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, 3-4, 7, 9, 11, 14-16, 19-20 and 25-26 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/GB2021/053332, filed on 12/16/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08Apr2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 19 is objected to because of the following informalities: “pentafluorophenyl” is misspelled as “pentafluorphenyl”. Appropriate correction is required.
Claim Rejections – Withdrawn
The prior rejection of claims 1, 3-4, 7, and 9-23 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, has been overcome by Applicant’s amendment of claims 1, 4, 11 and 15-16 and cancellation of claims 10, 12-13, 17-18 and 21-23 and is therefore withdrawn. Applicant’s amendment of claims 1 and 15-16 to redefine the “TBL” moiety as a BRD9 binding ligand and/or to redefine the target protein as BRD9, and Applicant’s amendment of claims 3-4 and 11 to remove the term “optionally”, and Applicant’s amendment of claim 19 to remove the limitation of “comprising the Z moiety” and to redefine the “G” moiety of the formula by structural means rather than functional means, have overcome the prior rejection.
The prior rejection of claim 22 under 35 U.S.C. 101 on the basis of the claimed invention not being directed to patent eligible subject matter, has been overcome by Applicant’s cancellation of claim 22, and is therefore withdrawn.
The prior rejection of claim 23 under 35 U.S.C. 101 on the basis of the claimed invention being directed to non-statutory subject matter, has been overcome by Applicant’s cancellation of claim 23, and is therefore withdrawn.
The prior provisional rejection of claims 10, 12-13 and 21-22 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25 and 29-30 of copending Application No. 19/110,659 is withdrawn in response to Applicant’s cancellation of claims 10, 12-13 and 21-22.
Claim Rejections - 35 USC § 112(b) – Necessitated by Amendment
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.
Claims 1, 3-4, 7, 9, 11, 14-16 and 25-26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is directed to a genus of bifunctional molecules, designated as formula (IIab), conforming to a general structure of “TBL-L-Z”, wherein one terminus of the molecule “Z” is a heterobicyclic ring system bearing a 3-substituted-2-cyanopropenoyl group, as shown below:
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Claim 1 defines “TBL” as “a BRD9 binding ligand”; however, claim 1 does not provide any structure for “a BRD9 binding ligand”. The instant Specification provides one exemplary structure for a BRD9 binding ligand, shown below (page 39, lines 10-12):
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However, the instant Specification does not limit, in any way, what genus of structure(s) fall within the definition of “a BRD9 binding ligand”. The instant disclosure includes numerous references, particularly within the Information Disclosure Statement dated 08Apr2026, that include exemplary structure(s) of PROTAC compounds and inhibitors that bind BRD9; however, none of these references put any limit on the definition of a BRD9 binding ligand, or otherwise define what is not a BRD9 binding ligand. Thus, the instant disclosure does not fully define the metes and bounds of instant claim 1, because the instant disclosure does not define any limitation on the functional term “BRD9 binding ligand”. Furthermore, according to the prior art, any assumption that a person of ordinary skill in the art would readily envisage a binding ligand for BRD9 is an unreasonable assumption, as evidenced by Bekes (Bekes, et al.; Nature Reviews Drug Discovery, v21, pp181-200; 2022). Bekes provides a review of the first two decades of discovery in proteolysis-targeting chimera (PROTAC) molecules, bifunctional molecules targeting proteins for proteolytic degradation (page 181, Abstract). Bekes teaches that although “proteins of interest” (POIs) “do not need an enzyme active site, they do need a small-molecule binding site that is approachable by an E3 ligase. Using these sites does not require a high-affinity ligand if coupled to the right E3 ligand, but moderate affinity (≥1-500 nM) is typically needed, and access to the POI surface near the binding site by a recruited E3 ligase is essential. Achieving such binding affinities can often be challenging and has promoted research into alternative degraders1. Selection of the ligand-binding site is particularly important in the case of proteins, where the scaffolding POI may only be partially exposed within a given complex. It may be possible to degrade a POI by targeting a neighboring protein within a protein complex (the bystander effect). This approach may prove useful in degrading scaffolding proteins in which the surface of the POI is mostly buried within the complex or the POI is a membrane-associated protein” (page 186). Thus, even selecting a specific protein of interest, for example BRD9, does not inherently inform the limits of what structures are or are not suitable binding ligand(s), and so a person of ordinary skill in the art would not know the metes and bounds of claim 1.
Claims 3-4, 7, 9, 11, 14-16 and 25-26 depend directly or indirectly from claim 1 and do not resolve the indefiniteness of the “BRD9 binding ligand”.
Claim 19 is drawn to a compound of formula (IVa), which contains the moiety “G”, as shown below, wherein “G” is defined further as “XG-RG” wherein XG is a moiety selected from a Markush group of substituents that includes “-C(O)-N-hydroxysuccinimide esters” and “-(CO)-pentafluorophenyl esters”:
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Claim 19 is indefinite because the claim does not further define what variable structures must be present within either of the groups of “-C(O)-N-hydroxysuccinimide esters” and “-(CO)-pentafluorophenyl esters”. Since each of these is written as plural, a person of ordinary skill in the art would understand that the claim is meant to be understood as representing groups of compounds for these moieties, whereas a person of ordinary skill in the art would expect “C(O)-N-hydroxysuccinimide” to represent one ester compound, and “-(CO)-pentafluorophenyl” to represent another individual ester compound. In the instant Specification, these esters are mentioned only once, as “-(CO)-N-hydroxysuccinimide and -(CO)pentafluorphenol esters”, which a person of ordinary skill in the art would understand is a plural group only in that it represents two individual ester substituents, rather than two groups or families of esters. In the example of pentafluorophenyl esters, there are no available locations on a pentafluorophenyl ring for further substitution, else a fluorine would need to be replaced, and the ring would then be tetrafluorophenyl. It would appear that a limitation from the Specification has been inaptly imported from the Specification into the claim in a manner that renders the claim indefinite.
Claim 20 is drawn to a compound comprising the structure L-Z, wherein the Z moiety is defined within the claim structurally, and the “L” moiety is merely defined as a linker, without structure of the linker, or the structure of whatever moiety to which the linker is attached. The instant Specification defines the term “Linker (L)” as follows (pages 26-27, bridging paragraph): “As described herein, the TBL is linked or coupled to moiety Z via a linker L. The linker may be a chemical linker (e.g., a chemical linker moiety) and, for example, may be a covalent linker, by which is meant that the linker is coupled to Z and/or TBL by a covalent bond.” Thus, a person of ordinary skill in the art would understand that for a linker “L” to be present in claim 20, the linker must be connecting the Z moiety to another moiety (i.e., a target binding ligand). However, no structure is provided for the remainder of the molecular structure of a compound as claimed in claim 20. The claim is therefore indefinite, since the definition of the element “L” requires that another element, the target binding ligand, must be present and is undefined by the claim.
Claim Rejections - 35 USC § 112(a) – Necessitated by Amendment(s)
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 15-16 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.
The Invention in General:
Applicant has disclosed an invention in the field of bifunctional molecules that are useful in a targeted or selective degradation of a protein.
The Claimed Invention:
Claim 15 depends from and further limits claim 1, regarding a genus of bifunctional molecules, to a method of selectively degrading and/or increasing proteolysis of BRD9 in a cell, the method comprising contacting and/or treating the cell with a bifunctional molecule as defined in claim 1.
Claim 16 depends from and further limits claim 1, regarding a genus of bifunctional molecules, to a method of selectively degrading and/or increasing proteolysis of BRD9 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bifunctional molecule as defined in claim 1.
The Instant Disclosure:
The instant Specification discloses numerous prepared compounds; however, it is difficult to determine how many of the disclosed compounds are in scope of claim 1, given the indefiniteness of claim 1 (see 112(b) section above). Going solely by the structure of the “Z” moiety of formula (IIab), the instant Specification includes 22 compounds that fulfill the limitations of the “Z” moiety, and these are: Compound 36b (page 124) and Examples 57 (page 130), A3 (pages 133 and 203), 62 and 63 (page 136), A8 and A9 (page 138), A38 (page 140), A37 (pages 151 and 212), A36 and A34 (pages 151 and 211), A44 and A45 (pages 154 and 213), A53 (pages 172 and 215), A54 (pages 173 and 214), A55 (pages 173 and 215), A56 (pages 176 and 214), A59 (pages 183 and 215), A7 and A8 (page 203), A35 (page 211), A38 (page 212). The instant Specification separately discloses an exemplary “Assay 5” of targeted degradation of BRD9, as measured by immunoblot (pages 197-198, bridging paragraph) and discloses that precisely two compounds were assayed by this Assay 5 – Example A65 and A66 (page 218, “Example 10”). Example compounds A65 and A66 are structurally described in the Specification, on pages 193-194, and neither of these compounds is in scope of the genus of compounds of instant claim 1. Thus, Applicant provides no example of BRD9 degradation with any disclosed compound within scope of instant claim 1.
The Prior Art:
The level of skill and knowledge in the art, as shown by An (An, S., and Fu., L.; EBioMedicine, v36, pp553-562; 2018), is such that a wide range of bifunctional molecules, with varying binding moieties, tethers, protein targets and directing proteins have been designed, synthesized, and reported. The review by An of the field of PROTAC molecules for targeted protein degradation describes a field of art that has been researched for more than 20 years and has employed peptides, small molecules, and hybrids of the two classes (such as LCL161) as binding moieties. Small molecule binding ligands range from terpenoids, macrocyclic antibiotics, and heterocyclic and polycyclic structures, and the linkers include PEG-based, alkyl, and combination alkyl/polyether chains. E3 ligases pursued for directed protein degradation by PROTACs have included SCF, VHL, CRBN, and IAP. Protein degradation targets have included bromodomain and extraterminal (BET) proteins, kinases, and steroid receptors. An reports that the effectiveness of reported PROTAC molecules, measured as the half-maximal degradation concentration, or DC50, meaning the amount of a molecule (such as a PROTAC) needed to achieve degradation of the target protein to half its expected concentration, has achieved values as low as nanomolar concentration (p555-557, sections 2.1, 2.1.1, and Table 1).
Predictability in the field of art:
An teaches that PROTAC efficacy can be very sensitive to ligand choice as well as linker structure and length (pp 558-559, sections 2.1.6-2.1.7), and some target ligands can be poorly selective of the protein degradation target but still work effectively and selectively when used in the context of a bifunctional molecule: JQ1, for example, is poorly selective in its inhibition of BET proteins BRD2/BRD3/BRD4 but when used in PROTAC molecules is a selective degrader of BRD4 protein (p558, section 2.1.6). An teaches additional examples of unpredictability: (1) PROTAC 7, a foretinib-based c-Met-depleting PROTAC exhibited an IC50 value of 66.7 nM for inhibition of cell proliferation in GTL16 cells, while the corresponding IC50 for a diastereomer of PROTAC 7 is 156 nM; and (2) while the IC50 value of BET inhibitor OTX015 is 398 nM, the corresponding IC50 of PROTAC “ARV-825” based on OTX015 is 16 nM for induction of apoptosis in Mino cells (p558, section 2.1.6). These observations show that structure of a bifunctional molecule is significant for such an invention and cannot be inferred from the intended function of the molecule.
The MPEP § 2163 states for inventions charactered by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. The courts state conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it. Conception does not occur unless one has a mental picture of the structure of the chemical, or is able to define it by its method of preparation, its physical or chemical properties, or whatever characteristics sufficiently distinguish it. It is not sufficient to define it solely by its principal biological property, e.g., dual binding of two different proteins or non-cleavable bonds, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. In such instances the alleged conception fails not merely because the field is unpredictable or because of the general uncertainty surrounding experimental sciences, but because the conception is incomplete due to factual uncertainty that undermines the specificity of the inventor’s idea of the invention. Burroughs Wellcome Co. v. Barr Labs. Inc., 40 F.3d 1223, 1229, 32 USPQ2d 1915, 1920 (Fed. Cir. 1994). Reduction to practice in effect provides the only evidence to corroborate conception (and therefore possession) of the invention. The exemplary molecular structures shown in the supporting disclosure do not suffice as a “reduction to practice” in the instant application since (1) the claims, as written, together with the definitions provided for the claim terminology, do not direct a reader to associate the exemplary molecular structures to the claims, and (2) no exemplary practice of BRD9 degradation is found for any of the exemplary molecular structure that even may be within scope of the claim 1.
Double Patenting – Maintained and Necessitated by Amendment
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.
The prior provisional rejection of claims 1, 3-4, 7, 9, 11, 14-15 and 19-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25 and 29-30 of copending Application No. 19/110,659, is maintained. Applicant has traversed the rejection on the grounds that the instant claims, as currently amended, will merit no other rejection, and that per MPEP § 1490 VI.D.2.(a), a double patenting rejection should not be maintained for an application that has an earlier filing date than a reference application when no other rejection is in effect. Given that other rejections are maintained in this Final Rejection, Applicant’s traverse is not persuasive.
Reiterated Rejection:
Claims 1, 3-4, 7, 9, 11, 14-15 and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25 and 29-30 of copending Application No. 19/110,659. Although the claims at issue are not identical, they are not patentably distinct from each other, for the following reasons:
Claims 1 and 16-23 of copending Application No. 19/110,659 claim genera of compounds that encompass the genera of compounds claimed in instant claims 1, 3-4, 7, 9-14 and 19-20;
Claim 24 of copending Application No. 19/110,659 claims a set of compounds disclosed in Table 1 of the Specification of 19/110,659, which includes multiple compounds that anticipate the genera of compounds of instant claims 1, 3-4, 7, 9-14 and 19-20, for example compound “A2”2:
Claim Number(s) of Instant Application
Instant Application
Related Application Number 19/110,659
1
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wherein:
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Claim 25 of copending Application No. 19/110,659 claims a pharmaceutical composition of any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 11;
Claim 29 of copending Application No. 19/110,659 claims a method of selectively degrading and/or increasing proteolysis of BRD9 (bromodomain protein 9) in a cell, the method comprising contacting and/or treating the cell with a bifunctional molecule as defined by any of the genera disclosed therein, and thereby anticipates instant claim 15;
Claim 30 of copending Application No. 19/110,659 claims a method of making a bifunctional molecule according to any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 21;
Claim 31 of copending Application No. 19/110,659 claims a method of screening the bifunctional molecule according to any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 22, because although instant claim 22 is directed to a method of “obtaining” bifunctional molecules rather than screening them, the steps of the method of claim 31 of copending Application No. 19/110,659 anticipate the steps of the method of instant claim 22.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25 and 29-30 of copending Application No. 19/110,659.
The limitations of instant claims 1 and 3-4 and the limitations of claims claims 1, 16-25 and 29-30 of copending Application No. 19/110,659 are discussed in the rejection above and hereby incorporated into the instant rejection.
Instant claim 24 further limits claim 1 to wherein the TBL moiety is structurally defined, and is anticipated by compound “A2” of claim 24 of copending Application No. 19/110,659.
Instant claim 25 further limits instant claim 3 to wherein the “R3” moiety is selected from a Markush group that includes thiazole, and is anticipated by compound “A2” of claim 24 of copending Application No. 19/110,659.
Instant claim 26 further limits instant claim 4 to wherein one of R2 and R2' is a hydrogen and the other is C1 to C6 alkyl, and this limitation is anticipated by compound “A2” of claim 24 of copending Application No. 19/110,659.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Italics added by Examiner for emphasis.
2 (2E)-2-[(E)-5-[(4-{[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl}piperazin-1-yl)methyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-3-(1,3-thiazol-2-yl)prop-2-enenitrile
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