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 .
Status of the Claims
Claims 1-2, 6, 8, 10, 15, 17, 27-28, 33-34, 37, 42-43, 50-52, 77-78, 80, and 91-93 are pending in this application. Claims 3-5, 7, 9, 11-14, 16, 18-26, 29-32, 35-36, 38-41, 44-49, 53-76, 79, 81-86, and 87-90 have been cancelled by applicant. Claims 1-2, 6, 8, 10, 15, 17, 27-28, 33-34, 37, 42-43, 50-52, 77-78, and 91-93 are under examination herein. Claims 80 is withdrawn from consideration.
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 42-43 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.
Claim 42 is rejected for failing to further limit claim 1, from which it depends. Amended claim 1 limits R2 to not contain alpha-beta unsaturated carbonyl groups, while claim 42 refers to any nitrogen protecting group, which encompasses alpha-beta unsaturated carbonyl groups.
Claim 43 is rejected for depending upon the limitations of claim 42. While claim 50 is also dependent upon claim 42, it cures the deficiencies of the rejected claim, and thus it is not included in the rejection.
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 § 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.
Claim 77 is rejected under 35 U.S.C. 103 as being unpatentable over Marx et al. (WO 2020/146613 A1 – previously cited) (“Marx”).
Regarding claim 77, Marx discloses the compounds of Formula I below (pages 2-3), wherein in Y-R2 (corresponding to instant R1), Y (corresponding to instant –(L1)m1-O or –(L1)m1-NR30R31) can be a bond, O, or -NR5, wherein R5 (corresponding to instant -R30/ 31) can be H or C1-3 alkyl, and R2 can be H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc.; R3 (corresponding to R11 when instant J3 is C-R11) can be H, halogen, -CN, C1-3 alkyl, haloalkoxy, -OH, or alkoxy, etc.; L-R4 (corresponding to instant R3), L can be a bond, and R4 can be aryl or heteroaryl, substituted with one or more R6-7,9, wherein R6-7,9 can independently be H, halogen, -OH, alkyl, etc.; ring X (corresponding to instant R2) is a 4-12-membered monocyclic, bridged, or fused bicyclic ring; and R1 can be an alpha-beta unsaturated acyl group.
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Marx discloses their preferred embodiments below, which read on the instant claims when J1-2,4 are N; R12A is H; R1 is H or –(L1)m1-OR20, wherein m1 is 0 and R20 is a substituted C1 alkyl or an optionally substituted heterocycle; R11 is F; and instant R3 is a halogen or OH-substituted naphthalene.
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(c.1; page 39, row 1, middle) (c.2; page 41, row 3, right) (c.3; page 40, row 4, right)
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(page 450; Ex. 220)
Marx further discloses that their acryloyl protected compounds of Formula I (such as c.1-3 and Ex. 220 above) are prepared from the free base compound of Formula 5, as shown in their scheme II below (step E; page 55, top). Marx also discloses their compounds of Formula 5 (page 56, [0209]; and page 57, top), which are used as precursors for Formula I [0213]. Thus, while the instant claims require R2 to be a ring structure with a basic functional group with a pKa of a conjugated acid of the basic functional group to be > 5 and to not contain an alpha-beta unsaturated acyl group – like Marx’s acryloyl group – Marx also discloses the free bases corresponding to c. 1-3 above. Therefore, Marx renders the instant compounds obvious when instant R2 is
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or
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, since in order to prepare Marx’s compounds c.1-3, one would have had to first prepare the instantly claimed compounds with the free base nitrogen. Furthermore, Marx discloses their compounds and pharmaceutical compositions thereof as KRAS G12C inhibitors for the treatment of cancer (abstract and page 1), which is the same intended use as the instant compounds.
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(Formula 5)
Therefore, regarding instant claim 77, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Marx’s disclosed formulae; In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2144.08. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of KRAS inhibitor compounds disclosed by Marx for the treatment of cancers. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, including those encompassed by the claims. The compounds below, in particular, are obvious in view of Marx’s disclosure.
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Applicant is advised, with respect to the position of the nitrogens within the bicyclic core, that the courts have found that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. In re Norris, 179 F.2d. 970, 84 USPQ 458 (CCPA 1970). Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results. In re Finely, 81 USPQ 383 (CCPA 1949); 84 USPQ 458 (CCPA 1950).
Claims 1-2, 6, 8, 10, 15, 17, 27-28, 33-34, 37, 42-43, 50-52, 78, and 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Marx et al. (WO 2020/146613 A1 – previously cited) (“Marx”); as applied to claim 77; in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”).
The teachings of Marx are disclosed above and incorporated herein.
While Marx’s compounds require the group corresponding to instant R12A to not be H; the teachings of Meanwell are relied upon to leverage these differences.
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell teaches H and F as classical monovalent bioisosteres (Table 1, page 2530) and discloses that the unique properties of fluorine have led to its widespread application in drug design as an isostere for hydrogen, since incorporation of this halogen can productively modulate a range of properties of interest to medicinal chemists (section 3.1.5, page 2531).
Therefore, regarding claims 1-2, 91, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, particularly those of Formula I and I-9 in claim 2, since they are generically embraced by Marx’s disclosed formulae in view of Meanwell. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of KRAS inhibitor compounds for the treatment of cancer disclosed by Marx; in view of Meanwell’s teaching that the unique properties of fluorine have led to its widespread application in drug design as an isostere for hydrogen, since incorporation of this halogen can productively modulate a range of properties of interest to medicinal chemists. Accordingly, one having ordinary skill in the art would have been motivated to substitute H for F in Marx’s generic formulae to arrive at the claimed invention, in view of Meanwell.
Regarding claim 6, Marx discloses the compounds c.1-3 above, wherein the group corresponding to instant R11 is F.
Regarding claim 8, Marx in view of Meanwell discloses the compounds c.1-3 above, wherein the group corresponding to instant R12 is absent, and R12A is hydrogen. Therefore, in view of Meanwell, as disclosed above, one would have been motivated to substitute H for F to arrive at the claimed invention. Applicant is advised, the instant claim reads, “wherein when present, R12 in Formula I is H…” – however, R12 is not present in this compound, and therefore, the claim language “when present” allows for this limitation to be optional when R12 is not present.
Regarding claims 10, 17, and 92-93, Marx discloses the compound c.1 and c.2 above, wherein the group corresponding to instant R1 is
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and
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, respectively, corresponding to -O-R20, wherein R20 is C1-alkylene-R101, wherein R101 is an unsubstituted and fluoro-substituted 8-membered heterocycle, respectively (reading on 4-10 membered heterocycle). Further regarding claims 92-93, Marx discloses their group corresponding to instant R3 as
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(see example 220 above); and the group corresponding to R2 as
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– thus rendering the instant claims obvious.
Regarding claim 15, Marx discloses the compound c.1 above, wherein the group corresponding to instant R101 is
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.
Regarding claims 27-28 and 33, Marx discloses their compound c.1. above, wherein the group corresponding to instant R1 is
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, anticipating the instant claims wherein q = 1; R16 together with R36 and the carbon and nitrogen to which they are respectively bonded, form a 5-member ring; and R15 together with R37 and the carbon and nitrogen to which they are respectively bonded, form a second 5-member ring; thus, resulting in an 8-member fused bicyclic ring.
Regarding claim 34, Marx discloses their compounds c.1. and c.2. above, wherein the groups corresponding to instant R2 are piperazines (6-member heterocycles with 2 nitrogens), reading on m2 = 0.
Regarding claim 37, Marx discloses that their acryloyl protected compounds of Formula I (such as c.1-3 above) are prepared from the free base compound of Formula 5, as shown above. Therefore, Marx renders the instant compounds obvious when R102 is
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or
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.
Regarding claims 42-43, Marx discloses their compounds c.3. above, wherein the group corresponding to instant R1 is H; and R2 is a bridged system. Marx’s compound renders the instant claim obvious when G1 is N, G3 is NR38, wherein R38 is an acyl amine protecting group (acryloyl – see 112(d) rejection for claim 42); A1 and A2 are CR18R19, wherein R18 and R19 are H; n2 = 2; and G2 is CR18R19, wherein R18 and R19 are H.
Regarding claim 50, Marx discloses their compound of Formula 5 above, as a precursor for their compounds of Formula I, such as c.3. Therefore, Marx’s discloses the instantly claimed compound wherein R2 is
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.
Regarding claim 51, Marx discloses their compounds c.1-3 above, wherein the groups corresponding to instant R3 are substituted naphthyl.
Regarding claim 52, Marx discloses their compounds c.1-3 above, wherein the groups corresponding to instant R3 are
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.
Regarding claim 78, Marx discloses pharmaceutical compositions comprising their compounds and a pharmaceutically acceptable excipient ([0030]; and Marx’s claim 76).
Further regarding claim 91, Marx in view of Meanwell reads on the instant compounds when R11 is F; R12A is F; R1 is as defined in (1)(v); R2 is as defined in (A) – piperazine and/or (B) – bridged piperazine; and R3 is (y) – a substituted naphthyl.
Response to Arguments
Claims
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see page 47, filed 02/27/2026, with respect to 35 USC § 112(b) rejections of the claims have been fully considered and are persuasive. The 35 USC § 112(b) rejections of the claims have been withdrawn.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see pages 47-48, filed 02/27/2026, with respect to 35 USC § 102 rejections of the claims have been fully considered and are persuasive. The 35 USC § 102 rejections of the claims have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments, see pages 47-48, filed 02/27/2026, with respect to 35 USC § 103 rejections of the claims have been fully considered and are persuasive for all claims except 77. The 35 USC § 103 rejections of the claims in view of Marx have been withdrawn for all claims, except claim 77, which is still rejected in view of Marx. However, upon further consideration, a new ground(s) of rejection is made in view of Marx and Meanwell.
With regards to claim 77, Applicant argues the compounds of this claim have a different core. Applicant is reminded that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results. See 103-rejections presented herein.
Double Patenting
Applicant’s arguments, see page 49, filed 02/27/2026, with respect to provisional non-statutory double patenting (NSDP) rejections of the claims have been fully considered and are persuasive. The provisional NSDP rejections of the claims have been withdrawn.
Conclusion
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 JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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