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 of Group I, claims 1-34 and 38-39, drawn to a compound represented by the structure of formula I or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutical composition comprising the therapeutically effective amount of the compound; and the following species:
Compound 66 having the structure of:
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as the elected compound species represented by the structure of formula I
are maintained.
Claims 40-46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the elected compound species:
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. In light of this discovery, the search was expanded to the subject matter of the full scope of the compound of the formula (I). Therefore, the restriction requirement among the compound species of Formula (I) as set forth in the Office action mailed on March 5, 2025 is hereby withdrawn. Claims 3, 6-9, 12-15, 19-21, 25-28, 30-31 and 33, directed to the compound species non-elected, hereby rejoined and fully examined for patentability.
Priority
The instant application 17/926,074 filed on November 17, 2022 is a 371 of PCT/US2021/033328 filed on May 20, 2021, which claims priority to, and the benefits of U.S. Provisional Application No.
63/028,011 filed on May 21, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 23, 2025, wherein claims 1, 2, 23, 34 and 38-40 are amended; claims 3-22, 24-33 and 41-46 are unchanged; and claims 35-37 are cancelled.
Claims 1-34 and 38-46 are pending.
Claims 40-46 remain withdrawn.
Claims 1-34, and 38-39 are under examination.
Action Summary
Claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement are withdrawn in light of the claim amendments.
Claim 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34 and 38-39 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 light of the claim amendments.
Claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives are withdrawn, but reapplied for the reasons sets forth herein.
Claims 1-2, 4, 10-11, 16-18, 23-24 and 39 rejected under 35 U.S.C. 102(a)(2) as being anticipated by Verano et al. (WO 2020/117759 A1) are withdrawn in light of the statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, i.e., May 21, 2020, the subject matter disclosed in the reference and the claimed invention were owned by the same entity, i.e., Dana-Farber Cancer Institute, Inc., or subject to an obligation of assignment to the same entity, i.e., Dana-Farber Cancer Institute, Inc.
Claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 rejected under 35 U.S.C. 103 as being unpatentable over Verano et al. (WO 2020/117759 A1; cited in the IDS filed on November 17, 2022), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are withdrawn in light of the statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, i.e., May 21, 2020, the subject matter disclosed in Verano et al. and the claimed invention were owned by the same entity, i.e., Dana-Farber Cancer Institute, Inc., or subject to an obligation of assignment to the same entity, i.e., Dana-Farber Cancer Institute, Inc.
Claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 38 and 41-42 of U.S. Patent No. 12,227,488 B2 (reference patent) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are withdrawn, but reapplied for the reasons sets forth herein.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-33 and 39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claim 1 recites “[a] compound species represented by a structure of formula I:
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or a pharmaceutically acceptable salt or stereoisomer thereof: wherein…Y1 is
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…
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… two R6 when on different nitrogen atoms, together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl group… R6 and R7, together with the atoms to which they are attached form a 4- to 8-membered heterocycloalkyl group… R7 and R7', when on different carbon atoms, together with the atoms to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group”. It is noted that multiple substituent(s) on different atoms can be joined together to form a cycloalkyl or heterocycloalkyl; However, the specification does not disclose a representative number of species that has one of these indicated substituent(s) joined together, for instance, there is no compound species composed of two R6 on different nitrogen atoms that are joined together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl group.
Regarding the requirement for adequate written description of chemical entities, Applicant's attention is directed to the MPEP §2163. In particular, Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plain for obtaining the claimed chemical invention." Eli Lilly, 119 F.3d at 1566. The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office ("PTO") Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.I "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5,2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter alia, "functional characteristics when coupled with a known or disclosed correlation between function and structure ..." Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)). Moreover, although Eli Lilly and Enzo were decided within the factual context of DNA sequences, this does not preclude extending the reasoning of those cases to chemical structures in general. Univ. of Rochester v G.D. Searle & Co., 249 Supp. 2d 216, 225 (W.D.N.Y. 2003).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
In the present case, applicant discloses compounds (1)-(89) (see [00128] of the specification); However, none of these compounds has a 4- to 7-membered heterocycloalkyl group form by two R6 on different nitrogen atoms; none of these compounds has a 4- to 8-membered heterocycloalkyl group form by R6 and R7; and none of these compounds has a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group form by R7 and R7' on different carbon atoms.
In the absence of a sufficient variety of species to reflect the variation within the genus, it is not apparent that applicant was actually in possession of the entire genus of compound represented by a structure of formula I, including those that has two of the indicated substituent(s), such as two R6, joined together to from a cycloalkyl or heterocycloalkyl group based on the limited disclosure provided.
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 is 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.
Regarding claim 1, the term “adjacent” recites in the claims, for instance, in the phrase of”
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” renders the claim indefinite, because the term “adjacent" is a relative term used to refer to something is located next to, bordering, or near a specific reference point or object. The term “adjacent” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, it is not clear what is considered adjacent or non-adjacent atoms. It is further noted that
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 4 and 10 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.
Regarding claims 4, the recitation of “R5 and R5’ are absent” fails to further limit the R5 and R5’ sets forth in claim 1. It is noted that the amendments to claim 1 deletes “absent” from R5 and R5’ ; and therefore, R5 and R5’ cannot selected from the list that includes “absent”.
Regarding claims 10, the recitation of “R7 and R7’ are absent” fails to further limit the R7 and R7’ sets forth in claim 1. It is noted that the amendments to claim 1 deletes “absent” from R7 and R7’ ; and therefore, R7 and R7’ cannot selected from the list that includes “absent”.
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.
Claims 1-34 and 38-39 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) The species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The Markush grouping of compound species represented by a structure of formula I is improper because the alternatives defined by the Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
Instant claim 1 recites “[a] compound species represented by a structure of formula I:
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or a pharmaceutically acceptable salt or stereoisomer thereof: wherein: R2 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl; R2’ is (C1-C6alkyl), or (C1-C6)haloalkyl, or R2 and R2’ together form =O; each R3 is independently hydrogen, halogen, (C1-C6)alkyl, or (C1-C6)haloalkyl; X is -NR6- or -C(R5)2-; Y1 is
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…
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”. The Markush grouping of compound species represented by the structure of formula I are improper, because the compound species are composed of different
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, X, and Y1 moieties that do not share a substantial feature and/or a common use (treating the entire scope of disease or disorder that is characterized or medicated by activity of any protein that is a substrate for the complex between CRBN and the compound, including degrading the protein of IKZF1 or IKZF2) that flows from the substantial structural feature. The compounds represented by a structure of formula I only shares the structure feature of:
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(referred to herein as “the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety [
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]) in common, and does not constitute a substantial structure feature (i.e., a significant structural element is shared by all of the alternatives) of the compound as a whole. According to El-Zanfally et al. (Journal of Pharmaceutical Sciences, 1965. Vol. 54, 3: 467-469; cited in the IDS filed on November 17, 2022), the compounds with glutar- and succinimido moieties (I) shown as follows:
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combine [Symbol font/0x61]-substituted glutarimide derivatives, which are used as sedative and hypnotic activities, and succinimide derivatives, which are used as anticonvulsant and in petit mal; and combining hypnotics and anticonvulsant is a common practice in the treatment of grand mal. Even though the compound of formula (I) taught by El-Zanfally et al. contains the same common structure feature (3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety), said compound is taught to be useful for treating grand mal rather than treating the entire scope of disease or disorder that is characterized or mediated by activity of any protein that is a substrate for a complex between CRBN and the compound. The compound of El-Zanfally et al. is also not known to degrade IKZF1 or IKZF3. Therefore, it is not apparent that this common structure alone (
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) shared among all the compound species contributes to the substantial feature essential for the compound to give the desired property of treating the entire scope of disease or disorder that is characterized or mediated by activity of any protein that is a substrate for a complex between CRBN and the compound, as well as IKZF1 or IKZF3 degradation activity
In addition, the Markush grouping of Y1 includes a wide variety of formulae, such as
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,
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,
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and
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. It is noted that each of these Y1 alternatives only shares
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in common and that does not constitute a substantial structure feature (i.e., a significant structural element is shared by all of the alternatives). The claim specifically recites “W1 is N, CR5, or a carbon atom that is the point of attachment”, such that
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includes chemical structures that belong to different chemical classes. For instance,
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of (a), (b), (c), (d), (f), (h), (i), (j), (l) and (m) can be a phenyl or a heteroaryl contain up to 4 nitrogen atoms in the 6-membered aromatic ring; and therefore, it includes pyridine, pyrimidine, pyrazine, pyridazine, and tetrazine. Phenyl and tetrazine are known in the art to belong to different chemical class or physical classes. Phenyl is an aromatic hydrocarbon group; and is known in the art to serve as electron withdrawing group to increase lipophilicity according to Tamaian et al. (see e.g., page 22192, 1st paragraph). Tetrazine is a six-membered heteroaromatic ring containing four nitrogen atoms; and tetrazine derivatives are known in art to be biologically active with antitumor, antibacterial, antifungal and anti-malarial activities according to Jaiswal et al. (Materials science & engineering. C, Materials for biological applications, 2013. Vol. 33(4): 1925–1934.) (see e.g., p. 1925, right column, last paragraph). In other words, phenyl and tetrazine does not share a single structural similarly; and they are not known in the art to share a common use.
Furthermore, the Markush grouping of Y1 includes a wide variety R8 and R21 that belong to different chemical or physical classes. Instant claim recites “R8 is a (C6-C10aryl), monocyclic or bicyclic 5- to 10-membered heteroaryl… R21 is a monocyclic or bicyclic 5- to 10-membered hetertoaryl”. It is known in the art that indazole, thiazole, and naphthalene belong to different chemical or physical classes.
Indazole (
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) is known in the art to have anti-inflammatory activity, as evidenced by Cheekavolu et al. (Journal of Clinical and Diagnostic Research, 2016. Vol. 10(9): FF01-FF06). Thiazole is a five-membered heterocyclic ring containing nitrogen and sulfur, and it is mainly used as dyes and fungicides, as evidenced by Wu et al. (RSC Adv, 2018. Vol. 8(69): 39593-39601). Naphthalene (
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) is commonly used as an insecticide and pest repellent, as evidenced by Gervais et al. (National Pesticide Information Center, Oregon State University Extension Services. Published online on December, 2010). In other words, indazole, thiazole and naphthalene are not known in the art to belong to the same chemical class, and they are not known to share a common use. In addition, Y1 also includes formulae (e.g.,
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(d)) such that multiple substituents can be separated or joined together to form a ring, for instance, R6 is hydrogen or (C1-C6)alkyl; or two R6 when on different nitrogen atoms, together with the atoms to which they are attached form a 4- to 7-membered heterocycloalkyl group; or R6 and R7, together with the atoms to which they are attached form a 4- to 8-membered heterocycloalkyl group. It is noted that hydrogen, alkyl, and heterocycloalkyl does not belong to the same chemical or physical classes.
Furthermore, the compounds of formula (I) embraced by the Markush grouping includes a wide variety of compound species, such as
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(see claim 39); and they that do not share a single structural similarities and a common use that flows from the substantial structure feature that is essential for treating the entire scope of disease or disorder that is characterized or medicated by activity of any protein that is a substrate for the complex between CRBN and the compound, including degrading the protein of IKZF1 or IKZF2. According to Crew et al. (US 2018/0215731 A1; cited in the IDS filed on November 17, 2022), the compound PROTAC-104 having the structure of:
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is a bifunctional compound that demonstrates activity in degrading estrogen receptor (ER) (see e.g., Table 5, PROTAC-104; Table 2, PROTAC-104). Even though the PROTAC-104 of Crew et al. contains the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety that is the common structure feature of the compound species instantly claimed, said compound is taught to exhibit activity in degrading estrogen receptor as the target protein rather than degrading any proteins, including IKZF1 or IKZF3; or treating the entire scope of disease or disorder that is characterized or mediated by activity of any protein that is a substrate for a complex between CRBN and the compound, including gout. In view of the foregoing, it is not apparent that the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety of instant formula I alone is the substantial structure feature that contribute to the desired properties instantly claimed as the compounds taught by the cited reference do not share a common use.
In view of the foregoing, the alternated compound species embraced by the instant claims fail to share a single structural similarity or a common use that flows from the substantial structural feature.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Response to Arguments
Applicant's arguments filed on December 23, 2025 with respect to the rejection of claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 on the judicially-created basis that it contains an improper Markush grouping of alternatives have been fully considered but they are not persuasive.
In Summary, applicant argues the alternated compound species embraced by the Markush grouping shares a much larger common structural feature. Specifically, applicant argues compounds
23 and 82 share the 3-(2,5-dioxo-3-(phenylamino)-2,5-dihydro-1H-pyrrol-1-yl) piperidine-2,6-dione moiety:
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; and the PROTAC-104 taught by Crews does not contain the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety
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in addition to the amino phenyl group; therefore, the amended claims share a single structural similarity and a common use as degraders of
IKZF1 or IKZF3.
In response, applicant’s argument is not found persuasive for the reasons set forth below:
In response to applicant’s argument that the Markush grouping of compounds represented by a structure of formula I shows a substantial structure features, i.e., the 3-(2,5-dioxo-3-(phenylamino)-2,5-dihydro-1H-pyrrol-1-yl) piperidine-2,6-dione moiety, it is noted that features upon which applicant relies are not clearly reflected in the rejected claims. As noted in the Non-Final Office Action mailed on September 23, 2025, claim 1 recites a compound species represented by a structure of formula I:
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. The compound species composed of a wide variety of different
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, X, and Y1 moieties do not share a structural similarity and a common substantial structure feature that is essential for treating the entire scope of disease or disorder that is characterized or medicated by activity of any protein that is a substrate for the complex between CRBN and the compound, including degrading the protein of IKZF1 or IKZF2.
Specifically, amended claim 1 now recites “[a] compound represented by a structure of formula I:
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or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R2 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl; R2’ is (C1-C6)alkyl, or (C1-C6)haloalkyl; or R2 and R2’ together form =O;”. In other words, R2 and R2’ does not need to be joined together to form =O. It is noted that R2 and R2’ can be selected from the alternatives that does not belong to the same chemical class, for instance, hydrogen and haloalkanes; and alkyl and haloalkyl are distinct chemical classes; and these alternatives are also structurally distinct than the oxo group (=O). and therefore, the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety (
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) which applicant relies are not reflected in the rejected claims.
Furthermore, amended claim 1 also recites “[a] compound represented by a structure of formula I:
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or a pharmaceutically acceptable salt or stereoisomer thereof…X is -NR6- or -C(R5)2-; Y1 is
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…
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; W1 is N, CR5, or a carbon atom that is the point of attachment”. In other words, X does not need to be -NH-, and
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of (a), (b), (c), (d), (f), (h), (i), (j), (l) and (m) also does not need to be phenyl. The
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(a), (b), (c), (d), (f), (h), (i), (j), (l) and (m) can also contain up to 5 nitrogen atoms in the 6-membered aromatic ring, such as pyridine (
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), pyrimidine (
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), pyrazine (
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), pyridazine (
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), and tetrazine (
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). It appears Y1 also constitutes significant structural element of compound as a whole rather than
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itself. Therefore, the 3-(2,5-dioxo-3-(phenylamino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione moiety (
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) which applicant relies are not reflected in the rejected claims. Each of these findings demonstrate that the compound species of formula I embraced by the Markush group are substantially structurally different.
Furthermore, applicant’s assertion that the compound species represented by a structure of formula I:
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embraced by the Markush groupings all shares a common use as degraders of IKZF1 or IKZF3 are not persuasive, because Applicant does not present a sufficient showing other compound species composed of different
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, X, and Y1 alternatives (structure (a), (b), (c), (d), (f), (h), (i), (j),(l), (m)) encompassed by the claim(s) would have a common use as degraders of IKZF1 or IKZF3. For instance, applicant does not disclose any compound species having the structure of
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or
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at
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; or having the structure of pyrimidine, pyrazine, or tetrazine at
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. As noted in the Non-Final Office Action mailed on September 23, 2025, the only structure feature these compound species have in common is the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety (
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), and that is not a substantial structure feature (i.e., a significant structural element is shared by all of the alternatives) of the compound as a whole. Even though the compound of El-Zanfally et al. (Journal of Pharmaceutical Sciences, 1965. Vol. 54, 3: 467-469; cited in the IDS filed on November 17, 2022) contains the same 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety, it is taught to be useful for treating grand mal rather than treating the entire scope of disease or disorder that is characterized or mediated by activity of any protein that is a substrate for a complex between CRBN and the compound or as a degrader of IKZF1 or IKZF3. It is further noted that the compound PROTAC-104 of Crew et al. (US 2018/0215731 A1; cited in the IDS filed on November 17, 2022), which also contains the 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety, is taught have activity in degrading estrogen receptor rather than IKZF1 or IKZF3. Since the Markush grouping includes a wide variety of compound species alternatives (see the analysis above), there is a question in doubt whether the common feature of 3-(2-oxo-1-pyrrolidinyl)-2,6-piperidinedione moiety (
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) alone contributes to the substantial structure essential for the desired properties (degrader of IKZF1 or IKZF3).
Solely to rebut applicant’s argument that Markush grouping of compounds represented by a structure of formula I shares the common use as a degrader of IKZF1 or IKZF3, it is noted that the instant specification does not disclose the IKZF3 degradation activity of any compounds represented by the structure of instant formula I; therefore, applicant’s assertion that IKZF3 degradation activity is the common use for the claimed compound appears to be mere argument without supportive evidence. Furthermore, the Markush grouping includes wide variety of compound species, such as compound 2 having the structure of:
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, compound 82 having the structure of:
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, and compound 15 having the structure of:
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. The specification does not disclose their IKZF1 degradation activity. It is noted that compound 82 is the only compound species instantly claimed that falls within the scope of
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, which is a subgenus formula of formula (I) (i.e.,
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, wherein X is -NH-; and Y1 is
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); and there is no other compound species that shares the same substantial structure feature. In addition, compound 2 is the only compound species instantly claimed that falls within the scope of
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and
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that has a bicyclic 9-membered heteroaryl. It is known in the art that bicyclic heteroaryl and aryl does not belong to the same chemical class; and they are not known to have the same common use. Specifically, it is known in the art that indazole (
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) has anti-inflammatory activity, as evidenced by Cheekavolu et al. (Journal of Clinical and Diagnostic Research, 2016. Vol. 10(9): FF01-FF06); and naphthalene (
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) is commonly used as an insecticide and pest repellent, as evidenced by Gervais et al. (National Pesticide Information Center, Oregon State University Extension Services. Published online on December, 2010). It is also known in the art that azetidine, hydrogen and alkyl, which are interchangeable at R5 and R5’, also does not belong to the same chemical class. Therefore, it is not apparent that these compound species composed of chemical structural elements belong to different chemical class all share the common use for degrading IKZF1 or IKZF3 even without any supportive evidence. Moreover, it is also noted that compound 22 (
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) has a half-maximal degradation concentration (DC50) of 134 nM for degrading IKZF1, and compound 66 has the DC50 1.2 nM (
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). In other words, there is roughly a 111 fold difference for the half-maximal degradation concentration between these two compound species; and it is not apparent that the 3-(2,5-dioxo-3-(phenylamino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione moiety (
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) alone constitute a significant structure elements that is essential for the compound as a whole to degrade IKZF1 or IKZF3.
Therefore, the rejection is reapplied for the reasons sets forth herein.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 10-11, 16-18, 21-32, 34, and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21, 27-32, 38-42 of U.S. Patent No. 12,227,488 B2 (reference patent) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of reference patent are drawn to a compound that falls within the scope of the claimed invention. For instance, the claims of the reference patent are drawn to compound having the structure of:
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(see e.g., claim 38);
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(see e.g., claim 20); and
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(see e.g., claim 31). The claims of the reference patent are also drawn to pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
The claims of reference patent does not teach the elected compound 66 and compound 9.
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (see e.g., “introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar biological activity, and have been classified as either classical or nonclassical (see e.g., p. 3148-3149). Patani et al. further teaches a list of bioisosteres of the amide bond shown below:
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(see e.g., Table 48). Patani et al. further teaches classical bioisosteres benzene and pyridine resulted in analogues with
retention of biological activity within different series of pharmacological agents (see e.g., p. 3158, left column, “E. Ring Equivalents”). Patani et al. further teaches fluorine, hydroxyl, amino and methyl are monovalent group of isosteres for replacements for hydrogen based on Grimm’s Hydride Displacement Law (see e.g., p. 3152, left column, “4. Fluorine and Hydroxyl, Amino, or Methyl Groups as
Replacements for Hydrogen (Grimm’s Hydride Displacement Law)”, 1st paragraph; Table 12).
To the extent that the claimed compound is compound 66, the difference between the compound 159 of the reference patent and the claimed compound 66 is that the reference patent contains the reverse amide (-CONH-) 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 select the compound 159 of the reference patent and then modify said compound by replacing the reverse amide (-CONH-) with a methyleneamino (-CH2NH-) based on the nonclassical bioisosteres of the amide bond taught by Patani et al. One would have been motivated to do so, because Patani et al. teaches reversed amide (-CONH-) and methyleneamino (-CH2NH-) are nonclassical bioisosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 159 of reference patent would have exerted the same or substantially similar activity as compound 159; and therefore, said modified compound would successfully incorporate into a pharmaceutical composition with a pharmaceutically acceptable carrier without any appreciable loss of activity.
To the extent that the claimed compound is compound 9, the difference between the compound 153 of the reference patent and the claimed compound 9 is that the reference patent contains the phenyl rather than pyridine and methyl rather than hydrogen 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 select the compound 153 of the reference patent and then modify said compound by replacing the hydrogen with methyl and phenyl and pyridine based on the classical bioisosteres taught by Patani et al. to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches phenyl and pyridine, and methyl and hydrogen are classical bioisosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 153 of reference patent would have exerted the same or substantially similar activity as compound 153; and therefore, said modified compound would successfully incorporate into a pharmaceutical composition with a pharmaceutically acceptable carrier without any appreciable loss of activity.
Therefore, the claimed invention are rejected on the ground of nonstatutory double patenting.
Response to Arguments
Applicant's arguments filed on December 23, 2025 with respect to the rejection of claims 1-2, 4-5, 10-11, 16-18, 22-24, 29, 32, 34, and 38-39 on the ground of nonstatutory double patenting as being unpatentable over claims 38 and 41-42 of U.S. Patent No. 12,227,488 B2 (reference patent) in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) have been fully considered.
Applicant requests the double patenting rejections be held in abeyance. Given that applicant did not put forth any arguments against the nonstatutory double patenting rejection noted above, the rejection has been reapplied for the reasons sets forth herein.
Claims 1-5, 10-11, 16-18, 21-32, 34, and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-13, 15-16, 18-20, 24-25, 42, 46-47, 64, and 67-68 of copending Application No. 19/012,206 (reference application), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of reference application are drawn to numerous compound species that falls within the scope of claimed invention. For instance, the claims of the reference application is drawn to a compound having the structure of:
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,
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,
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,
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; and
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(see e.g., claim 67). The claims of the reference application is further drawn to a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. For instance, compound 97 is a compound represented by a structure of formula I:
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, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
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is
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; X is -NH-; Y1 is
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(i.e.,
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, wherein
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is
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; n1 is 0; R9 and R9’ are independently hydrogen; n2 is 1 and R6 is hydrogen; n3 is 1 and R6 is methyl; n1 is 0; R8 is
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.
The claims of reference patent does not teach the elected compound 66 and compound 9.
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (see e.g., “introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar biological activity, and have been classified as either classical or nonclassical (see e.g., p. 3148-3149). Patani et al. further teaches a list of bioisosteres of the amide bond shown below:
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(see e.g., Table 48). Patani et al. further teaches classical bioisosteres benzene and pyridine resulted in analogues with
retention of biological activity within different series of pharmacological agents (see e.g., p. 3158, left column, “E. Ring Equivalents”). Patani et al. further teaches fluorine, hydroxyl, amino and methyl are monovalent group of isosteres for replacements for hydrogen based on Grimm’s Hydride Displacement Law (see e.g., p. 3152, left column, “4. Fluorine and Hydroxyl, Amino, or Methyl Groups as
Replacements for Hydrogen (Grimm’s Hydride Displacement Law)”, 1st paragraph; Table 12).
To the extent that the claimed compound is compound 66, the difference between the compound 159 of the reference patent and the claimed compound 66 is that the reference patent contains the reverse amide (-CONH-) 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 select the compound 159 of the reference patent and then modify said compound by replacing the reverse amide (-CONH-) with a methyleneamino (-CH2NH-) based on the nonclassical bioisosteres of the amide bond taught by Patani et al. One would have been motivated to do so, because Patani et al. teaches reversed amide (-CONH-) and methyleneamino (-CH2NH-) are nonclassical bioisosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 159 of reference patent would have exerted the same or substantially similar activity as compound 159; and therefore, said modified compound would successfully incorporate into a pharmaceutical composition with a pharmaceutically acceptable carrier without any appreciable loss of activity.
To the extent that the claimed compound is compound 9, the difference between the compound 153 of the reference patent and the claimed compound 9 is that the reference patent contains the phenyl rather than pyridine and methyl rather than hydrogen 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 select the compound 153 of the reference patent and then modify said compound by replacing the hydrogen with methyl and phenyl and pyridine based on the classical bioisosteres taught by Patani et al. to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches phenyl and pyridine, and methyl and hydrogen are classical bioisosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 153 of reference patent would have exerted the same or substantially similar activity as compound 153; and therefore, said modified compound would successfully incorporate into a pharmaceutical composition with a pharmaceutically acceptable carrier without any appreciable loss of activity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628