,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 .
2. Applicant’s response filed on 07/07/0226 is acknowledged.
3. Claims 43-68 are pending.
4. Applicant's election with traverse of Group I, claim 43-60 and 63 in the reply filed on 07/07/2026 is acknowledged. The traversal is on the ground(s) that the cited prior art is not available as a priority document. This is found persuasive but the Groups lack unity of invention in view of the contribution of the prior art cited in the instant Office Action. The Examiner has withdrawn the species election.
The requirement is still deemed proper and is therefore made FINAL.
5. Claims 61-62 and 64-68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07/07/2026.
6. Applicant’s IDS documents filed on 06/16/2023 and 08/16/2024 have been considered.
7. Claims 43-60 and 63 are currently under consideration for their full scope.
Nucleotide and/or Amino Acid Sequence Disclosures
8. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification at least on pages 11-12, 58 and 93 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Applicant is required to go through the entire specification to check for sequence compliance.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
9. 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.
10. Claims 43-60 and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-48 of copending Application No. 17/785,427 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 25-48 of 17/785,427 are directed to:
A bifunctional molecule comprising an interleukin 7 (IL-7) variant conjugated to a binding moiety, wherein: - the binding moiety binds to a target specifically expressed on immune cells surface, - the IL-7 variant presents at least 75% identity with a wild type human IL-7 (wth-IL-7) comprising SEQ ID NO: 1, wherein the variant comprises at least one amino acid mutation selected from the group consisting of (i) W142H, W142F or W142Y, (ii) C2S-C141S and C47S- C92S, C2S-C141S and C34S-C129S, or C47S-C92S and C34S-C129S, (iii) D74E, D74Q or D74N, iv) Q11E, Y12F, M17L, Q22E and/or K81R; or any combination thereof, the amino acid numbering being as shown in SEQ ID NO: 1, which i) reduces affinity of the IL-7 variant for IL-7 receptor (IL- 7R) in comparison to the affinity of wth-IL-7 for IL-7R, and ii) improves pharmacokinetics of the bifunctional molecule comprising the IL-7 variant in comparison with a bifunctional molecule comprising wth-IL-7 of claim 25; wherein the IL-7 variant comprises an amino acid substitution selected from the group consisting of W142H, W142F and W142Y, the amino acid numbering being as shown in SEQ ID NO: 1 of claim 26; wherein the IL-7 variant comprises a group of amino acid substitutions selected from the group consisting of C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, and C47S-C92S and C34S-C129S, the amino acid numbering being as shown in SEQ ID NO: 1 of claim 27; wherein the IL-7 variant comprises an amino acid substitution selected from the group consisting of D74E, D74Q and D74N, the amino acid numbering being as shown in SEQ ID NO: 1 of claim 28; wherein the IL-7 variant comprises SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 of claim 29; wherein the binding moiety comprises a heavy chain constant domain or a Fc domain of a human IgG1, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; and K322A and K444A of claim 30; wherein the binding moiety comprises a heavy chain constant domain or a Fc domain of a human IgG4, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E.17 and K444A of claim 31; wherein the immune cell is a T cell or an exhausted T cell of claim 32; wherein the target is expressed by T cells and the binding moiety binds to a target selected from the group consisting of PD-1, CD28, CD80, CTLA-4, BTLA, TIGIT, CD160, CD40L, ICOS, CD27, OX40, 4-1BB, GITR, HVEM, Tim-1, LFA-1, TIM3, CD39, CD30, NKG2D, LAG3, B7-1, 2B4, DR3, CD101, CD44, SIRPG, CD28H, CD38, CXCR5, CD3, PDL2, CD4 and CD8 of claim 33; wherein the target is expressed by T exhausted cells and the binding moiety binds to a target selected from the group consisting of PD-1, CTLA-4, BTLA, TIGIT, LAG3 and TIM3 of claim 34; wherein the binding moiety is an antibody or an antigen fragment thereof, and the N-terminus of the IL-7 variant is fused to the C-terminus of a heavy or light chain constant domain of the antibody or antibody fragment thereof, optionally via a peptide linker of claim 35; wherein the IL-7 variant is fused to the binding moiety by a peptide linker selected from the group consisting of GGGGS (SEQ ID NO: 68), GGGGSGGGS (SEQ ID NO: 67), GGGGSGGGGS (SEQ ID NO: 69) and GGGGSGGGGSGGGGS (SEQ ID NO: 70) of claim 36; wherein the molecule comprises a first monomer comprising an antigen-binding domain covalently linked via its C-terminal end to N-terminal end of a first heterodimeric Fc chain optionally via a peptide linker, said first heterodimeric Fc chain being covalently linked by the C-terminal end to the N- terminal end of the IL-7 variant, optionally via a peptide linker, and a second monomer comprising a complementary second heterodimeric Fc chain devoid of antigen-binding domain of claim 37;
wherein, in the second monomer, the complementary second heterodimeric Fc chain covalently linked to the IL-7 variant, optionally via a peptide linker of claim 38; wherein the molecule comprises a first monomer comprising an antigen-binding domain covalently linked by C-terminal end to N-terminal end of a first heterodimeric Fc chain, optionally via a peptide linker, said first heterodimeric Fc chain being devoid of IL-7 variant, and a second monomer comprising a complementary second heterodimeric Fc chain devoid of antigen-binding domain, said second heterodimeric Fc chain being covalently to the IL-7 variant, optionally via a peptide linker of claim 39; wherein the molecule comprises a first monomer comprising an antigen-binding domain covalently linked via its C-terminal end to N-terminal end of a first heterodimeric Fc chain optionally via a peptide linker, and a second monomer comprising an antigen-binding domain covalently linked via C- terminal end to N-terminal end of a complementary second heterodimeric Fc chain optionally via a peptide linker, wherein only one of heterodimeric Fc chains is covalently linked by the C- terminal end to the N-terminal end of the IL-7 variant of claim 40; wherein the antigen- binding domain is a Fab domain, a Fab', a single-chain variable fragment (scFV) or a single domain antibody (sdAb) of claim 41; wherein the antigen- binding domain comprises: (i) a heavy chain comprising a CDR1 of SEQ ID NO: 51, a CDR2 of SEQ ID NO: 53 and a CDR3 of SEQ ID NO: 55, 56, 57, 58, 59, 60, 61 or 62; and (ii) a light chain comprising a CDR1 of SEQ ID NO: 64 or SEQ ID NO: 65, a CDR2 of SEQ ID NO: 66 and a CDR3 of SEQ ID NO: 16 of claim 42; wherein the antigen- binding domain comprises: (a) a heavy chain variable region (VH) comprising SEQ ID NO: 18, 19, 20, 21, 22, 23, 24 or 25; (b) a light chain variable region (VL) comprising SEQ ID NO: 27 or SEQ ID NO: 28 of claim 43; wherein the antigen- binding domain comprises or consists essentially of a heavy chain variable region (VH) of SEQ ID NO: 24 and a light chain variable region (VL) of SEQ ID NO: 28 of claim 44; a pharmaceutical composition comprising the bifunctional molecule according to claim 25 and a pharmaceutically acceptable carrier of claim 47; and a method of treating cancer or an infectious disease comprising the administration of a molecule according to claim 25, or a pharmaceutical composition comprising said molecule, to a subject having cancer or an infectious disease of claim 48.
The reference sequences and sequence identification numbers are identical to the instant sequences and sequence identification numbers.
The reference teachings anticipate the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 43-60 and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-59 of copending Application No. 17/414,970 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 34-59 are directed to a bifunctional molecule comprising: (a) an anti-human PD-1 antibody or an antigen-binding fragment thereof, which anti-human PD- 1 antibody or antigen-binding fragment comprises a full-length IgG Fc domain and further comprises a constant light chain, wherein the C-terminus of the IgG Fc domain and/or the C- terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment is covalently linked to, (b) a human interleukin 7 (IL-7) variant having at least 90% sequence identity to SEQ ID NO: 51, wherein said IL-7 variant comprises the mutation W142H, and binds to an IL-7 receptor; and further wherein the covalent linkage of the IL-7 variant to the C-terminus of the IgG Fc domain and/or to the C-terminus of the constant light chain of the anti-human PD-1 antibody or antigen-binding fragment thereof is direct or by a flexible linker peptide of claim 34; wherein the N- terminus of the human IL-7 variant is connected to the C-terminus of said full-length IgG Fc domain and/or to the constant light chain of said anti-human PD-1 antibody or antigen-binding fragment thereof of claim 35; wherein said anti- human PD-1 antibody or said antigen-binding fragment is a chimeric, humanized or human antibody or antigen-binding fragment of claim 36; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof, comprises: (i) a variable heavy chain region (VH) comprising the same VH CDR1, CDR2 and CDR3 peptides as one of SEQ ID NO:19, 22 or 24 and (ii) a variable light chain region (VL) comprising the same CDR1, CDR2 and CDR3 peptides as are in the amino acid sequence of SEQ ID NO:28, wherein said VH and VL CDRs are defined according to Kabat of claim 37; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof, comprises or consists of (i) a variable heavy chain region (VH) comprising the same amino acid sequence as any one of SEQ ID NO:19, 22 or 24 and (ii) a variable light chain region (VL) comprising the same amino acid sequence as SEQ ID NO:28, wherein said VH and VL CDRs are defined according to Kabat of claim 38; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof, comprises or consists of (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence of SEQ ID NO: 24; and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence of SEQ ID NO: 28 of claim 39; wherein, the anti- human PD-1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, tisleizumab, pidilizumab, camrelizumab, spartalizumab, genolimzumab, AGEN2034, PF-06801591, JNJ-63723283, LZM-009, MGA012, BCD-100, BI-754091, BAT-1306, and BI-754091comprises said W142H mutation comprises or consists of an amino acid sequence having at least 95% identity with a wild type human IL-7 (wth-IL-7) having the sequence of SEQ ID NO: 51 of claim 41; wherein the IL-7 variant comprises or consists of an amino acid sequence which only differs from the amino acid sequence set forth in SEQ ID NO: 51 by said W142H mutation of claim 42; wherein the IL-7 variant which comprises said W142H mutation i) possesses reduced affinity for the IL-7 receptor (IL-7R) in comparison to the affinity of wild-type IL-7 for IL-7R, and ii) said IL-7 variant improves the pharmacokinetics of the bifunctional molecule comprising the IL-7 variant in comparison with a bifunctional molecule comprising wild-type IL-7 wherein said wild-type IL-7 consists of the amino acid sequence of SEQ ID NO: 51 of claim 43; wherein the IL-7 variant which comprises said W142H mutation further comprises another amino acid substitution or a group of amino acid substitutions selected from the group consisting of (i) C2S C141S, C47Sand C92S; or C2S, C141S, C34Sand C129S;or C47S, C92S, C34S, and C129S(ii) D74E, D74Q or D74N, (iii) Q11E, Y12F, M17L, Q22E and/or K81R; or any combination thereof of claim 44; wherein the IL-7 variant comprises or consists of the amino acid sequence set forth in SEQ ID NO: 56 of claim 45; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and wherein numbering for each of the afore-identified substitutions is according to EU numbering of claim 46; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E; and K322A; and wherein for each of the afore-identified substitutions the numbering is according to EU numbering of claim 47; wherein the covalent linkage is by a flexible peptide linker of claim 48; wherein the anti- human PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; wherein the numbering of each of the afore-identified substitutions is according to EU numbering; and wherein the C-terminus of the IgG Fc domain in the anti-human PD-1 antibody or antigen binding fragment thereof is linked to IL-7 variant by the flexible peptide linker (GGGGS)3 (SEQ ID NO. 70) of claim 49; pharmaceutical composition comprising the bifunctional molecule according to of claim 34 and a pharmaceutically acceptable carrier of claim 54.
The reference teachings anticipate the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112(b)
12. 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.
13. Claims 44, 48-49 and 51 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 44 recites numerous groups of mutations and then recites “or any combination thereof”. It is unclear if the mutations can be picked and chosen amongst all of the recited mutations or if the combination of mutations must be within the groups.
Claims 48-49 and 51 recite specific heavy chain constant domain substitutions, but there is no reference to the numbering scheme, making the claims unclear.
Correction is required.
Claim Rejections - 35 USC § 112(a)
14. 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.
15. Claims 43-56 and 63 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.
Claim 25 is drawn to a bifunctional molecule comprising an IL-7 variant. Claims 44, 46 and 57 further limit the variant to specific single substitutions or combination of single substitutions compared to wth-IL-7.
The specification teaches that the IL-7 variant differs by at least one amino acid mutation which i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) in comparison to the affinity of wth-IL-7 for IL-7R and ii) improves pharmacokinetics of the IL7 variant in comparison to wth-IL-7. However, the specification only discloses the specific variants comprising SEQ ID NOs: 2-15. The specification does not disclose any other examples of IL-7 “variants” that i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) in comparison to the affinity of wth-IL-7 for IL-7R and ii) improves pharmacokinetics of the IL7 variant in comparison to wth-IL-7. The specification further does not provide any guidance on which residues, other than those comprised in SEQ ID NOs: 2-15, could be modified while still maintaining the function of i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) in comparison to the affinity of wth-IL-7 for IL-7R and ii) improves pharmacokinetics of the IL7 variant in comparison to wth-IL-7.
One means of providing adequate written description and evidence of
possession of a claimed genus is through providing sufficient distinguishing identifying
characteristics of the genus. The factors to be considered include disclosure of
complete or partial structure, physical and/or chemical properties, functional
characteristics, structure/function correlation, methods of making the claimed product,
or any combination thereof. In this case, the claim does not require that the modifications, other than those specifically listed, be made at specific amino acid residues or in a particular region of the sequence, and thus, the claims are drawn to a broad genus of IL-7 variants with up to 38 substitutions and/or deletions in SEQ ID NO: 1.
Making deletions, insertions, or substitutions to a polypeptide sequence, while requiring the polypeptide to still maintain its function, is highly unpredictable. The structure of variable sequences of proteins does not predictably correlate with the function thereof.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v.
American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he
description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
A "representative number of species" means that the species, which are
adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species
to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if
the disclosure "indicates that the patentee has invented species sufficient to constitute
the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v.
Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir.
2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus
after only describing a limited number of species because there may be unpredictability
in the results obtained from species other than those specifically enumerated."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, based on the lack of teachings in the specification and the teachings in the art, Applicant has failed to meet the written description requirement of an IL-7 variant encompassed by the claimed invention.
16. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
17. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
18. Claims 43-60 and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Morello et al. (PTO-892; Reference U).
Morello et al. teaches despite the clinical success of anti-PD(L)1 therapy, the majority of patient remain unresponsive or fail to develop a durable response. We explored a second generation of PD-1 antibody by fusing IL-7 cytokine to the Fc portion, called BiCKI® IL-7. The high affinity of the anti PD-1 antibody will allow the concentration/retention of the drug into the tumor microenvironment and preferentially deliver IL-7 in cis-dependent manner to PD-1+ cells. IL-7 is an optimal target for immunotherapy to preferentially stimulate effector T-cell (Teff) functions over regulatory T-cells (Treg)due to the differential expression of IL-7R and poor capacity of IL-7 to stimulate Treg proliferation. Moreover, It has been published that PD-1 blockades increase IL-7R expression and improve IL-7 signaling in exhausted T-cells rationalizing our combinatorial approach.
Results Our anti PD-1/IL-7 bispecific antibody efficiently blocks the PD-1/PD-L1 and PD-L2 interactions and the PD-1-mediated inhibitory signal (pSHP1) and in parallel activates IL-7R pSTAT5 signaling into T cells. Anti PD-1/IL-7 preferentially binds in cis to T cells coexpressing PD-1 and CD127 enabling a selective activation of primed antigen- experienced T cells over PD1-negative (e.g. naïve) cells. A high affinity/avidity of the molecule was observed using biosensor when both receptor CD127 and PD-1, supporting the cis-targeting activity of the drug. Using in vitro T cell activation bioassay, we observed that IL-7 portion fused to the anti-PD-1 synergizes to enhance TCR mediated signaling (NFAT) through activation of the non-canonical pathway while IL-7 in combination with anti-PD1 (two separates product) has no additive effect. Although IL-7R expression decrease over chronic stimulation of Teff cells, we demonstrated that IL-7 efficiently activates progenitor and some fully-exhausted human T-cells (pSTAT5) and maintain their proliferation and survival capacity. This IL-7R signaling activation was associated with a significant increased IFNγ secretion using ex-vivo fresh human tumor explant culture. A significant higher IFNγ production was obtained with anti PD-1/IL-7compared to anti PD-1 treatment alone, including in non-responder patients to anti-PD1, suggesting that the anti PD-1/IL-7 bispecific can reactivate TILs that are resistant to PD-1 therapy. Knowing that Tregs have a key suppressive function, we also explored the possibility that anti-PD-1/IL-7 affect Treg functions. In a human Treg/Teff coculture assay, anti PD-1/IL-7 abrogates the Treg capacity to inhibit proliferation and IFN-g secretion of CD8+ Teff. Moreover, IL-7 and anti-PD-1/IL-7 does not stimulate Treg proliferation, in contrast to IL-2 and IL-15.
As evidenced by the specification, the BiCKI® IL-7 comprises W142H and instant SEQ ID NOs 24 and 28/ SEQ ID NOs 71 and 72 and is encompassed by the recitations of claims 43-60 and 63.
The reference teachings anticipate the claimed invention.
19. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
20. Claims 43-60 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Morello et al. (PTO-892; Reference U) in view of WO 2019/144945 (PTO-892; Reference N).
Morello et al has been discussed supra.
The claimed invention differs from the prior art in the recitation of additional amino acid changes in the IL-7 molecule.
WO 2019/144945 teaches a PD-L1 inhibitor (binding moiety) fused to an IL-7 protein through a peptide linker (bifunctional molecules) [page 2, third paragraph], wherein the IL-7 has an amino acid residue other than Trp at location 142 [page 4, first paragraph]. WO 2019/144945 also teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function [page 29, first paragraph]. WO 2019/144945 further teaches that a series of single site mutations on W142 of IL7 were generated, with amino acids divided into four categories: non-polar (inclusive of F), polar (inclusive of Y), positively charged (inclusive of H), and negatively charged, with a few representative amino acids from each group selected to construct the anti-PDL1-IL7 molecules [page 29, fourth paragraph]. WO 2019/144945 also teaches that the IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142 [page 30, second paragraph]. WO 2019/144945 also teaches that PD-L1 is expressed on T cells, NK cells, and macrophages (immune cells) [page 2, second paragraph]. Thus, the anti-PDL1 inhibitor (binding moiety) of WO 2019/144945 would necessarily bind to PDL1 (a target) specifically expressed on immune cells surface.
It would have been obvious to one of ordinary skill in the in view of the teachings of WO 2019/144945 to have arrived at the claimed bifunctional molecule of Morello et al. (i.e. IL7 variant conjugated to a binding moiety) wherein the IL-7 variant comprises the amino acid mutation of W124H, W142F, or W142Y, because WO 2019/144945 teaches that these are mutations that could be chosen for W142 and generally suggests that IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142. One of ordinary skill in the art would have been motivated to do the W142H substitution because WO 2019/144945 teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function. Further, since the structure of the IL7 variant is 100% identical the IL7 variant would necessarily i) reduce affinity for IL-7 and ii) improve pharmacokinetics.
Instant SEQ ID NO: 5 comprises only a W142H mutation compared to wth-IL-7 SEQ ID NO: 6 comprises only a W142Y mutation compared to wth-IL-7, and SEQ ID NO: 7 comprises only a W142F mutation to wth-IL-7. Thus, the teachings of WO 2019/144945 would result in an IL-7 variant comprising SEQ ID NO: 5, 6, or 7.
SEQ ID NOs: 1-2 of WO 2019/144945 have 100% sequence identity to SEQ ID NOs: 69 and 70, respectively, of the instant claim.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
20. Claims 43-60 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Morello et al. (PTO-892; Reference V) in view of WO 2019/144945 (PTO-892; Reference N).
Morello et al. teaches Our anti PD-1/IL-7 bispecific antibody efficiently blocks the PD-1/PD-L1 and PD-L2 interactions and the PD-1-mediated inhibitory signal (pSHP1). Importantly, we observed that the IL-7 portion synergizes with the anti-PD-1 to enhance TCR mediated signaling (NFAT). Although IL-7R expression on T cells decrease over repeated antigen stimulation, we demonstrated that IL-7 still efficiently activate partially and fully-exhausted human T-cells (pSTAT5) and maintain their proliferation capacity. We next characterized sensitivity of TILs to IL-7 in multiple orthotopic mouse models. In PD-1 sensitive tumor (Mesothelioma), only 10% of TILs express IL-7R whereas in PD-1 resistant model (Hepatocarcinoma and Lung carcinoma), 40-60% of TILs (CD4 and CD8) express IL-7R and respond to IL-7 stimulation ex vivo as measured by pSTAT5 signaling. These data suggest that the anti PD-1/IL-7 bispecific can reactivate TILs that are resistant to PD-1 therapy. Knowing that Tregs have a key suppressive function, we also explored the possibility that the anti-PD-1/IL-7 fusion protein affect Treg functions. In a human Treg/Teff coculture assay, we observed that the anti PD-1/IL-7 molecule abrogate the Treg capacity to inhibit proliferation and IFN-gamma secretion of CD8+ Teff. Moreover, IL-7 and the anti-PD-1/IL-7 does not stimulate Treg proliferation, in contrast to IL-2 and IL-15 cytokines.
The claimed invention differs from the prior art in the recitation of additional amino acid changes in the IL-7 molecule.
WO 2019/144945 teaches a PD-L1 inhibitor (binding moiety) fused to an IL-7 protein through a peptide linker (bifunctional molecules) [page 2, third paragraph], wherein the IL-7 has an amino acid residue other than Trp at location 142 [page 4, first paragraph]. WO 2019/144945 also teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function [page 29, first paragraph]. WO 2019/144945 further teaches that a series of single site mutations on W142 of IL7 were generated, with amino acids divided into four categories: non-polar (inclusive of F), polar (inclusive of Y), positively charged (inclusive of H), and negatively charged, with a few representative amino acids from each group selected to construct the anti-PDL1-IL7 molecules [page 29, fourth paragraph]. WO 2019/144945 also teaches that the IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142 [page 30, second paragraph]. WO 2019/144945 also teaches that PD-L1 is expressed on T cells, NK cells, and macrophages (immune cells) [page 2, second paragraph]. Thus, the anti-PDL1 inhibitor (binding moiety) of WO 2019/144945 would necessarily bind to PDL1 (a target) specifically expressed on immune cells surface.
It would have been obvious to one of ordinary skill in the in view of the teachings of WO 2019/144945 to have arrived at the claimed bifunctional molecule of Morello et al. (i.e. IL7 variant conjugated to a binding moiety) wherein the IL-7 variant comprises the amino acid mutation of W124H, W142F, or W142Y, because WO 2019/144945 teaches that these are mutations that could be chosen for W142 and generally suggests that IL7 variants have different and attenuated IL7 activities by modifying a single site mutation of W142. One of ordinary skill in the art would have been motivated to do the W142H substitution because WO 2019/144945 teaches that IL7 variants with a different activity level may have better synergism with the anti-PDL1 function. Further, since the structure of the IL7 variant is 100% identical the IL7 variant would necessarily i) reduce affinity for IL-7 and ii) improve pharmacokinetics.
Instant SEQ ID NO: 5 comprises only a W142H mutation compared to wth-IL-7 SEQ ID NO: 6 comprises only a W142Y mutation compared to wth-IL-7, and SEQ ID NO: 7 comprises only a W142F mutation to wth-IL-7. Thus, the teachings of WO 2019/144945 would result in an IL-7 variant comprising SEQ ID NO: 5, 6, or 7.
SEQ ID NOs: 1-2 of WO 2019/144945 have 100% sequence identity to SEQ ID NOs: 69 and 70, respectively, of the instant claim.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
21. No claim is allowed.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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September 19, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641
Prosecution Insights