous phrases should be deleted. Appropriate correction is required.
Maintained Rejections
Claim Rejections - 35 USC § 112(a)
Claims 1-3, 6-20, 22-23 and 25 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for a compound, an optical isomer or a pharmaceutically acceptable salt of formula (I-B) where R1 and R2 are H; R10 is H or halogen; T1 is C(R8) where R8 is halogen; X1 is -C(R7)= or -C(R7)2-; and R3 is C1-3alkyl; does not reasonably provide enablement for all of the other R, T1, X1, m or n variables listed within the broad Claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims
The reasons for this rejection were set forth in the previous Office Action mailed July 26, 2024 and are incorporated herein by reference.
Response to Arguments
Applicant' s arguments filed January 24, 2025 have been fully considered but they are not persuasive.
Applicant argues that the claim amendments have sufficiently narrowed the scope of the claims that one of skill in the art could, upon review of Applicant's specification, practice the full scope of the invention without undue experimentation. Applicant notes that the invention relates to organic chemical compounds and their activity as KRAS inhibitors. The person of skill in the art would be highly skilled as a medicinal chemist, able to follow instructions provided in the specification without undue experimentation. One skilled in the art would furthermore be able to test synthesized compounds following the general guidance provided in the examples without undue experimentation (page 27 of remarks).
Applicant arguments are not found persuasive because the direction provided by Applicant and scope of compounds prepared represents a very narrow subgenus of Formula (I-B) presently claimed. Applicant is not enabled for the full scope of R5, R6, R7, R8 and R9 for the reason that chemistry is unpredictable and the compounds prepared and tested in no way represent the full scope of what is claimed. Upon examination of the specification, it appears that support is only provided for Formula (I-B) wherein R5 is a pyridinyl; pyrimidinyl; or phenyl; R6 is C1-6 alkyl, C1-6 alkyl substituted with one group selected from
PNG
media_image1.png
51
51
media_image1.png
Greyscale
, -OH, halogen, -COOH, -CONH2 or -CO2CH3; C3 cycloalkyl-C(=O)-; or 3-6 membered heterocycloalkyl; R7 is H; R8 is a halogen; and R9 is H, alkyl, halo, haloalkyl. Applicant, for instance, has prepared no compounds wherein R6 is an alkyl substituted with any 5-6 membered heterocycloalkyl ring. Nor has applicant prepared any compounds R5 is benzo 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-fused 5-6 membered heterocycloalkyl. Chemistry is unpredictable, syntheses often fail, and given that the support provided in the specification does not represent the full scope of what is claimed, one could not practice the full scope of the invention without undue and unreasonable experimentation.
Applicant additionally argues, with these examples, one of skill in the art would be able to adjust the synthetic examples to prepare other compounds within the scope of the claims, using no more than ordinary skill and without engaging in undue experimentation. Following the examples, the skilled person would then be able to test those compounds for KRAS inhibitory activity and would have had a high degree of confidence that such compounds, or at least a large percentage of those compounds, would possess KRAS inhibitor activity.
Examiner respectfully disagrees for the reason that the starting materials, and therefore chemical reactions, required to practice the full scope of the invention are not represented by the examples prepared by Applicant. No starting materials nor chemical reactions or schemes have been provided to show, for instance, how one skilled in the art would prepare Formula (I-B) wherein R6 is a C1-6 alkyl substituted with C1-6 heterocycloalkyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, or C3-6 cycloalkyl-O-. Similarly, no starting materials nor chemical reactions or schemes have been provided to show how one skilled in the art would prepare Formula (I-B) wherein R5 is cycloalkyl or heterocycloalkyl. As noted above, R5 is always an aromatic group which chemically is very different that a non-aromatic group such as cycloalkyl or heterocycloalkyl. Applicant seems to be arguing that it is appropriate to require a person skilled in the art to first figure out how to make the claimed invention and then screen the invention to see if it has the claimed activity; however, this degree of experimentation is undue and unreasonable at least for the reason that chemical reactivity is unpredictable and syntheses often fails.
This rejection is still deemed proper and maintained.
Rejections Necessitated by Applicant Amendment
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.
Claim 1-3, 6-20, 22-23, 25 and 28-29 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. The claims are indefinite for the reason that follow:
Claim 1 recites “wherein the C1-6 alkyl” (see definitions of R5). There is insufficient antecedent basis for this limitation because R5, as amended, can no longer be C1-6 alkyl. Appropriate correction is required.
Claim 1 has been amended to recite m is 0 or 1. This limitation is indefinite because R3 can be H and therefore m cannot be 0 or 1. Because R3 is H, m must always be 4. Take for example the compound of claim 28, which depends from claim 1, pictured below. In the highlighted structure, m is 4 where three R3 groups are H and the fourth R3 group is C1 alkyl. Appropriate correction is required.
PNG
media_image2.png
200
400
media_image2.png
Greyscale
Claims 2-3, 6-20, 22-23 and 25 depend from claim 1, do not cure the above mentioned deficiency, and are thus also indefinite.
Claims 8-9 require the limitation R3 is halogen. There is insufficient antecedent basis for this limitation because claims 8-9 depend from claim 1 which, as amended, requires that R3 is H or C1-6 alkyl.
Claims 10-11 require the limitation R4 is C1-3 alkoxy. There is insufficient antecedent basis for this limitation because claims 10-11 depend from claim 1 which, as amended, does not allow R4 to be C1-3 alkoxy.
Claims 14 requires the limitation R5 is C1-3 alkyl. There is insufficient antecedent basis for this limitation because claim 14 depends from claim 1 which, as amended, does not allow R5 to be C1-3 alkyl.
Claims 18-19 require the limitation R6 is H. There is insufficient antecedent basis for this limitation because claims 18-19 depends from claim 1 which, as amended, does not allow R6 to be H.
Claim 23 is drawn to structures wherein the group corresponding to R6 is CN, or X2 is SO or SO2. These structures (examples pictured below) lack antecedent basis because claim 23 depends from claim 1 which, as amended, does not allow R6 to be CN or for X2 to be S=O or SO2.
PNG
media_image3.png
200
400
media_image3.png
Greyscale
PNG
media_image4.png
170
300
media_image4.png
Greyscale
Claim 28 is drawn to compounds of Formula (I) which lack antecedent basis because the compounds have R6 groups not recited in amended claim 1. In the example compounds pictured below, R6 is CN, C1 or C3 alkyl; however, R6 in amended claim 1 cannot be CN, C1 alkyl or C3 alkyl.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
PNG
media_image6.png
200
400
media_image6.png
Greyscale
Claims 28 and 29 depend from claim 1 and recite compounds of Formula (I-B) wherein R3 is H or C1 alkyl and m is 4 (highlighted in the compound of claim 29 below). There is insufficient antecedent basis for the compounds of claims 28 and 29 because claim 1 requires that m is 0 or 1.
PNG
media_image7.png
200
400
media_image7.png
Greyscale
Claim 28 is further indefinite because many of the claimed structures are blurry and illegible, and therefore the claimed structures are ambiguous. See for example all compounds listed on page 19 of the claims. The metes and bounds cannot be ascertained. Examiner suggests submitting new claims with clear and unambiguous structures.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8-11, 14, 18-19, 23 and 28-29 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Each of claims 8-11, 14, 18-19, 23 and 28-29 depend directly or indirectly from claim 1 and are drawn to limitations beyond the scope of amended Formula (I-B). The claims are therefore broader in scope that Formula (I-B) and are rejected for failing to further limit the claim from which they depend. See details below.
Claims 8-9 require the limitation R3 is halogen which is not required by claim 1.
Claims 10-11 require the limitation R4 is C1-3 alkoxy which is not required by claim 1.
Claims 14 requires the limitation R5 is C1-3 alkyl which is not required by claim 1.
Claims 18-19 require the limitation R6 is H which is not required by claim 1.
Claim 23 is drawn to structures wherein the group corresponding to R6 is CN, or X2 is SO or SO2. These R6 groups are not required by claim 1.
PNG
media_image3.png
200
400
media_image3.png
Greyscale
PNG
media_image4.png
170
300
media_image4.png
Greyscale
Claim 28 is drawn to compounds of Formula (I) which have R6 groups not recited in claim 1. In the example compounds pictured below, R6 is CN, C1 and C3 alkyl; however, R6 in amended claim 1 cannot be CN, C1 or C3 alkyl.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
PNG
media_image6.png
200
400
media_image6.png
Greyscale
Claims 28 and 29 depend from claim 1 and recite compounds of Formula (I-B) wherein R3 is H or C1 alkyl and m is 4 (highlighted in the compound of claim 29 above). However, the claim 1 requires that m is 0 or 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 6-15, 18-20, 22-23, and 25 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Zhou et al. (US 12,054,497 B2; effectively filed October 30, 2019).
Zhou teaches compounds Z152 (col 128, pictured below for convenience) which corresponds to instant Formula (I-B) wherein A is a C6 aryl; n is 2 and R4 is -OH and halogen (F); T1 and T2 are each -C(R8)- where R8 is halogen (Cl or F); R5 is 6 membered heteroaryl (pyrimidinyl) substituted with two C1-6 alkyl (isopropyl); X1 is -C(=O)-; X2 is -N(R6) wherein R6 is C2 alkyl substituted with
PNG
media_image1.png
51
51
media_image1.png
Greyscale
; Y is N; R3 is H and m is 1; L1 is -C(=O)-; each of R1, R2 and R10 is H;
PNG
media_image8.png
48
110
media_image8.png
Greyscale
and
PNG
media_image9.png
48
176
media_image9.png
Greyscale
. Zhou further teaches a pharmaceutical composition comprising Z152 (Abstract).
PNG
media_image10.png
200
400
media_image10.png
Greyscale
Claim Rejections - 35 USC § 103
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, 6-20, 22-23, 25, and 28 are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Zhou et al. (US 12,054,497 B2; effectively filed October 30, 2019).
Zhou teaches a generic group of compounds which embraces Applicants’ claimed compounds (See col 1-7) for use as pharmaceuticals and compositions for the treatment of cancer (see Abstract). The claims differ from the reference by reciting specific species and a more limited genus than the reference. However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the instant application to select any of the species of the genus taught by the reference, including those instantly claimed, because the skilled chemist would have the reasonable expectation that any of the species of the genus would have similar properties and, thus, the same use as taught for the genus as a whole. One of ordinary skill in the art would have been motivated to select the claimed compounds from the genus in the reference since such compounds would have been suggested by the reference as a whole. It has been held that a prior art disclosed genus of useful compounds is sufficient to render prima facie obvious a species falling within a genus. In re Susi, 440 F.2d 442, 169 USPQ 423, 425 (CCPA 1971), followed by the Federal Circuit in Merck & Co. v. Biocraft Laboratories, 847 F.2d 804, 10 USPQ 2d 1843, 1846 (Fed. Cir. 1989).”
In particular, Zhou teaches compounds Z10 and Z157 (cols 84 and 129, pictured below for convenience) which corresponds to instant Formula (I-B) wherein A is a C6 aryl; n is 2 and R4 is -OH and halogen (F); T1 is N; T2 is -C(R8)- where R8 is halogen (F); R5 is 6 membered heteroaryl (pyridinyl) substituted with two C1-6 alkyl (methyl and isopropyl); X1 is -C(=O)- or C(R7)2 wherein R7 is H; X2 is -N(R6) wherein R6 is C1 alkyl; Y is N; R3 is H or C1 alkyl and m is 1; L1 is -C(=O)-; each of R1, R2 and R10 is H;
PNG
media_image8.png
48
110
media_image8.png
Greyscale
and
PNG
media_image9.png
48
176
media_image9.png
Greyscale
. Zhou further teaches the genus of I-1 (col 6, pictured below for convenience) which provides that the C1 alkyl group corresponding to instant R6 can be substituted with a halogen (see col 7, lines 15-25: In Formula I-1, P is NRm wherein Rm is halogenated C1 alkyl). Zhou therefore teaches the equivalence of C1 alkyl and C1 alkyl substituted with halogen at the position of R6 of the instant claims.
PNG
media_image11.png
200
400
media_image11.png
Greyscale
The difference between the prior art and the instant claims is that the instant claims require that R6 is C1 alkyl substituted with halogen. However, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant claims to modify the C1 alkyl group of compound Z10 or Z157 with halogen, as is required by the instant claims, because Zhou had disclosed that C1 alkyl and C1 alkyl substituted with halogen where equivalent groups at the position corresponding to R6 of the instant claims.
One would have been motivated as a matter of making additional compounds to treat cancer.
One would have had a reasonable expectation of success because Zhou had already disclosed that C1 alkyl and C1 alkyl substituted with halogen where equivalent groups at the position corresponding to R6 of the instant claims and therefore there would have been an expectation that such a modification would result in a compound useful for treating cancer.
Examiner further notes that Zhou teaches many additional groups which correspond to instant R6 (see col 6, P is C1-6 alkylhydroxy, C1-6 alkylcyano….). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to also modify compound Z10 or Z157 with any of these groups to arrive at the instant claims for the reasons indicated above. Similarly, Zhou teaches many additional compounds which differ from the instant claims by a single group (e.g. R6) which is taught by Zhou. See, e.g., compounds Z111, Z112, Z114…(col 115-116) and generic teachings of Formula I-1. The instant claims are also obvious over these compounds for the reasons provided in this rejection.
Conclusion
No claim is 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 KEVIN MARTIN whose telephone number is (571)270-0917. The examiner can normally be reached Monday - Friday 8 am - 5 pm.
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, Jeffrey Murray can be reached on (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
May 13, 2025
/K.S.M./Examiner, Art Unit 1624
/BRUCK KIFLE/Primary Examiner, Art Unit 1624