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 1-3, 30-31, 40-43, 47-49, 53-55, 58-60, 63 and 76-80 are pending in this application. Claims 4-29, 32-39, 44-46, 50-52, 56-57, 61-62, 64-75, 81-82 have been cancelled by Applicant. Claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78 are under consideration herein. Claims 47-49, 53-54, 60, 63, and 79-80 are withdrawn from consideration.
Claim Objections
Please fix the unrendered characters, which appear as squares in claim 1 (
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) – see definitions (8) and (10) of L1-2.
Appropriate correction is required.
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 1-2, 30-31, 40, 55, 58-59, and 76-78 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (WO 2019/152440 A1 – previously cited) (“Zhou”); and Arnold et al. (US 2014/0243286 A1 – previously cited) (“Arnold”).
Regarding claims 1, 55, 58-59 and 76-78, Zhou discloses their compounds A-L-B of Formula I, wherein A (corresponding to instant L1 and/or L3) is a BRD9 binding moiety, L (corresponding to instant C1 and/or C3) is a linker, and B is a degradation moiety (corresponding to instant E3ULB and/or E3ULB2) (page 5, lines 12-end). Zhou teaches their compounds may be administered in combination with additional therapeutic agents, such as other agents that treat cancer (page 57, lines 23-25).
Zhou teaches their B (degradation element) can have the structures 2a or 1a below (reading on elected E3ULB and/or E3ULB2) (page 6, bottom; and page 180, bottom).
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Zhou discloses their linker has Formula II below (page 8), wherein f-k can be 0 or 1; A1 can be a bond to A and A2 is a bond to B; B1-4 are C1-2 alkyl, optionally substituted with -C-, -S-, -NH-, etc.; C1-2 can be -C(O)-; and D can be alkyl; with some preferred embodiments having the structures II-a-c below (page 9).
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Zhou discloses their A BRD9 binding moiety can have the structure E-a below, wherein R22-23 can be H, alkyl, etc.; R24 can be halogen, alkyl, etc.; R25 can be alkyl, hydroxyl, amino, etc.; and s and s’ can be 0, 1, 2, etc. (page 9, bottom).
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Zhou specifically discloses the compound D10 below as a preferred embodiment – labeled with the instantly used labels for clarity (page 39, bottom). The linker element corresponding to instant L1/L3 has a MW of about 296, also reading on the claimed range of 54-420 daltons. While Zhou does not specifically disclose an embodiment in which their group corresponding to instant L1/L3 is an aromatic diol (as in the elected species), Zhou teaches 1,2 methoxy-phenyl group in the compound below and discloses that in their Formula E-a- (which corresponds to instant L1/L3 in their Formula A-L-B) R25 may be hydroxy and s may be 2. Regarding instantly elected species E3ULB-C1-L1, while Zhou does not disclose any specific embodiments comprising their 2a element above as B in Zhou’s A-L-B, Zhou specifically discloses their B group (corresponding to instant E3ULB) may be Formula 2a (shown above). Thus, Zhou discloses a relatively narrow subgenus, encompassed by the broad genus of the instant claims, which encompasses the instantly elected species.
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Therefore, regarding the instant compounds elected as E3ULB-C1-L1 and/or E3ULB2-C3-L3 in instant claims 1, 55, 58-59, and 76-78, one having ordinary skill in the art would have found the instant compounds prima facie obvious, since they are generically embraced by Zhou’s disclosed formulae and preferred embodiments; 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 cancer therapeutic compounds disclosed by Zhou. 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.
Applicant is advised that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. Note In re Bowers 149 USPQ 570. Note also In re Fauque 121 USPQ 425 in which differences were 2H’s vs 2 methyl groups. Also see MPEP 2144.09.
Further regarding claims 55 and 58-59, Zhou’s compound above read on the at least the compounds below, for the reasons outlined above.
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and
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Regarding the limitations “wherein E3ULB is an E3 ligase binding moiety” or “wherein the E3ULB binds to the CRBN subunit of the CULLIN4A or CULLIN4B” in claims 1, 55, and 58, Applicant is advised that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02.
While Zhou does not teach the instantly elected TBP-C2-L2 or TBP2-C4-L4 in a composition with their compounds; the teachings of Arnold are relied upon for these disclosures.
Arnold discloses that current drug design has not addressed the need for therapies that interact with multiple areas/domains of biomolecules ([0002]). Arnold discloses monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]). Arnold further teaches their compounds may form dimers with a second monomer that has a diol (such as Zhao’s compounds) (see [0590], col. 2). Arnold teaches their bromodomain modulators are useful for diseases related to malignant cell activation and proliferation (reading on cancer – which is the same intended use of Zhou’s and the instant invention) ([0004]). Arnold discloses the elected compounds 1, 59, and 65 below (pages 200, 201 and 312), which anticipate/read on the instantly elected TBP-C2-L2 (Applicant is reminded that elected TBP-C2-L2 and TBP2-C4-L4 species are being treated as being interchangeable in the claimed compositions, as they are all encompassed by the limitations of instant claim 1).
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While elected compound TBP2-C4-L4 is not disclosed exactly, Arnold discloses the constitutional isomers 59 and 65 above, which render the instant elected compound obvious. Specifically, 59 differs only because the boronic acid is para- to the amide (vs meta- in elected compound). For compound 65, the nitrogen and carbonyl of the amide meta- to the phenyl boronic acid are inverted. However, Applicant is advised 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).
Therefore, regarding claims 1, 40, 55, 58-59 and 76-78, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to prepare a therapeutic composition comprising one or two of Zhou’s compounds, further comprising one or two of Arnold’s compounds. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Zhou discloses their compounds as BRD9 inhibitors for the treatment of cancers, and teaches that their BRD9 inhibitors may be administered alone or in combination with other anticancer treatments; further because Arnold discloses their monomers, intended for combination with BRD9 therapeutics – see [0035] – (such as Zhou’s) for the preparation of multimers when combined with diols in vivo, for the treatment of proliferative diseases, such as cancer.
Applicant is advised that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two or more agents.
Regarding claim 2, Zhou discloses their compounds corresponding to instant E3ULB-C1-L1 and E3ULB2-C3-L3, wherein their group corresponding to instant L1 reads on the instant claim when instant R4 binds to -C1-E3ULB; R2 is heteroaryl; and R1,3 are H. Arnold discloses their compounds corresponding to instant TBP-C2-L2 and TBP2-C4-L4, wherein their group corresponding to instant L2 is derived from an aromatic boronic acid containing compound
Regarding claims 30-31, Zhou discloses their L (corresponding to instant C1 and C3) can have the structure II-c above, which read on instant
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when m is 1. While the instantly disclosed preferred embodiment of L shows a methylene between -NH- and Z1, Zhou teaches that in their linkers of Formula II, g, h, i, j, and k can be 0; leaving A1-B1-D-A2, wherein A1 (corresponding to Z2) can be a bond to B (which corresponds to instant E3ULB/E3ULB2) and A2 (corresponding to Z1) is a bond to A (which corresponds to instant L1); B1 can be N; and D can be -CH2-. Therefore, one having ordinary skill in the art would have found the claimed C1 “connectors” prima facie obvious, since they are generically embraced by Zhou’s disclosed formula for their linkers and preferred embodiments. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of linkers/ connectors disclosed by Zhou. 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.
Applicant is advised that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Claims 1-3, 30-31, 40-43, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al. (WO 2009/145899 A1 – previously cited) (“Muller”); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591 – previously cited) (“Meanwell”); further in view of Arnold et al. (US 2014/0243286 A1 – previously cited) (“Arnold”).
Regarding claims 1-3 and 55, Muller discloses their compound below in methods of treating cancer (pages 1-2) – which is the same intended use of the compounds of the instant invention. Muller teaches their compounds may be administered in combination with other therapeutic agents (para. bridging pages 3-4). Muller’s compound reads on a E3ULB-C1-L1 (presently elected as E3ULB2-C3-L3, however, as mentioned in the election/restriction section of the non-final filed 03/11/2026, E3ULB-C1-L1 and E3ULB2-C3-L3 will be considered as being interchangeable).
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(page 12, top left)
While Muller does not disclose their compounds wherein the group corresponding to instant L1 is an aromatic 1,2 diol; the teachings of Meanwell are relied upon for these disclosures.
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 -Cl and -OH and monovalent bioisosteres (Table 1, page 2529, col. 1).
Therefore, regarding claims 1-3 and 55, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they encompass Muller’s compound 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 compounds for the treatment of cancer disclosed by Muller, in view of Meanwell’s teaching that -Cl and -OH are classical monovalent bioisosteres, rendering their substitution for one another a routine modification in medicinal chemistry. Accordingly, one having ordinary skill in the art would have been motivated to prepare Muller’s compound wherein the -Cl’s have been replaced by ‘OH, in view of Meanwell.
Further regarding claim 55, the compound below is particularly obvious in view of Muller in view of Meanwell’s disclosure when X is O.
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While Muller in view of Meanwell do not teach the instantly elected TBP-C2-L2 in a composition with their compounds; the teachings of Arnold are relied upon for these disclosures.
Arnold discloses that current drug design has not addressed the need for therapies that interact with multiple areas/domains of biomolecules ([0002]). Arnold discloses monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]). Arnold teaches their bromodomain modulators are useful for diseases related to malignant cell activation and proliferation (reading on cancer – which is the same intended use of Muller’s and the instant invention) ([0004]). Arnold discloses the elected compounds 1, 59, and 65 below (pages 200, 201 and 312), which anticipate/read on the instantly elected TBP-C2-L2 (Applicant is reminded that elected TBP-C2-L2 and TBP2-C4-L4 species are being treated as being interchangeable in the claimed compositions, as they are all encompassed by the limitations of instant claim 1).
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While elected compound TBP2-C4-L4 is not disclosed exactly, Arnold discloses the constitutional isomers 59 and 65 above, which render the instant elected compound obvious. Specifically, 59 differs only because the boronic acid is para- to the amide (vs meta- in elected compound). For compound 65, the nitrogen and carbonyl of the amide meta- to the phenyl boronic acid are inverted. However, 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.
Therefore, regarding claims 1-3, 40-43, and 55, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to prepare a therapeutic composition comprising one or two of Muller’s in view of Meanwell’s compounds, further comprising one or two of Arnold’s compounds. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Muller in view of Meanwell discloses their compounds for the treatment of cancers, which may be administered alone or in combination with other anticancer treatments; further because Arnold discloses their monomers, intended for combination with other therapeutics for the preparation of multimers in vivo, for the treatment of proliferative diseases, such as cancer.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” It is therefore obvious to provide a mixture of the two or more agents.
Further regarding claim 41 and 43, the compounds below are particularly obvious in view of Muller in view of Meanwell’s disclosure:
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wherein L1 corresponds to
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Further regarding claims 41 and 43, Applicant is advised 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).
Regarding the limitations: “wherein E3ULB is an E3 ligase binding moiety” or “wherein the E3ULB binds to the CRBN subunit of the CULLIN4A or CULLIN4B” in claims 1 and 55, Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding claims 30-31, Muller discloses their compound wherein the connecting element is
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Claims 1, 58-59, and 76-78 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al. (WO 2009/145899 A1 – previously cited) (“Muller”); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591 – previously cited) (“Meanwell”); further in view of Arnold et al. (US 2014/0243286 A1 – previously cited) (“Arnold”); as applied to claims 1-3, 30-31, 40-43, and 55; further in view of Zhou et al. (WO 2019/152440 A1 – previously cited) (“Zhou”).
The teachings of Muller, Meanwell, and Arnold are disclosed above and incorporated herein.
While Muller, Meanwell, and Arnold do not teach the instantly elected E3ULB-C1-L1 compound (interpreted as being interchangeable with E3ULB2-C3-L3); the teachings of Zhou are relied upon for these disclosures.
Zhou teaches their compounds A-L-B of Formula I, wherein A (corresponding to instant L1 and/or L3) is a BRD9 binding moiety, L (corresponding to instant C1 and/or C3) is a linker, and B is a degradation moiety (corresponding to instant E3ULB and/or E3ULB2) (page 5, lines 12-end). Zhou teaches their compounds may be administered in combination with additional therapeutic agents, such as other agents that treat cancer (page 57, lines 23-25).
Zhou teaches their B (degradation element) can have the structures 2a or 1a below (reading on elected E3ULB and/or E3ULB2 – interpreted as being interchangeable herein) (page 6, bottom; and page 180, bottom).
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Zhou discloses their linker has Formula II below (page 8), wherein f-k can be 0 or 1; A1 can be a bond to A and A2 is a bond to B; B1-4 are C1-2 alkyl, optionally substituted with -C-, -S-, -NH-, etc.; C1-2 can be -C(O)-; and D can be alkyl; with some preferred embodiments having the structures II-a-c below (page 9).
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Zhou discloses their A BRD9 binding moiety can have the structure E-a below, wherein R22-23 can be H, alkyl, etc.; R24 can be halogen, alkyl, etc.; R25 can be alkyl, hydroxyl, amino, etc.; and s and s’ can be 0, 1, 2, etc. (page 9, bottom).
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Zhou specifically discloses the compound D10 below as a preferred embodiment – labeled with the instantly used labels for clarity (page 39, bottom). The linker element corresponding to instant L1/L3 has a MW of about 296, also reading on the claimed range of 54-420 daltons. While Zhou does not specifically disclose an embodiment in which their group corresponding to instant L1/L3 is an aromatic diol (as in the elected species), Zhou teaches 1,2 dimethoxy-phenyl group in the compound below and discloses that in their Formula E-a- (which corresponds to instant L1/L3 in their Formula A-L-B) R25 may be hydroxy and s may be 2. Regarding instantly elected species E3ULB-C1-L1, while Zhou does not disclose any specific embodiments comprising their 2a element above as B in Zhou’s A-L-B, Zhou specifically discloses their B group (corresponding to instant E3ULB) may be Formula 2a (shown above). Thus, Zhou discloses a relatively narrow subgenus, encompassed by the broad genus of the instant claims, which encompasses the instantly elected species.
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Therefore, regarding the instant compounds (elected as E3ULB-C1-L1 and/or E3ULB2-C3-L3) in instant claims 1, 58-59, and 76-78, one having ordinary skill in the art would have found the instant compounds prima facie obvious, since they are generically embraced by Zhou’s disclosed formulae and preferred embodiments. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of cancer therapeutic compounds disclosed by Zhou. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula. Applicant is also reminded that H vs. Me is considered an obvious modification in the absence of superior, unexpected results.
Further regarding claims 58-59, Zhou’s compound above reads on the at least the compounds below, for the reasons outlined above.
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Regarding the limitations “wherein E3ULB is an E3 ligase binding moiety” or “wherein the E3ULB binds to the CRBN subunit of the CULLIN4A or CULLIN4B” in claims 1 and 58-59, Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Further regarding claims 58-59 and 76-78, one having ordinary skill in the art would have been motivated to prepare any of the claimed compositions, with a reasonable expectation of success, because (Muller in view of Meanwell, further in view of Arnold) teach their compositions and compounds for the treatment of cancer; further because Zhou discloses their compounds, also useful for the treatment of cancer, and teaches that their compounds may be administered in combination with other chemotherapeutic agents.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two or more agents.
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 1-3, 30-31, 40-43, 55, 58-59 and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 29-30, 37-40, 47-52, 54-56 of copending Application No. 18/020,025 (Copending ‘025); in view of Arnold et al. (US 2014/0243286 A1) (“Arnold”).
Regarding instant claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78, Copending ‘025 claims the instant compounds of Formula E3ULB-C1-L1 and E3ULB2-C3-L3, including the elected species below: (all claims of Copending ‘025) for the treatment of cancer.
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While Copending ‘025 does not teach the instant compounds of Formulae TBP-C2-L2 or TBP2-C4-L4 in a composition with their compounds; the teachings of Arnold are relied upon for these disclosures.
Arnold discloses that current drug design has not addressed the need for therapies that interact with multiple areas/domains of biomolecules ([0002]). Arnold discloses monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]). Arnold teaches their bromodomain modulators are useful for diseases related to malignant cell activation and proliferation (reading on cancer – which is the same intended use of Muller’s and the instant invention) ([0004]). Arnold discloses the elected compounds 1, 59, and 65 below (pages 200, 201 and 312), which anticipate/read on the instantly elected TBP-C2-L2 (Applicant is reminded that elected TBP-C2-L2 and TBP2-C4-L4 species are being treated as being interchangeable in the claimed compositions, as they are all encompassed by the limitations of instant claim 1).
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(59)
While elected compound TBP2-C4-L4 is not disclosed exactly, Arnold discloses the constitutional isomers 59 and 65 above, which render the instant elected compound obvious. Specifically, 59 differs only because the boronic acid is para- to the amide (vs meta- in elected compound). For compound 65, the nitrogen and carbonyl of the amide meta- to the phenyl boronic acid are inverted. However, 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.
Therefore, regarding instant claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78, one having ordinary skill in the art would have been motivated to prepare any of the claimed compositions, with a reasonable expectation of success, because Copending ‘025 discloses their compositions for the treatment of cancer; further because Arnold discloses their compounds, also useful for the treatment of cancer, and discloses their monomers are capable of forming a multimer with other monomers (such as Copending ‘025’s BRD inhibitors) in vivo, allowing for modulation of one or more biomolecules substantially simultaneously.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two or more agents.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 26, and 29 of copending Application No. 18/269,122 (Copending ‘122) – Notice of Allowance Mailed 09/12/2026; in view of Arnold et al. (US 2014/0243286 A1) (“Arnold”).
Regarding instant claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78, Copending ‘122 claims a compound of Formula I below, reading on the instant compounds when: Degron is a E3 ubiquitin ligase, Q is a bond, R2 is -OH, and n1 is 2 (at least in Copending ‘122 claims 1, 26, and 29).
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Degron is
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or
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While Copending ‘122 does not teach the instant compounds of Formulae TBP-C2-L2 or TBP2-C4-L4 in a composition with their compounds; the teachings of Arnold are relied upon for these disclosures.
Arnold discloses that current drug design has not addressed the need for therapies that interact with multiple areas/domains of biomolecules ([0002]). Arnold discloses monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]). Arnold teaches their bromodomain modulators are useful for diseases related to malignant cell activation and proliferation (reading on cancer – which is the same intended use of Muller’s and the instant invention) ([0004]). Arnold discloses the elected compounds 1, 59, and 65 below (pages 200, 201 and 312), which anticipate/read on the instantly elected TBP-C2-L2 (Applicant is reminded that elected TBP-C2-L2 and TBP2-C4-L4 species are being treated as being interchangeable in the claimed compositions, as they are all encompassed by the limitations of instant claim 1).
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(65)
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(59)
While elected compound TBP2-C4-L4 is not disclosed exactly, Arnold discloses the constitutional isomers 59 and 65 above, which render the instant elected compound obvious. Specifically, 59 differs only because the boronic acid is para- to the amide (vs meta- in elected compound). For compound 65, the nitrogen and carbonyl of the amide meta- to the phenyl boronic acid are inverted. However, 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.
Therefore, regarding instant claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78, one having ordinary skill in the art would have been motivated to prepare any of the claimed compositions, with a reasonable expectation of success, because Copending ‘122 discloses their compositions for the treatment of cancer; further because Arnold discloses their compounds, also useful for the treatment of cancer, and discloses their monomers are capable of forming a multimer with other monomers (such as Copending ‘122’s anticancer agents) in vivo, allowing for modulation of one or more biomolecules substantially simultaneously.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two or more agents.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 30-31, 42-55, 67-72, and 74-75 of copending Application No. 18/020011 (Copending ‘011).
Regarding instant claims 1-3, 30-31, 40-43, 55, 58-59, and 76-78, Copending ‘011 claims the compounds below, which are prepared after the combination of the instantly claimed E3ULB-C1-L1 or E3ULB2-C3-L3 with either TBP-C2-L2 or TBP2-C4-L4 (all claims of Copending ‘011). Since condensation of the diol of E3ULB-C1-L1 or E3ULB2-C3-L3 with the boronic acid of TBP-C2-L2 or TBP2-C4-L4 would be expected to happen spontaneously in the instantly claimed compositions, then Copending ‘011’s compounds read on the instant compositions. Copending ‘011 specifically claims therapeutic compositions comprising their compounds (Copending ‘011 claims 71-72) – thus anticipating the instant compositions.
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This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Specification
Amendments to the specification are acknowledged and have been entered. No new matter has been introduced. Objections to the Specification have been withdrawn.
Claims/ Claim Objections
Amendments to the claims are acknowledged and have been entered. No new matter has been introduced. Objections to the claims have been withdrawn. However, a new ground of objections has been raised in view of claim amendments.
Claim Rejections - 35 USC § 112(b)
In view of claim amendments, 35 USC § 112(b) rejections have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 08/11/2026 have been fully considered but they are not persuasive.
Applicant argues a POSITA would have had no reason or motivation to select compound D10 as a starting point for the proposed modifications, or any indication that this was a preferred embodiment over other compounds with allegedly better BRD9 degrading affinity. Applicant argues one of ordinary skill would have had no reason to make the many modifications required to arrive from Formula E-a to the instant claims. Applicant argues Zhao’s compounds are designed to specifically bind BRD9 via its corresponding L1 portion while the instant compounds are meant to form a reversible heterodimer with a separate compound having a biorthogonal L2 linker. Applicant alleges that modification of D10 to make a diol would undermine Zhao’s intended goal of achieving BRD9-binding. Applicant argues modifying “methoxy” for “hydroxy” does not constitute a simple substitution of H for Me and states the two groups are substantially different in reactivity and properties. Applicant states a POSITA would not have had a reasonable expectation of success in creating the claimed composition in view of Zhao in view of Arnold (see page 36 of remarks, last para.).
Applicant further argues that selection of Muller’s compound benefits from hindsight reasoning by comparing to the compounds of the instant invention. Applicant alleges that Muller’s “treating cancer” is an oversimplification of the instant intended use of targeted protein degradation. Applicant states Muller discloses hundreds of compounds, and a POSITA would not have had a reason or motivation to elect the cited compound and make the required modifications to arrive at the instant claims. Applicant argues Meanwell provides no predictability of success as to whether swapping -Cl for -OH would result in beneficial properties. Applicant also states a POSITA would not have had a reasonable expectation of success in creating the claimed composition in view of Zhao in view of Arnold (see page 40 of remarks, first para.).
As an initial matter, Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)).
Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's arguments against the references individually (like arguments attacking Zhao or Muller or Meanwell when rejections were made over Zhao in view of Arnold and Muller in view of Meanwell and Arnold), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Zhou discloses their compounds A-L-B of Formula I, wherein A (corresponding to instant L1 and/or L3) is a BRD9 binding moiety, L (corresponding to instant C1 and/or C3) is a linker, and B is a degradation moiety (corresponding to instant E3ULB and/or E3ULB2) (page 5, lines 12-end). Zhou teaches their compounds may be administered in combination with additional therapeutic agents, such as other agents that treat cancer (page 57, lines 23-25).
Zhou teaches their B (degradation element) can have the structures 2a or 1a below (reading on elected E3ULB and/or E3ULB2) (page 6, bottom; and page 180, bottom).
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Zhou discloses their linker has Formula II below (page 8), wherein f-k can be 0 or 1; A1 can be a bond to A and A2 is a bond to B; B1-4 are C1-2 alkyl, optionally substituted with -C-, -S-, -NH-, etc.; C1-2 can be -C(O)-; and D can be alkyl; with some preferred embodiments having the structures II-a-c below (page 9).
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(II-a)
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(II-c)
Zhou discloses their A BRD9 binding moiety can have the structure E-a below, wherein R22-23 can be H, alkyl, etc.; R24 can be halogen, alkyl, etc.; R25 can be alkyl, hydroxyl, amino, etc.; and s and s’ can be 0, 1, 2, etc. (page 9, bottom).
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Zhou specifically discloses the compound D10 below as a preferred embodiment – labeled with the instantly used labels for clarity (page 39, bottom). The linker element corresponding to instant L1/L3 has a MW of about 296, also reading on the claimed range of 54-420 daltons. While Zhou does not specifically disclose an embodiment in which their group corresponding to instant L1/L3 is an aromatic diol (as in the elected species), Zhou teaches 1,2 methoxy-phenyl group in the compound below and discloses that in their Formula E-a- (which corresponds to instant L1/L3 in their Formula A-L-B) R25 may be hydroxy and s may be 2. Regarding instantly elected species E3ULB-C1-L1, while Zhou does not disclose any specific embodiments comprising their 2a element above as B in Zhou’s A-L-B, Zhou specifically discloses their B group (corresponding to instant E3ULB) may be Formula 2a (shown above). Thus, Zhou discloses a relatively narrow subgenus, encompassed by the broad genus of the instant claims, which encompasses the instantly elected species.
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Therefore, regarding the instant compounds elected as E3ULB-C1-L1 and/or E3ULB2-C3-L3, one having ordinary skill in the art would have found the instant compounds prima facie obvious, since they are generically embraced by Zhou’s disclosed formulae and preferred embodiments; 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 cancer therapeutic compounds disclosed by Zhou. 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.
Arnold discloses that current drug design has not addressed the need for therapies that interact with multiple areas/domains of biomolecules ([0002]). Arnold discloses monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]). Arnold teaches their bromodomain modulators are useful for diseases related to malignant cell activation and proliferation (reading on cancer – which is the same intended use of Zhou’s and the instant invention) ([0004]). Arnold discloses the elected compounds 1, 59, and 65 below (pages 200, 201 and 312), which anticipate/read on the instantly elected TBP-C2-L2 (Applicant is reminded that elected TBP-C2-L2 and TBP2-C4-L4 species are being treated as being interchangeable in the claimed compositions, as they are all encompassed by the limitations of instant claim 1).
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(65)
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(59)
While elected compound TBP2-C4-L4 is not disclosed exactly, Arnold discloses the constitutional isomers 59 and 65 above, which render the instant elected compound obvious. Specifically, 59 differs only because the boronic acid is para- to the amide (vs meta- in elected compound). For compound 65, the nitrogen and carbonyl of the amide meta- to the phenyl boronic acid are inverted. However, Applicant is advised 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.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to prepare a therapeutic composition comprising one or two of Zhou’s compounds, further comprising one or two of Arnold’s compounds. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Zhou discloses their compounds as BRD9 inhibitors for the treatment of cancers, and teaches that their BRD9 inhibitors may be administered alone or in combination with other anticancer treatments; further because Arnold discloses their monomers, intended for combination with BRD9 therapeutics – see [0035] – (such as Zhou’s) for the preparation of multimers in vivo, for the treatment of proliferative diseases, such as cancer.
Furthermore, Muller discloses their compound below in methods of treating cancer (pages 1-2) – which is the same intended use of the compounds of the instant invention. Muller teaches their compounds may be administered in combination with other therapeutic agents (para. bridging pages 3-4). Muller’s compound reads on a E3ULB-C1-L1 (presently elected as E3ULB2-C3-L3, however, as mentioned in the election/restriction section of the non-final filed 03/11/2026, E3ULB-C1-L1 and E3ULB2-C3-L3 will be considered as being interchangeable).
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(page 12, top left)
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 -Cl and -OH and monovalent bioisosteres (Table 1, page 2529, col. 1).
Therefore, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they encompass Muller’s compound 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 compounds for the treatment of cancer disclosed by Muller, in view of Meanwell’s teaching that -Cl and -OH are classical monovalent bioisosteres, rendering their substitution for one another a routine modification in medicinal chemistry. Accordingly, one having ordinary skill in the art would have been motivated to prepare Muller’s compound wherein the -Cl’s have been replaced by -OH, in view of Meanwell.
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to prepare a therapeutic composition comprising one or two of Muller’s in view of Meanwell’s compounds, further comprising one or two of Arnold’s compounds. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Muller in view of Meanwell discloses their compounds for the treatment of cancers, which may be administered alone or in combination with other anticancer treatments; further because Arnold discloses their monomers, intended for combination with other therapeutics for the preparation of multimers in vivo, for the treatment of proliferative diseases, such as cancer.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” It is therefore obvious to provide a mixture of the two or more agents.
In response to Applicant’s arguments that Zhao’s compounds are designed to specifically bind BRD9 via its corresponding L1 portion while the instant compounds are meant to form a reversible heterodimer with a separate compound having a biorthogonal L2 linker, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In response to Applicant’s arguments that a POSITA would not have chosen the cited compounds from the art of record, Applicant is advised that MPEP 2123 (I) states: “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").”
In response to Applicant’s arguments that modifying “methoxy” for “hydroxy” does not constitute a simple substitution of H for Me; Applicant’s allegation is inaccurate, as the entire difference between a “methoxy” and a “hydroxy” is the replacement of methyl in methoxy for a hydrogen to obtain hydroxy. Furthermore, Zhao specifically discloses their R25 groups can be hydroxy – thus, contrary to what applicant purports, Zhao provides clear motivation for arriving at the claimed compounds, as stated in the rejections presented herein.
In response to Applicant’s argument that Muller’s “treating cancer” is an oversimplification of the instant intended use of targeted protein degradation, Applicant is advised that the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). While Applicant may have disclosed the pathway for cancer treatment comprises a protein degradation, the fact that the prior art does not disclose this pathway does not render the instant compounds (or combinations thereof) patentable when they are obvious in view of the prior art compounds, which have also been used to treat cancer.
In response to Applicant’s arguments that Meanwell provides no predictability of success as to whether swapping -Cl for -OH would result in beneficial properties; per MPEP 2143.02 (I): “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).”
In response to Applicant’s arguments that a POSITA would not have arrived at the instant composition with components which form reversible covalent bonds in vivo; Arnold specifically discloses their boronic acid monomers capable of forming a multimer with other monomers in vivo, allowing for modulation of one or more biomolecules substantially simultaneously ([0006]); Arnold further teaches their compounds may form dimers with a second monomer that has a diol (such as Zhao’s and Muller’s cited compounds) (see [0590], col. 2). Thus, the claimed composition is obvious in view of the prior art of record in the absence of unexpected results.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections.
All rejections are maintained in this final action.
Double Patenting
Applicant requests that provisional NSDP rejections be held in abeyance until allowable subject matter is identified. This is not persuasive. Rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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
Prosecution Insights