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 .
DETAILED ACTION
The amendment after non-final office action filed November 7, 2025 is acknowledged. Claims 1-43, 45-66 were cancelled, claim 44 was amended, claims 67-91 were newly added and claims 44, 67-91 are pending.
*After further review, a new rejection under obvious type Double patenting is presented below due to amendment and thus, a second Non-final follows.
Election/Restrictions
The restriction was deemed proper and made FINAL in the previous office action. Claims 87-88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Claims 44, 67-86, 89-91 are examined on the merits of this office action.
Withdrawn Objections/Rejections
The objection to claims 60 and 63 are withdrawn in view of cancelation of the claims filed November 7, 2025.
The rejection of claims 44-52, 54-60, 63-66 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of amendment of the claims filed November 7, 2025.
The rejection of claims 44-48, 54-59, 64-66 on the ground of nonstatutory double patenting as being unpatentable over claim 1-26 US Patent No. 11613560 B2 (reference application) is withdrawn in view of amendment of the claims filed November 7, 2025.
The rejection of claims 44-46, 54, 64-66 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of Co-pending Application No. 18/271360 (reference application). is withdrawn in view of amendment of the claims filed November 7, 2025.
Maintained/revised Rejections
Claim Rejections - 35 USC § 112, First Paragraph
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 44, 67-86, 89-91 are/remain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
Claim 44 is now drawn to “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold.” Claims 67-68 and 90 claim wherein the first peptide ligand comprises a first polypeptide comprising a means for binding Nectin-4, EphA2, or PD-L1 on a cancer cell; a second polypeptide comprising a means for binding CD137 on an immune cell.
The instant claim (i) does not recite an specific amino acid sequence for the CD137-binding peptides, (ii) do not recite any specific tumor binding sequence, (iii) do not limit the CD137 binding epitope;; (iv) do not recite any affinity or emax threshold; do not structurally limit linker length, orientation, or scaffold geometry beyond general bicyclic architecture. The claims do define the invention functionally by requiring that the construct be a CD137 agonist.
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. 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 specification includes examples of individual peptides ligands that bind to known immune cell components, including OX40, CD137 and PD-L1. The specification further provides data (anti-tumor activity), with specific peptide complexes such as BCY11863 (Nectin 4, CD137 binding) and BCY12762/BCY12491 (both bind to EphA2 but BCY12491 does not bind to CD137). Other complexes assessed for activity include BCY11027, BCY12967, BCY13272 (EphA2/CD137), BCY13048, BCY13050.
IN particular, Applicants provide Binding data for BCY11863 and related constructs and selectivity screening. Applicants further utilize CD137 Report assay and find that BCY11863 induces CD137 activation in coculture assays, multiple Nectin-4/CD137 heterotandem constructs (e.g. BCY12484, BCY11385, BCY11864, BCY12586, BCY11021, etc..) demonstrate reporter activity. Applicants show one PD-L1/CD137 construct (BCY11617) lacking CD137 binding fails to induce agonism. The specification therefore demonstrates reduction to practice for specific heterotandem constructs within Applicant’s platform. However, the demonstrated agonist activity is confined to constructs incorporating a limited subset of CD137 binding bicyclic peptides and a limited number of tumor-binding peptides.
One of ordinary skill in the art would not consider peptides reduced to practice representative of the full scope of the claimed genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
Although multiple heterotandem constructs are shown, the CD137 binding peptides disclosed appear confined to a narrow sequence family sharing high sequence similarity and conserved loop architecture (e.g., BCY8928 and closely related variants). The specification does not demonstrate structurally distinct CD137 binding sequence classes, binding to distinct CD137 epitopes, representative structural diversity spanning the full genus of bicyclic polypeptides encompassed by the claims. Possession of a limited number of closely related CD137 binding sequences does not demonstrate possession of the entire genus of bicyclic CD127 binding polypeptides recited in instant claim 44.
For PDL-1 targeted embodiments, the specification disclose only a single heterotandem construct (BCY11780) exhibiting activity. No representative structural diversity of PD-L1-binding bicyclic peptides is demonstrated. Accordingly, the specification does not demonstrate possession of the full scope of PD-L1 targeted CD137 agonists encompassed by claim 44.
While more data are provided for Nectin-4 embodiments, the tumor binding peptides likewise appear confined to closely related scaffold variants rather than structurally diverse sequence classes spanning the breadth of bicyclic polypeptides capable of binding those targets.
The lack of structural detail means that the claimed genus lacks sufficient relevant identifying characteristics. The data in the specification does not suggest the physical basis for the claimed activity and therefore does not describe what structure is required of the peptide ligands/peptide complex that would retain the ability to bind any cancer cell or immune cell and be used therapeutically. Understanding the physical basis for the claimed activity is critical to determining which of the peptides that meet the structural requirements of the genus also meet the functional requirements of the genus.
Physical and Chemical Properties
The specification provides KD values for selected constructs, EC50 and Emax values in reporter assays, fold induction data relative to controls. However, the specification does not identify structural parameters predictive of CD137 agonism, a binding affinity threshold that ensures agonist activity, structural characteristics that distinguish agonist CD137 binders from non-agonist binders. CD137 is a TNFR superfamily receptor known to require receptor clustering and geometry dependent activation. Agonism cannot be inferred solely from binding. The specification does not establish structural features common to all CD137 agonists encompassed by the claims.
Functional characteristics when coupled with a known or disclosed correlation between function and structure
The claims require the construct to be a CD137 agonist. The specification demonstrates that specific constructs induce CD137 signaling and that loss of CD137 binding abolishes activity. However, it does not establish that structurally diverse CD137 binding bicyclic peptides within the claimed breadth will function as agonists, a structural motif common to all agonists CD137 binding peptides, a predictable correlation between CD137 binding and agonist function across the claimed genus. Because the claims are structurally broad and defined in part by a functional requirement (agonist activity and tumor targeting), the specification must demonstrate possession of the structural genus capable of performing that function. The disclosure of a limited number of closely related CD137-binding sequences does not reasonably convey possession of the entire genus of bicyclic CD137 binding polypeptides encompassed by claim 44.
The specification does not describe a general correlation between structure and function for the claimed genus of peptide ligands. The specification fails to provide sufficient examples of within the breadth of the genus of instant claim 44.
A functional description may satisfy the written description requirement only if the specification discloses a correlation between structure and function sufficient to show possession of the claimed invention. Here, although the individual peptide ligands for CD137, PDL1 and Nectin-4 are shown to bind their respective targets, the specification does not disclose a correlation between the chemical structure or chemical structural combination (e.g. multiple ligands on a scaffold) and functional outcome (tumor targeting and CD137 agonist activity).
The specification does not provide a structure function correlation that links the disclosed peptides to binding behavior across genus or any guidance on predicting whether a new ligand will work when incorporated into the bicyclic scaffold.
Taken as a whole, the structure/function relationship regarding the peptide ligands/ bicyclic peptide complex encompassed by the instant claims is not sufficiently described.
Method of Making
The specification provides methods for synthesizing bicyclic peptides, conjugating ligands and performing reporter and in vivo assays. While these teachings enable preparation and testing of specific embodiments, the issue under written description is not the ability to test candidates, but whether the inventors were in possession of the full structural genus a the time of filing. The specification does not describe structural criteria that allow one skilled in the art to recognize which CD137 binding bicyclic peptides within the claimed breadth would function as agonists.
Conclusion
Although the specification provides substantial experimental support for specific heterotandem constructs within a defined scaffold platform, claim 44 and claims depending therefrom without structural sequence limitation encompass a structurally broad genus of tumor targeted CD137 agonists defined primary by functional binding and agonist activity.
The disclosed CD137-binding peptides are confined to a narrow sequence family, and PD-L1 embodiments are supported by only a single working species. The specification does not demonstrate representative structural diversity across the breadth of the claimed genus nor identify structural features common to all claimed CD137 agonists. Accordingly, the specification does not reasonably convey to one skilled in the art that the inventors were in possession of the full scope of the claimed genus at the time of filing.
The “means for binding CD137” and “means for binding Nectin-4, EphaA2, or PDL-1” limitations invoke 35 U.S.C. 112(f). Accordingly, these limitations are construed to cover the corresponding structures and equivalents disclosed in the specification. However, invocation of 112(f) does not obviate the written description requirement for 112(a). The specification discloses only limited of structurally similar peptide ligands and does not demonstrate possession of a representative genus of structurally diverse CD137-binding agonists or tumor targeting binders. Therefore the written description rejection is maintained.
Response to Applicant’s Arguments
Applicants argue that “As amended, claim 44 states that the heterotandem bicyclic peptide complex (or a pharmaceutically acceptable salt thereof) comprises (a) a first peptide ligand that binds to Nectin-4, EphA2, or PD-L1 present on a cancer cell and (b) two or more second peptide ligands that bind to CD137 present on an immune cell. Each of the first peptide ligand and the two or more second peptide ligands comprises a polypeptide having at least three reactive groups separated by at least two loop sequences, and a molecular scaffold that forms covalent bonds with the reactive groups such that at least two polypeptide loops are formed on the scaffold.
The written description requirement is satisfied by the disclosure of a representative number of peptide ligands that bind Nectin-4 (e.g., pp. 8-10), EphA2 (e.g., pp. 11-17), PD-L1 (e.g., pp. 19- 20), and CD137 (e.g., pp. 22-26), as well as by actual reduction to practice. The application provides extensive data showing that complexes comprising cancer-targeting ligands (Nectin-4, EphA2, or PD-L1) paired with CD137-binding ligands exhibit anticancer activity. The examiner has acknowledged that the specification describes and provides data for such conjugates. Accordingly, Applicant respectfully requests withdrawal of this rejection.”
Applicant’s arguments have been fully considered but not found persuasive. Claim 44 is not limited to any specific sequences. It broadly encompasses any first peptide that binds to Nectin-4, Epha2 or PDL-1 and any two or more second peptide ligands that bind to CD137 provided the ligands have at least three reactive groups and form at least two loops via a molecular scaffold, wherein the resulting construct is a CD137 agonist. This is a broad genus defined by binding activity, agonist function with minimal structural architecture. The claim is not restricted to the disclosed BCY sequences. The specification discloses a limited number of CD137 peptides (e.g. BCY8928 and close variants). As stated in the above rejection, these peptides share high sequence similarity, share common loop structure and conserved residues. There is not disclosure or structurally diverse CD137 binding peptides spanning the breadth of any CD137 binding peptide.
Furthermore, claim 44 requires a CD137 agonist and applicants arguments combines binding CD137 and agonistic activation of CD137. The data show that certain specific heterotandem constructs induce CD137 reporter activity. A Nectin-4 binder that does not bind CD137 (BCY11863) does not induce agonism. This demonstrates that not all binders are agonists and that agonism is dependent on specific structural features. The specification does not identify structural features required for agonist and correlation between sequence variation and agonistic potency. Thus, the disclosure does not provide guidance sufficient to show possession of the full genus of CD137 binding agonists.
Applicants further rely on functional data to show possession. However, the data are limited to specific disclosed conjugates. Furthermore, a structure function relationship is not described and no identification other CD137 binding peptides that would also function as agonists when incorporated into the scaffold. There is no evidence that Applicants were in possession of the full scope of heterotandem bicyclic peptide complexes comprising any peptide that binds CD137/Nectin-4/Epha2/PD-L1 and functions as an agonist.
Applicants assert a “representative number” of species. However, the number of disclosed CD137/PDL-1 binding species is small, the specs is structurally similar and they do not reflect the breadth of the claimed functional genus. Applicants demonstrate actual reduction to practice of certain specific constructs. However, reduction to practice of specific embodiments does not establish written description support for a broad genus defined by function particularly wherein the genus structurally open ended, the art is unpredictable and agonist is structure dependent. Accordingly, the specification does not reasonably convey to one of ordinary skill in the art that Applicants were in possession of the full scope of claim 44 at the time of filing. Applicant’s arguments have been fully considered but are not persuasive.
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 44, 67-77, 84-86, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-17 US Patent No. 11453703 B2 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent No. 11453703 B2 claims “A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to CD137 on an immune cell;
conjugated via a linker to
(b) a second peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is EphA2; wherein each of said peptide ligands comprises a polypeptide comprising three cysteine residues, separated by two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that two polypeptide loops are formed on the molecular scaffold,
wherein the first peptide ligand is a CD137 binding bicyclic peptide ligands…and wherein the second peptide ligands were EphA2 (cancer binding) binding bicyclic peptide ligands” (see claim 1). US Patent No. 11453703 further claims wherein the scaffold is TATA (claim 3); wherein the peptide complex is a free acid (claim 4); pharmaceutically acceptable excipients (claim 5); SEQ ID NO:1 which is identical to instant SEQ ID NO:5 (CD137 peptide); N- and C-terminal modifications of the CD137 binding peptides (claim 6).
US Patent No. 11453703 B2 does not claim two or more second peptide ligands (i.e. two or more CD137 peptides) or including radiochelator/chromophore. However, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘703 by adding additional binding ligands in order to enhance binding affinity or targeting (to the cancer cell or immune cell), a well-known design choice with a reasonable expectation of success. Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘703 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells (claim 13) as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-86, 89-91 are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-19 US Patent No. 11306123 B2 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent No. 11306123 B2 claims “A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to Nectin-4 and which has the sequence CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 1); conjugated via an N-(acid-PEG3)-N-bis(PEG3-azide) linker to
(b) two second peptide ligands which bind to CD137 both of which have the sequence Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2, which is instant SEQ ID NO:11);
or a pharmaceutically acceptable salt thereof,
wherein each of said peptide ligands comprise a polypeptide comprising three reactive cysteine groups (Ci, Cii and Ciii), separated by two loop sequences, and a molecular scaffold which is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and which forms covalent bonds with the reactive cysteine groups of the polypeptide such that two polypeptide loops are formed on the molecular scaffold;
wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine”. SEQ ID Nos:1-2 overlap with the sequences in instant claims 73-76, 79-80, 82-83. US Patent No. 11306123 B2 further claims free acid salt form (claim 3); pharmaceutically acceptable excipients (claim 4) and treating cancer (claim 16).
Furthermore, regarding instant claim 86, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘123 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-81, 84-86, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-21 US Patent No. 11332500 B2 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent NO. 11332500 B2 claims “A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to a component present on a cancer cell; conjugated via a linker to
(b) a second peptide ligand which binds to a component present on an immune cell; wherein each of said peptide ligands comprise a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, characterized in that said heterotandem bicyclic peptide complex comprises the following first and second peptide ligands” (claim 1). The peptides are EphaA2, CD137 or PDL1 binding peptides (claims 1, 9-13, 19) that over lap with the instant sequences. US Patent NO. 11332500 further claims TATA as the scaffold (claim 15); free acid salt (claim 16); pharmaceutically acceptable excipients (Claim 17)
US Patent NO. 11332500 does not claim two or more second peptide ligands (i.e. two or more CD137 peptides etc..) or including a chromophore or radiochelator. However, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘500 by adding additional binding ligands in order to enhance binding affinity or targeting (to the cancer cell or immune cell), a well-known design choice with a reasonable expectation of success.
Furthermore, regarding instant claim 86, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘500 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-86, 89-91 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 3, 5-15, 18, 21-24 and 46 of Co-pending Application No. 18/271593 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
Co-pending Application No. 18/271593 claims “A method of treating a cancer in a patient, comprising administering to said patient a therapeutically effective amount of a heterotandem bicyclic peptide complex, or a pharmaceutically acceptable salt thereof, and an immuno-oncology agent, wherein the heterotandem bicyclic peptide complex comprises:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on the cancer cell is Nectin-4, and the first peptide ligand comprises an Nectin-4 binding bicyclic peptide ligand; conjugated via a linker to (b) one or more CD137 binding bicyclic peptide ligands; wherein each of said peptide ligands comprise a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (claim 1). Co-pending Application No. 18/271593 further claims wherein the reactive groups are cysteine residues (claim 2); two or more CD137 binding bicyclic peptide ligands (claim 3); specific CD137 peptides that overlap with the instant claims (claims 5-6); wherein the heterotandem bicyclic peptide complex comprises two CD137 binding bicyclic peptide ligands, wherein both of said two CD137 binding bicyclic peptide ligands have the same peptide sequence which comprises Ac-(SEQ ID NO: 11)-A (herein referred to as BCY8928), or a pharmaceutically acceptable salt thereof (claim 9); Nectin-4 binding bicyclic peptide ligands that overlap with the instant claims (claim 10-11); TATA as the scaffold (claim 22). The CD137 and Nectin-4 (claims 7 and 10) binding peptides overlap with the sequences of the instant claims.
Co-pending Application No. 18/271593 does not claim including a chromophore or radiochelator.
However, it would have been obvious to one of ordinary skill in the art to modify the composition of Co-pending Application No. 18/271593 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-86, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No. 12435107 (previously referred to as Co-pending Application No. 18/424386 (reference application)). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent No. 12435107 claims “A method of synthesizing compound BCY11863”. THe compound of BCY11863 comprises one nectin-4 binding peptide (SEQ ID NO:1 is the same as instant SEQ ID NO:1) and two CD137 binding peptides (SEQ ID NO:2 is the same as instant SEQ ID NO:11) that are encompassed by the sequences of the instant claims and the full compounds of instant claims 82-83 with linkers. US Patent No. 12435107 further claims TATA (Claim 20). US Patent No. 12435107 does not claim that the compound is in a pharmaceutical formulation and in salt form for administration or including a radiochelator or chromophore. However, the main utility of the conjugate in US Patent No. 12435107 is to be used for treating cancer and it would have been obvious to include an acceptable excipient, including water, in using the conjugate for treating cancer. Furthermore, in the process of making the conjugate, the conjugate is in salt form.
Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘107 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-77, 84-86, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-21 US Patent No. 11312749 B2 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent No. 11312749 B2 claims “A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to EphA2 and which has the sequence A-[HArg]-D-Ci[HyP]LVNPLCiiLEP[d1Nal]WTCiii (SEQ ID NO: 1); conjugated via an N-(acid-PEG3)-N-bis(PEG3-azide) linker to
(b) two second peptide ligands which bind to CD137 both of which have the sequence Ac—Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2);
or a pharmaceutically acceptable salt thereof,
wherein each of said peptide ligands comprise a polypeptide comprising three reactive cysteine groups (Ci, Cii and Ciii), separated by two loop sequences, and a molecular scaffold which is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and which forms covalent bonds with the reactive cysteine groups of the polypeptide such that two polypeptide loops are formed on the molecular scaffold;
wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine” (see claim 1)”. US Patent No. 11312749 B2 further claims wherein the peptide is in free acid form (claim 3); pharmaceutically acceptable excipient (claim 4). The CD137 peptides of US Patent. 11312749 B2 read on instant claims 73-76.
Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘749 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-86, 89-91are/remain rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-21 US Patent No. 11970553 B2 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
US Patent No. 11970553 B2 A method of treating cancer in a patient, comprising administering to the patient a heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand, which binds to Nectin-4 and which comprises the sequence CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 1); conjugated via an N-(acid-PEG3)-N-bis(PEG3-azide) linker to
(b) two second peptide ligands, each of which binds to CD137 and each of which comprises the sequence Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2);
or a pharmaceutically acceptable salt thereof,
wherein Ci, Cii and Ciii of SEQ ID NOs: 1 and 2 each from covalent bonds with a molecular scaffold comprising 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) thereby forming two polypeptide loops for each of SEQ ID NOs: 1 and 2; and
wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine.” US Patent No. 11970553 B2 further claims wherein the complex is a free acid (claim 10), in combination with a pharmaceutically acceptable excipient (claim 11). The Nectin-4 and CD137 peptides fall within the scope of instant claims 73-76, 79-81.
Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of US Patent No. ‘553 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
Claims 44, 67-77, 84-86, 89-91 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-6, 8-14, 16-22 of Co-pending Application No. 17/590875 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
Co-pending Application No. 17/590875 claims “A method of suppressing or treating cancer in a patient comprising administering to the patient a heterotandem bicyclic peptide complex, or pharmaceutically acceptable salt thereof, wherein the heterotandem bicyclic peptide complex comprises:(a) a first peptide ligand which binds to EphA2 and which has the sequence A-[HArg]- D-Ci[HyP]LVNPLCiLEP[d1Nal]WTCiii (SEQ ID NO: 1; BCY13118); conjugated via an N-(acid- PEG3)-N-bis(PEG3-azide) linker to (b) two second peptide ligands which bind to CD 137 both of which have the sequence Ac-CitBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2; BCY8928);wherein each of said peptide ligands comprise a polypeptide comprising three reactive cysteine groups (Ci,Ci and Ciii), separated by two loop sequences, and a molecular scaffold which is 1,1',1"- (1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and which forms covalent bonds with the reactive cysteine groups of the polypeptide such that two polypeptide loops are formed on the molecular scaffold; wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L- proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4- pentynoic acid and Nle represents norleucine,and wherein the cancer cells express EphA2” (Claim 5). Co-pending Application No. 17/590875 further claims free acid salt form (Claim 13); in combination with an acceptable excipient (claim 14). The CD137 peptides of the co-pending application read on the CD137 peptides of instant claims.
Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of Co-pending 17/590875 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants respectfully request that they be held in abeyance pending reconsideration in view of the instant response. Thus, the rejection is maintained.
New Objections
Claims 82-83 are objected to for the following informality: the limitation of “at the N-terminus” throughout both claims should be replaced with -at its N-terminus-.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 73, 75-76, 79-81 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.
Claims 73 and 79 and recite the following limitation “wherein [MerPro]I, Ci, Cii, Ciii and [Cysam]iii represent first (i), second (ii) and third (iii) reactive groups selected from cysteine, MerPro and Cysam… The wherein clause of claims 73 and 79 are internally inconsistent regarding the identity of the reactive groups. Specifically, the clause defines the term [MerPro]I as representing a “first (i)” reactive group selected from cysteine, MerPro and Cysam. The use of MerPro or Cysam as a variable placed holder for a position that may be occupied by a different chemical species (i.e. cysteine) is inherently contradictory. It is unclear if [MerPro] or [Cysam] in SEQ ID NO:15 (for example) is fixed as MerPro or Cysam only by virtue of the name or if it is variable and may be substituted by any member of the markush group. Because the claim is susceptible to multiple interpretations regarding the scope, the metes and bounds cannot be determined with reasonable certainty.
Claims 75-76 and 80-81 are also rejected due to their dependence on claims 73 or 79 and not further clarifying this point of confusion.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 80 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 80 is dependent on claim 79 and claims “wherein the Nectin-4 binding bicyclic peptide ligand comprises an amino acid sequence selected from:….[PYA]-[B-Ala]-{Sar10]-(SEQ ID NO:2)…” Claim 79 does not claim wherein the Nectin-4 binding peptide ligand comprises SEQ ID NO:2. Thus, this limitation broadens the scope of instant claim 79 and does not further limit.
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.
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 44, 67-86, 89-91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Co-pending Application No. 18/710083 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
Co-pending AN18/710083 claims “solid pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, Tris base, mannitol, and sodium hydroxide” (claim 1). Co-pending AN18/710083 further claims use in a pharmaceutical formulation (claims 14-18). BT7480 is a heterotandem bicyclic peptide complex comprising Nectin-4 binding peptide linked to two CD137 peptides via a linker (see paragraph 001 of specification) which falls within the scope and the sequences of the instant claims.
Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of Co-pending 18/710083 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 44, 67-86, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 6, 21-46 Co-pending AN17/663169 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A tumor-targeted CD137 agonist which is a heterotandem bicyclic peptide complex or a pharmaceutically acceptable salt thereof comprising:(a) a first peptide ligand which binds to a component present on a cancer cell, wherein the component present on a cancer cell is Nectin-4, EphA2, or PD-L1; conjugated via a linker to (b) two or more second peptide ligands which bind to a component present on an immune cell, wherein the component present on an immune cell is CD137;wherein each of said the first peptide ligand and the two or more second peptide ligands comprises a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold” (see claims 44, 90). The instant application further claims wherein the immune cell is WBCs, CD8 or CD4 (see claim 45); reactive groups of cysteine or cysteamine residues (see claim 73); wherein the two or more second peptide ligands comprise a CD137 binding bicyclic peptide ligand (see claim 73); CD137 binding peptide (SEQ ID Nos:5-12, 60-81) (claim 75); SEQ ID NO:11 (claim 74); N- and C-terminal modifications of the CD137 peptide (claims 75-76); wherein the cancer cell is HT1080, A549 etc… (Claim 77); Nectin 4 on the cancer cell (claim 78); nectin-4 binding bicyclic peptide ligand (claim 79); Nectin-4 peptide ligand as the first ligand (SEQ ID Nos:1, 3-4, 14-23, see claims 79-80, 82, Nectin-4:CD137(s)); TATA as the scaffold (claim 84); free acid salt thereof (Claim 85) and pharmaceutically acceptable excipients (claim 89, 91). The instant application claims specific agonists with linkers (see claims 82-83).
Co-pending Application 17/663169 claims A heterotandem bicyclic peptide complex comprising:(a) a first peptide ligand which binds to CD 137 on an immune cell;conjugated via a linker to (b) a second peptide ligand which binds to a component present on a cancer cell, wherein the component present on the cancer cell is Nectin-4; wherein each of said peptide ligands comprises a polypeptide comprising three cysteine residues, separated by two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that two polypeptide loops are formed on the molecular scaffold, wherein the first peptide ligand is a CD 137 binding bicyclic peptide ligand comprising an amino acid sequence selected from:CiIEEGQYCiiFADPY[Nle]Ciii (SEQ ID NO: 1);Ci[tBuAla]PE[D-Ala]PYCiiFADPY[Nle]Ciii (SEQ ID NO: 3);CiIEEGQYCiiF[D-Ala]DPY[Nle]Ciii (SEQ ID NO: 4);Ci[tBuAla]PK[D-Ala]PYCiiFADPY[Nle]Ciii (SEQ ID NO: 5);Ci[tBuAla]PE[D-Lys]PYCiiFADPY[Nle]Ciii (SEQ ID NO: 6);Ci[tBuAla]P[K(PYA)][D-Ala]PYCiiFADPY[Nle]Ciii (SEQ ID NO: 7);Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii (SEQ ID NO: 8);CiIEE[D-Lys(PYA)]QYCiiFADPY(Nle)Ciii (SEQ ID NO: 9); and[dCi] [dI] [dE] [dE] [K(PYA)] [dQ] [dY] [dCii] [dF] [dA] [dD] [dP] [dY] [dNle] [dCiii] (SEQ ID NO: 10); andwherein the second peptide ligand is a Nectin-4 binding bicyclic peptide ligand comprising an amino acid sequence selected from:CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 15);CiP Clip[1Nal][dD]CiiM[HArg]D[dW]STP[HyP][dW]Ciii (SEQ ID NO: 16);14333899 Application No.: 17/663,169 3 Docket No.: B1701.70048US01 CiP[1Nal][dK](Sar10-(B-Ala))CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 17); and CiPFGCiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 18); wherein Ci, Cii and Ciii represent first, second and third cysteine residues, respectively, Nle represents norleucine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline, dD represents aspartic acid in D-configuration, Sar10 represents 10 sarcosine units, B-Ala represents beta-alanine, or a pharmaceutically acceptable salt of said heterotandem bicyclic peptide complex” (claim 1). Co-pending Application 17/663169 further claims CD137 binding peptides and Nectin-4 peptides that overlap with the instant claims (claims 6 and 21-22); N-terminal modifications (claim 28); TATA as the scaffold (Claim 32); free acid or salt (claim 33); pharmaceutical formulation (claim 34).
Co-pending AN17/663169 does not claim two or more second peptide ligands (i.e. two or more CD137 peptides) or including radiochelator/chromophore. However, it would have been obvious to one of ordinary skill in the art to modify the composition of Co-pending AN17/663169 by adding additional binding ligands in order to enhance binding affinity or targeting (to the cancer cell or immune cell), a well-known design choice with a reasonable expectation of success. Furthermore, it would have been obvious to one of ordinary skill in the art to modify the composition of Co-pending AN17/663169 by including a chromophore or radio chelator for visualization or therapeutic use in cancer cells as this is a well-known design choice with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/ Examiner, Art Unit 1654