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 .
Claims 1, 11-12, 14, 17-18 and 58 pending.
Claims 1, 11-12, 14, 17-18 and 58, drawn to a construct that is a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1 that read on construct has been extended to include SEQ ID NO: 704, 705, 710-725, 729-740, 1475 and residues 20-732 of SEQ ID NO: 1475 (claim 12) comprising a dAb of SEQ ID NO: 59 as the species of dAb, Gly-Ser linker, human serum albumin (HSA) or modified Fc as the species of activity modifier (half-life extending moiety, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 16, 2026 been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Specification
The substitute specification filed March 16, 2026 has been entered.
Objection and Rejection Withdrawn
The objection to the Abstract is withdrawn in view of the amendment filed March 16, 2026.
The objection to the specification is withdrawn in light of the substitute specification filed March 16, 2026.
The objection to claims 2, 6, 11, 12, 16 and 19 is withdrawn in view of the claim amendment.
The rejection of claims 1, 15 and 16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
The rejection of claims 20-26 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph is withdrawn in light of the claims have been canceled.
The rejection of claims 1-4, 6-10, 13 and 15 under 35 U.S.C. 102 (a)(1) as being anticipated by Jespers (US20100254972, published Oct 7, 2010; PTO 892) as evidenced by WO 03076567 publication, published September 18, 2003; PTO 892) is withdrawn in view of the claim amendment. In particular, Jespers teaches fusion protein (para. [0164]) comprising dAb to another dAb that binds to human serum albumin via (GGGGS)n=3 linker, see para. [0188], [0265], [0267] as opposed to dAb fused to human serum albumin via a linker.
The rejection of claims 1, 5, 6, 16, 17 and 19 under 35 U.S.C. 103 as being unpatentable over Jespers (US20100254972, published Oct 7, 2010; PTO 892) in view of Kumar (US20180163187, published June 14, 2018; PTO 892) is withdrawn in view of the claim amendment.
The rejection of claims 1, 2 and 11 under 35 U.S.C. 103 as being unpatentable over Jespers (US20100254972, published Oct 7, 2010; PTO 892) in view of Mendlein (WO2018195338 publication (published Oct 25, 2018; PTO 892) is withdrawn in view of the claim amendment. The addition of Mendlein does not cure the deficiency of Jespers.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 11, 14, 17-18 and 58 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
Claim 1 encompass any construct, comprising a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1:
(TNFR 1 inhibitor)n-linkerp-(activity modifier)q, wherein:
each of n and q is an integer, and each is independently 1-or 2, p is 1;
a TNFR1 inhibitor is a molecule that binds TNFR1 to inhibit (antagonize) activity of TNFR1;
the TNFRI inhibitor comprises a domain antibody (dAb), or antigen-binding portion thereof or comprises the sequence of amino acids set forth in any of SEQ ID NOs: SEQ ID NOs:54-83, 503-672, 1478, and 1479 or
a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity;
an activity modifier is a moiety that modulates or alters the activity or the pharmacological property of the construct compared to the construct in the absence of the activity modifier;
the activity modifier is a modified Fe or human serum albumin (HSA); the modified Fc is a modified Fc that has one or more of
a) a modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and
c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP); and
the linker is selected from the group consisting of:
a) a linker that comprises all or a portion of the hinge sequence of trastuzumab,
SCDKTH (corresponding to residues 222-227 of SEQ ID NO:26) or up to the full sequence of
the hinge region of trastuzumab, that contains or has the sequence EPKSCDKTHTCPPCP
(corresponding to residues 219-233 of SEQ ID NO:26), or at least 5, 6, 7, 8, 9, 10, or 11
contiguous residues thereof, or residues ESKYGPPCPPCP, set forth as residues 212-223 of SEQ
ID NO:29, or a sequence having at least 98% or 99% sequence identity thereto that is a linker;
b) a GS linker selected from among linker comprising SEQ ID NOs. 814-830, which
comprise (GlySer)n, where n= 1-10; (GlySer₂); (Gly4Ser)n, where n= 1-10; (Gly₃Ser)ₙ, where n=
1-5; (SerGly₄)ₙ, where n= 1-5; (GlySerSerGly)n, where n= 1-5; GSGGSSGG (SEQ ID NO: 820);
GSSSGSGSGSSG (SEQ ID NO: 821); GSSSGSGSGSSGG (SEQ ID NO: 822); GGSSGG (SEQ ID NO: 823); GGSSGGSGGSSSG (SEQ ID NO: 824); GSSSGSGSGGSSSGSGSG (SEQ ID NO: 825);
GGSSGGSSGGGSSGGSSG (SEQ ID NO: 826); and GSSSGS (SEQ ID NO: 827);
c) a linker that comprises a GS linker and all or a portion of the hinge sequence of
trastuzumab, corresponding to residues EPKSCDKTHTCPPCP, set forth as residues 219-233 of
SEQ ID NO:26;
d) a linker that comprises a GS linker and comprises the sequence SCDKTH,
corresponding to residues 217-222 of SEQ ID NO:31; and
e) a linker that comprises a GS linker and all or a portion of the hinge sequence of
nivolumab, corresponding to residues 212-223 of SEQ ID NO:29.
Claim 11 encompasses the construct of claim 1 that comprises a linker, wherein the dAb comprises SEQ ID NO:59 or a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity.
Claim 17 encompasses the construct of claim 1, comprising a human serum albumin (HSA) linked to the dAb directly or via a linker, wherein the dAb comprises the sequence of amino acids set forth in SEQ ID NO:54 or 59.
Claim 18 encompasses the construct of claim 1, comprising residues 20-732 of SEQ ID NO:1475, containing the dAb of SEQ ID NO:59, linked via a linker to HSA, as set forth in SEQ ID NO:1475, or a construct having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the construct of SEQ ID NO: 1475 and having TNFR1 antagonist activity.
Claim 58 encompasses the construct of claim 1 comprising the dAb of sequence ID NO:59 and
the modified Fc.
The specification discloses just five exemplary TNFR1 antagonist molecules that are produced for initial evaluation. The TNFR1 antagonist molecules include an H398-derived scFv (SEQ ID NO:678), containing one V.sub.L and one V.sub.H domain of H398, linked together by a (GGGGS).sub.3 peptide linker; the TNFR1 antagonist domain antibody (dAb) DOM1h-574-16 (SEQ ID NO:57); the TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO:58); a fusion protein (SEQ ID NO:704), containing the TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO:54) from DMS5541 (described elsewhere herein), fused to the anti-serum albumin dAb (albudAb) of DMS5541 (DOM7h-11-3; SEQ ID NO:52) by a (GGGGS).sub.3 peptide linker; and a fusion protein (SEQ ID NO:705), containing the anti-TNFR1 dAb designated DOM1h-131-206 (SEQ ID NO:59), fused to the anti-serum albumin dAb (albudAb or DOM7h-11-3; SEQ ID NO:52) of DMS5541 by a (GGGGS).sub.3 peptide linker. The insertion of a (GGGGS).sub.3 linker in the H398 scFv, and in the DOM1h-574-208 and DOM1h-131-206 fusion proteins, provides more flexibility between the V.sub.H and V.sub.L domains, and the two dAbs, respectively, and increases the stability and resistance to denaturation of the molecules, improving the manufacturing process. The sequences of each of these TNFR1 antagonist molecules is provided in Table 12, below
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567
803
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297
765
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598
740
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265
737
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650
725
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435
740
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193
742
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150
772
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However, the specification does not describe the structure-identifying information, e.g., amino acid sequence about the corresponding makeup of the claimed Fc having any one or more a) a modification(s) to introduce knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) in claim 1.
The term “modified” encompasses substitution, deletion, addition or a combination thereof. The specification does not describe where and what amino acid within the Fc of which antibody, e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD from which species to be substituted, deleted, added or a combination thereof such that the modified Fc has the claimed functions, knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed construct comprising any modified Fc themselves.
The specification does not disclose a representative number of species falling within the scope of the genus or structural features common to the members of the genus. A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property. Thus, one of skill in the art cannot "visualize or recognize" the members of the genus of the modified Fc encompassed by the claimed construct set forth in claims 1, 11, 14, 17-18 and 58 to demonstrate possession at the time of filing.
At the time the invention was made, it was known in the prior art that small changes in antigen structure profoundly affect antibody-antigen interactions.
For example, Lund et al. (of record, The Journal of Immunology 1996, 157:4963-4969, PTO 892) show that even a single amino acid replacement within the CH2 domain of IgG can alter the glycosylation profile of an antibody therefore influence its effector functions of Fc receptor binding and complement activation (see entire document, particularly Discussion on pages 4966-4968).
Lazar et al. (WO 03/074679 of record) teach that the determinants of antibody properties, such as stability, solubility and affinity for antigen, important to its functions are overlapping; thus engineering an antibody to be more soluble may cause a loss in affinity for its antigen (see entire document, particularly page 3). Further, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
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.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a construct that is a tumor necrosis factor receptor 1 (TNFR1) antagonist that is a fusion protein comprising a tumor necrosis factor receptor 1 (TNFR1) comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 704, SEQ ID NO: 705, SEQ ID NO: 710 to 725, SEQ ID NO: 729 to 740, SEQ ID NO: 1475, residues 20-732 of SEQ ID NO: 1475 and a variant having at least 95% sequence identity to SEQ ID NO: SEQ ID NO: 705, SEQ ID NO: 710 to 725, SEQ ID NO: 729 to 740, SEQ ID NO: 1475, or residues 20-732 of SEQ ID NO: 1475, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicants’ arguments filed March 16, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that claim 1 is amended to define and describe each element of the claims by reciting specific sequences of the TNFR1 inhibitors, the linkers, and the modified Fc's, thereby providing structure for each of the elements. Claim 1 is amended to recite the sequences of linkers, which all are exemplified and described in the application (see, e.g., Section F. 4.c.1,which details and describes the linkers; see also section F.4.c, which also describes and details linkers; and see, also the sequence listing, which provides sequences of the all of the linkers recited in the claims).
The application details and exemplifies assembly of the various components, and shows that the resulting constructs have activity as claimed and improved properties compared to the cited prior art.
Claim 17, which depends on claim 1, limits claim 1 to constructs that comprise a human serum albumin (HSA), an optional linker, and the dAb of SEQ ID NO: 54 or 59, which are not only detailed in the application but are exemplified in the working examples. Therefore, Applicant had possession at the at the time of the earliest claimed priority date of the constructs of claims 1, 11, and 17.
In response, the amendment to claims 1, 11 and 17 is acknowledged.
Claim 1 encompass any construct, comprising a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1:
(TNFR 1 inhibitor)n-linkerp-(activity modifier)q, wherein:
each of n and q is an integer, and each is independently 1-or 2, p is 1;
a TNFR1 inhibitor is a molecule that binds TNFR1 to inhibit (antagonize) activity of TNFR1;
the TNFRI inhibitor comprises a domain antibody (dAb), or antigen-binding portion thereof or comprises the sequence of amino acids set forth in any of SEQ ID NOs: SEQ ID NOs:54-83, 503-672, 1478, and 1479 or
a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity;
an activity modifier is a moiety that modulates or alters the activity or the pharmacological property of the construct compared to the construct in the absence of the activity modifier;
the activity modifier is a modified Fe or human serum albumin (HSA); the modified Fc is a modified Fc that has one or more of
a) a modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and
c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP); and
the linker is selected from the group consisting of:
a) a linker that comprises all or a portion of the hinge sequence of trastuzumab,
SCDKTH (corresponding to residues 222-227 of SEQ ID NO:26) or up to the full sequence of
the hinge region of trastuzumab, that contains or has the sequence EPKSCDKTHTCPPCP
(corresponding to residues 219-233 of SEQ ID NO:26), or at least 5, 6, 7, 8, 9, 10, or 11
contiguous residues thereof, or residues ESKYGPPCPPCP, set forth as residues 212-223 of SEQ
ID NO:29, or a sequence having at least 98% or 99% sequence identity thereto that is a linker;
b) a GS linker selected from among linker comprising SEQ ID NOs. 814-830, which
comprise (GlySer)n, where n= 1-10; (GlySer₂); (Gly4Ser)n, where n= 1-10; (Gly₃Ser)ₙ, where n=
1-5; (SerGly₄)ₙ, where n= 1-5; (GlySerSerGly)n, where n= 1-5; GSGGSSGG (SEQ ID NO: 820);
GSSSGSGSGSSG (SEQ ID NO: 821); GSSSGSGSGSSGG (SEQ ID NO: 822); GGSSGG (SEQ ID NO: 823); GGSSGGSGGSSSG (SEQ ID NO: 824); GSSSGSGSGGSSSGSGSG (SEQ ID NO: 825);
GGSSGGSSGGGSSGGSSG (SEQ ID NO: 826); and GSSSGS (SEQ ID NO: 827);
c) a linker that comprises a GS linker and all or a portion of the hinge sequence of
trastuzumab, corresponding to residues EPKSCDKTHTCPPCP, set forth as residues 219-233 of
SEQ ID NO:26;
d) a linker that comprises a GS linker and comprises the sequence SCDKTH,
corresponding to residues 217-222 of SEQ ID NO:31; and
e) a linker that comprises a GS linker and all or a portion of the hinge sequence of
nivolumab, corresponding to residues 212-223 of SEQ ID NO:29.
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.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Further, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
The genera encompass by the claims are of large size and substantial variability.
The specification does not describe the structure-identifying information, e.g., amino acid sequence about the corresponding makeup of the claimed Fc having any one or more a) a modification(s) to introduce knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) in claim 1.
The term “modified” encompasses substitution, deletion, addition or a combination thereof. The specification does not describe where and what amino acid within the Fc of which antibody, e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD from which species to be substituted, deleted, added or a combination thereof such that the modified Fc has the claimed functions, knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed construct comprising any modified Fc themselves.
At the time the invention was made, it was known in the prior art that small changes in antigen structure profoundly affect antibody-antigen interactions.
For example, Lund et al. (of record, The Journal of Immunology 1996, 157:4963-4969, PTO 892) show that even a single amino acid replacement within the CH2 domain of IgG can alter the glycosylation profile of an antibody therefore influence its effector functions of Fc receptor binding and complement activation (see entire document, particularly Discussion on pages 4966-4968).
Lazar et al. (WO 03/074679 of record) teach that the determinants of antibody properties, such as stability, solubility and affinity for antigen, important to its functions are overlapping; thus engineering an antibody to be more soluble may cause a loss in affinity for its antigen (see entire document, particularly page 3).
The specification does not disclose a representative number of species falling within the scope of the genus or structural features common to the members of the genus. A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property. Thus, one of skill in the art cannot "visualize or recognize" the members of the genus of the modified Fc encompassed by the claimed construct set forth in claims 1, 11, 14, 17-18 and 58 to demonstrate possession at the time of filing.
While the Federal Circuit has recognized that “the written description requirement can in some cases be satisfied by functional description,” it has made clear that “such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art.” In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc.,323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied “if the functional characteristic of preferential binding . . . were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed”); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an “adequate written description must contain enough information about the actual makeup of the claimed products”). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
For these reasons, the rejection is maintained.
Claims 1, 11, 14, 17-18 and 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a construct that is a fusion protein comprising a tumor necrosis factor receptor 1 (TNFR1) antagonist, a linker and a half-life extending moiety, wherein the antagonist is dAb comprises the amino acid sequence of SEQ ID NO: 59, wherein the half-life extending moiety is a human serum albumin or an Fc of IgG1 or IgG4, and wherein the construct comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 704, SEQ ID NO: 705, SEQ ID NO: 710 to 725, SEQ ID NO: 729 to 740, SEQ ID NO: 1475, residues 20-732 of SEQ ID NO: 1475 and a variant having at least 95% sequence identity to SEQ ID NO: 704, SEQ ID NO: 705, SEQ ID NO: 710 to 725, SEQ ID NO: 729 to 740, SEQ ID NO: 1475, or residues 20-732 of SEQ ID NO: 1475, does not reasonably provide enablement for any construct as set forth in claims 1, 11-12, 14, 17-18 and 58. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompass any construct, comprising a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1:
(TNFR 1 inhibitor)n-linkerp-(activity modifier)q, wherein:
each of n and q is an integer, and each is independently 1-or 2, p is 1;
a TNFR1 inhibitor is a molecule that binds TNFR1 to inhibit (antagonize) activity of TNFR1;
the TNFRI inhibitor comprises a domain antibody (dAb), or antigen-binding portion thereof or comprises the sequence of amino acids set forth in any of SEQ ID NOs: SEQ ID NOs:54-83, 503-672, 1478, and 1479 or
a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity;
an activity modifier is a moiety that modulates or alters the activity or the pharmacological property of the construct compared to the construct in the absence of the activity modifier;
the activity modifier is a modified Fe or human serum albumin (HSA); the modified Fc is a modified Fc that has one or more of
a) a modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and
c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP); and
the linker is selected from the group consisting of:
a) a linker that comprises all or a portion of the hinge sequence of trastuzumab,
SCDKTH (corresponding to residues 222-227 of SEQ ID NO:26) or up to the full sequence of
the hinge region of trastuzumab, that contains or has the sequence EPKSCDKTHTCPPCP
(corresponding to residues 219-233 of SEQ ID NO:26), or at least 5, 6, 7, 8, 9, 10, or 11
contiguous residues thereof, or residues ESKYGPPCPPCP, set forth as residues 212-223 of SEQ
ID NO:29, or a sequence having at least 98% or 99% sequence identity thereto that is a linker;
b) a GS linker selected from among linker comprising SEQ ID NOs. 814-830, which
comprise (GlySer)n, where n= 1-10; (GlySer₂); (Gly4Ser)n, where n= 1-10; (Gly₃Ser)ₙ, where n=
1-5; (SerGly₄)ₙ, where n= 1-5; (GlySerSerGly)n, where n= 1-5; GSGGSSGG (SEQ ID NO: 820);
GSSSGSGSGSSG (SEQ ID NO: 821); GSSSGSGSGSSGG (SEQ ID NO: 822); GGSSGG (SEQ ID NO: 823); GGSSGGSGGSSSG (SEQ ID NO: 824); GSSSGSGSGGSSSGSGSG (SEQ ID NO: 825);
GGSSGGSSGGGSSGGSSG (SEQ ID NO: 826); and GSSSGS (SEQ ID NO: 827);
c) a linker that comprises a GS linker and all or a portion of the hinge sequence of
trastuzumab, corresponding to residues EPKSCDKTHTCPPCP, set forth as residues 219-233 of
SEQ ID NO:26;
d) a linker that comprises a GS linker and comprises the sequence SCDKTH,
corresponding to residues 217-222 of SEQ ID NO:31; and
e) a linker that comprises a GS linker and all or a portion of the hinge sequence of
nivolumab, corresponding to residues 212-223 of SEQ ID NO:29.
Claim 11 encompasses the construct of claim 1 that comprises a linker, wherein the dAb comprises SEQ ID NO:59 or a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity.
Claim 17 encompasses the construct of claim 1, comprising a human serum albumin (HSA) linked to the dAb directly or via a linker, wherein the dAb comprises the sequence of amino acids set forth in SEQ ID NO:54 or 59.
Claim 18 encompasses the construct of claim 1, comprising residues 20-732 of SEQ ID NO:1475, containing the dAb of SEQ ID NO:59, linked via a linker to HSA, as set forth in SEQ ID NO:1475, or a construct having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the construct of SEQ ID NO: 1475 and having TNFR1 antagonist activity.
Claim 58 encompasses the construct of claim 1 comprising the dAb of sequence ID NO:59 and
the modified Fc.
The specification discloses five exemplary TNFR1 antagonist molecules for initial evaluation. The TNFR1 antagonist molecules include an H398-derived scFv (SEQ ID NO:678), containing one V.sub.L and one V.sub.H domain of H398, linked together by a (GGGGS).sub.3 peptide linker; the TNFR1 antagonist domain antibody (dAb) DOM1h-574-16 (SEQ ID NO:57); the TNFR1 antagonist dAb DOM1h-549 (SEQ ID NO:58); a fusion protein (SEQ ID NO:704), containing the TNFR1 antagonist dAb DOM1h-574-208 (SEQ ID NO:54) from DMS5541 (described elsewhere herein), fused to the anti-serum albumin dAb (albudAb) of DMS5541 (DOM7h-11-3; SEQ ID NO:52) by a (GGGGS).sub.3 peptide linker; and a fusion protein (SEQ ID NO:705), containing the anti-TNFR1 dAb designated DOM1h-131-206 (SEQ ID NO:59), fused to the anti-serum albumin dAb (albudAb or DOM7h-11-3; SEQ ID NO:52) of DMS5541 by a (GGGGS).sub.3 peptide linker. The insertion of a (GGGGS).sub.3 linker in the H398 scFv, and in the DOM1h-574-208 and DOM1h-131-206 fusion proteins, provides more flexibility between the V.sub.H and V.sub.L domains, and the two dAbs, respectively, and increases the stability and resistance to denaturation of the molecules, improving the manufacturing process. The sequences of each of these TNFR1 antagonist molecules is provided in Table 12, below
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567
803
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297
765
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598
740
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265
737
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650
725
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435
740
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media_image7.png
193
742
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150
772
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Enablement is not commensurate in scope with how to make and use any construct set forth in claim 1 without specific guidance. The specification does not teach the structure-identifying information, e.g., amino acid sequence about the corresponding makeup of the claimed Fc having any one or more a) a modification(s) to introduce knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) in claim 1.
The term “modified” encompasses substitution, deletion, addition or a combination thereof. The specification does not teach where and what amino acid within the Fc of which antibody, e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD from which species to be substituted, deleted, added or a combination thereof such that the modified Fc has the claimed functions, knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use construct comprising any modified Fc themselves without undue experimentation.
At the time the invention was made, it was known in the prior art that small changes in antigen structure profoundly affect antibody-antigen interactions.
For example, Lund et al. (of record, The Journal of Immunology 1996, 157:4963-4969, PTO 892) show that even a single amino acid replacement within the CH2 domain of IgG can alter the glycosylation profile of an antibody therefore influence its effector functions of Fc receptor binding and complement activation (see entire document, particularly Discussion on pages 4966-4968).
Lazar et al. (WO 03/074679 of record) teach that the determinants of antibody properties, such as stability, solubility and affinity for antigen, important to its functions are overlapping; thus engineering an antibody to be more soluble may cause a loss in affinity for its antigen (see entire document, particularly page 3).
There are insufficient in vivo working examples. It is unpredictable which modifications in the Fc has the claimed functions.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
As such, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention as claimed.
Applicant’s position is that the claims, as amended are limited to constructs that comprise specifically defined elements. The sequence of each element is recited in the claim and/or provided in the application.
The level of skill in the art is recognized to be high as recognized in Wands 858 F.2d 731 (Fed. Cir. 1988).
The knowledge of those skilled in the art is extensive, as evidenced by the art cited in the rejections under 35 U.S.C. §§102 and 103, which shows that the properties of the dAbs are known in the art; the art cited in the application demonstrating the detailed knowledge in the art regarding each claimed element and synthesis of constructs containing the elements, and the understanding and demonstration in the art that the activities of each element, such as the properties of Fc's, as claimed have been demonstrated to be retained in other constructs.
In this application, Applicant did not invent the individual Fc's or linkers or TNFR1 inhibitors, each with known and demonstrated activities, but provides new combinations to provide new constructs with improved properties. Fc's are well characterized and defined elements known in the art. For example, a search of the US patent database for claims that recite an Fc yielded 11,071 patents in 8100 families, most with priority dates before the August 2020 priority date of this application. This evidences that those of skill in this art can make and use Fc's in constructs. Included among the hits are descriptions of the effects of mutations of every residue in an Fc.
The description in the application is comprehensive. The application provides 500+ pages of details describing each element, providing about 1500 sequences, and demonstrates that combining the elements results in constructs with the recited properties.
The application provides working Examples and detailed descriptions. Table 12 provides a subset of sequences of the dAbs provided in the application (see, SEQ ID NOs: 54-672, which provides the sequences hundreds of dAbs. Example 1 exemplifies preparation of the constructs. Example 4 provides more than 30 constructs and their sequences, Example 5 provides another 25 constructs, and Examples 6 and 7 provides expression data and other data for additional constructs.
The application shows and describes that the properties of the elements are known and that they can be combined as claimed such that the properties of the resulting constructs are predictable.
In response, the amendment to claims 1, 11 and 17 is acknowledged.
Claim 1 encompass any construct, comprising a tumor necrosis factor receptor 1 (TNFR1) antagonist construct of formula 1:
(TNFR 1 inhibitor)n-linkerp-(activity modifier)q, wherein:
each of n and q is an integer, and each is independently 1-or 2, p is 1;
a TNFR1 inhibitor is a molecule that binds TNFR1 to inhibit (antagonize) activity of TNFR1;
the TNFRI inhibitor comprises a domain antibody (dAb), or antigen-binding portion thereof or comprises the sequence of amino acids set forth in any of SEQ ID NOs: SEQ ID NOs:54-83, 503-672, 1478, and 1479 or
a sequence having at least 95% sequence identity thereto that retains TNFR1 inhibitor activity;
an activity modifier is a moiety that modulates or alters the activity or the pharmacological property of the construct compared to the construct in the absence of the activity modifier;
the activity modifier is a modified Fe or human serum albumin (HSA); the modified Fc is a modified Fc that has one or more of
a) a modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and
c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP); and
the linker is selected from the group consisting of:
a) a linker that comprises all or a portion of the hinge sequence of trastuzumab,
SCDKTH (corresponding to residues 222-227 of SEQ ID NO:26) or up to the full sequence of
the hinge region of trastuzumab, that contains or has the sequence EPKSCDKTHTCPPCP
(corresponding to residues 219-233 of SEQ ID NO:26), or at least 5, 6, 7, 8, 9, 10, or 11
contiguous residues thereof, or residues ESKYGPPCPPCP, set forth as residues 212-223 of SEQ
ID NO:29, or a sequence having at least 98% or 99% sequence identity thereto that is a linker;
b) a GS linker selected from among linker comprising SEQ ID NOs. 814-830, which
comprise (GlySer)n, where n= 1-10; (GlySer₂); (Gly4Ser)n, where n= 1-10; (Gly₃Ser)ₙ, where n=
1-5; (SerGly₄)ₙ, where n= 1-5; (GlySerSerGly)n, where n= 1-5; GSGGSSGG (SEQ ID NO: 820);
GSSSGSGSGSSG (SEQ ID NO: 821); GSSSGSGSGSSGG (SEQ ID NO: 822); GGSSGG (SEQ ID NO: 823); GGSSGGSGGSSSG (SEQ ID NO: 824); GSSSGSGSGGSSSGSGSG (SEQ ID NO: 825);
GGSSGGSSGGGSSGGSSG (SEQ ID NO: 826); and GSSSGS (SEQ ID NO: 827);
c) a linker that comprises a GS linker and all or a portion of the hinge sequence of
trastuzumab, corresponding to residues EPKSCDKTHTCPPCP, set forth as residues 219-233 of
SEQ ID NO:26;
d) a linker that comprises a GS linker and comprises the sequence SCDKTH,
corresponding to residues 217-222 of SEQ ID NO:31; and
e) a linker that comprises a GS linker and all or a portion of the hinge sequence of
nivolumab, corresponding to residues 212-223 of SEQ ID NO:29.
The specification discloses just human IgG1 Fc having a knob mutation comprising SEQ ID NO: 1469 and a hole mutation comprising SEQ ID NO: 1470. The specification discloses human IgG1 Fc from trastuzumab comprising SEQ ID NO: 27 and a human IgG4 Fc from nivolumab comprising the amino acid sequence of SEQ ID NO: 30.
The term “modified” encompasses substitution, deletion, addition or a combination thereof. The specification does not teach where and what amino acid within the Fc of which antibody, e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD from which species to be substituted, deleted, added or a combination thereof such that the modified Fc has the claimed functions, knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use construct comprising any modified Fc themselves without undue experimentation.
At the time the invention was made, it was known in the prior art that small changes in antigen structure profoundly affect antibody-antigen interactions.
For example, Lund et al. (of record, The Journal of Immunology 1996, 157:4963-4969, PTO 892) show that even a single amino acid replacement within the CH2 domain of IgG can alter the glycosylation profile of an antibody therefore influence its effector functions of Fc receptor binding and complement activation (see entire document, particularly Discussion on pages 4966-4968).
Lazar et al. (WO 03/074679 of record) teach that the determinants of antibody properties, such as stability, solubility and affinity for antigen, important to its functions are overlapping; thus engineering an antibody to be more soluble may cause a loss in affinity for its antigen (see entire document, particularly page 3).
There are insufficient in vivo working examples. It is unpredictable which modifications in the Fc has the claimed functions. As such, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention as claimed.
For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 11 are rejected under 35 U.S.C. 102 (a)(1) or (a)(2) as being anticipated by Stoop (of record, US20120107330, published May 3, 2012; PTO 892) as evidenced by WO2005077042 (newly cited) and WO2003076567 (newly cited).
Regarding claims 1 and 11, Stoop teaches a construct comprising anti-TNFR1 dAb and a human serum albumin SEQ ID NO 1 as disclosed WO2005077042 (see para. [0336], [0340], in particular. The half-life extending moiety (e.g., albumin) and the anti-TNFR1dAb can be fused to or conjugated using a peptide linker having the sequence [Gly-Gly-Gly-Gly- Ser] n where n is 1, 2, 3, 4, or 5 as evidenced by WO2003076567, see para. [0346]).
Evidentiary reference WO2005077042 publication teaches fusion protein comprising human serum albumin (HAS or HA). The human serum albumin is a protein of 585 amino acids in its mature form shown in Figure 1 (SEQ ID NO: 1), see p. 1, in particular.
Evidentiary reference WO2003076567 publication teaches that the human serum albumin (HA) fusion protein being non-immunogenic in humans, see paragraph bridging p. 23-24. Evidentiary reference WO2003076567 publication teaches that linker peptide having the [Gly-Gly-Gly-Gly- Ser] n where n is 1, 2, 3, 4, or 5, see p. 57, reference claim 3.
Stoop teaches that the domain antibody (dAb) comprises the amino acid sequence of SEQ ID NO: 205, which is 97.7% identical to the elected claimed SEQ ID NO: 59, see sequence alignment below:
ALIGNMENT:
Query Match 97.7%; Score 628; Length 119;
Best Local Similarity 98.3%;
Matches 117; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPVGQDPFY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSS 119
||||||||||||||||||||||||||||||||||:||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCALLPKRGPWFDYWGQGTLVTVSS 119
The reference 98.3 sequence identity is at least 95% to the claimed SEQ ID NO: 59 as per claim 1 and 11. The term “or” does not require the dAb comprises SEQ ID O 59 as per claim 11 or the modified Fc as per claim 1 or any of the linker in claim 1a) and c).
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 17, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Stoop (of record, US20120107330, published May 3, 2012; PTO 892) in view of Jespers (of record, US20100254972, published Oct 7, 2010; PTO 892) and WO2013192131 publication (published December 27, 2013; PTO 892).
The teachings of Stoop have been discussed supra.
The reference does not teach the TNFR1 inhibitor comprises a domain antibody (dAb) comprises the amino acid sequence of SEQ ID NO: 59 as per claim 17 and the modified Fc as per claims 1 and 58.
However, Jespers teaches that the domain antibody (dAb) comprises the amino acid sequence of SEQ ID NO: 214, which is 100% identical to the elected claimed SEQ ID NO: 59, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 643; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSS 119
Jespers further teaches fusion protein comprising DOM 15-26-593 and Fc, see para. [0109], Fig. 46, para. [0112], in particular. Jespers teaches that antibody dAb is fused to an activity modifier, e.g., Fc fusions, albumin fusion, etc., see para. [0419] through a short intervening linker, see para. [0420]. Jespers teaches that by tagging the Fc portion to the dAb, it is ensured that the dAbs will expose for long period to two at least compartments--the serum and the pre-endosomal compartments, each of which containing a specific set of proteolytic enzymes. In addition, the FcRn receptor mediates transcytosis whereby Fc-bearing proteins migrate to and from the extravascular space, see para. [0419], [0444]. Jespers teaches that the TNFR1 may antagonize TNF alpha and useful for treating various conditions such as TNF alpha-mediated rheumatoid arthritis, IBD, psoriasis, or Crohn’s disease (see para. 0006]) or GI tract disease or condition, see para. [0055], [0057], in particular.
Jespers does not teach the modified Fc that has modifications has one or more of a) a modification(s) to introduce knobs-into-holes; b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) as per claim 1.
However, the WO2013192131 publication teaches modified human IgG1 Fc having a combination of P329G, L234A and L235A (“LALA”, reference SEQ ID NO: 49 that strongly inhibit effector function, e.g., antibody-dependent cellular cytotoxicity (ADCC) and complement (C1q) binding, activation and complement-dependent cytotoxicity (CDC), see p. 5, p. 9, p. 31, p. 34, in particular. The WO2013192131 publication further teaches that a variant human Fc-region in of IgG1 isotype with a hole mutation comprising the amino acid sequence of SEQ ID NO 44, or a knob mutation comprising the amino acid sequence of SEQ ID NO: 45, or a combination of a L234A, L235A and knob mutation comprising the amino acid sequence of SEQ ID NO: 47 or a combination of L234A, L235A, P329G and knob mutation comprising the amino acid sequence of SEQ ID NO: 53, see p. 34-35. The WO2013192131 publication teaches it would be advantageous to decrease or eliminate antibody effector function to reduce wanted toxicity. The WO2013192131 publication further teaches the circulating half-life of the Fc fusion molecule can be achieved by amino acid mutation that increases binding for the FcRn such as T256A, T307A, E380A, and N434A, see p. 38, in particular. Examples of GS linkers include Gly-Gly-Ser, Gly-gly-gly-Ser (SEQ ID NO: 88), Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 90), (GGGS)n wherein n =1-6, (GGGGS)m wherein m=1 to 6), see reference claim 3-4, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute Stoop’s TNFR1 dAb antagonist for Jespers’ TNFR1 inhibitor dAb DOM 15-26-593 comprises the amino acid sequence of SEQ ID NO: 214, which is 100% identical to the claimed SEQ ID NO: 59, and then fused to any one of the WO2013192131 publication’s modified human IgG1 Fc that has one or more a) knobs-into-holes; b) increase or enhance neonatal receptor (FcRn) recycling and reduce or eliminate one or more ADCC and CDC in order to antagonize TNF alpha mediated disease.
One of ordinary skill in the art would have a reasonable expectation of success, because Jespers teaches fusion protein comprising DOM 15-26-593 and Fc for antagonize TNF alpha and is useful for treating various conditions such as TNF alpha-mediated rheumatoid arthritis, IBD, psoriasis, or Crohn’s disease (see para. 0006]) and WO2013192131 publication teaches that the modified human Fc is expected to enhance the circulating half-life of the fusion protein while minimizing toxicity.
One of ordinary skill in the art would have been motivated to do so because WO2013192131 publication teaches that the combination of substitution such as L234A, L235A, P329G is expected to decrease or eliminate antibody effector function to reduce wanted toxicity, while the T256A, T307A, E380A, and N434A mutation is expected to enhance half-life of the fusion protein and the knob-into-hole mutation in the Fc is expected to promote heterodimerization.
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
New Ground of Objection and Rejection Necessitated by claim amendment filed March 16, 2026
Claim Objection
Claim 1 is objected to because of the following informalities:
Duplicate “SEQ ID Nos” at line 9 should be deleted.
“a TNFR1 inhibitor is a molecule that binds TNFR1 to inhibit (antagonize) activity of TNFR1; the TNFR1 inhibitor comprises a domain (dAb), or antigen-binding portion thereof or comprise the sequence of amino acids” starting at line 6 should have been “wherein the TNFR1 inhibitor is a domain (dAb), or antigen-binding portion thereof that comprises the amino acid sequence”.
“the modified Fc is a modified Fc” at line 16 should have been “the modified Fc”.
“a modification(s)” at lines 17, 18 and 20 should have been “a modification”.
“a) a linker that comprises all or a portion of the hinge … of SEQ ID NO:29” should have been:
“a) a linker comprises the sequence SCDKTH, corresponding to residues 222-227 of SEQ ID NO:26,
a linker comprises the sequence EPKSCDKTHTCPPCP, corresponding to residues 219-233 of SEQ ID NO:26, or at least 5, 6, 7, 8, 9, 10, or 11 contiguous residues thereof,
a linker comprises the sequence ESKYGPPCPPCP which corresponds to residues 212-223 of SEQ ID NO:29;
b) a GS linker selected from the group consisting of
(GlySer)ₙ, where n= 1-10;
(GlySer2); (Gly₄Ser)ₙ, where n= 1-10;
(Gly₃Ser)n, where n= 1-5; (SerGly4)n, where n= 1-5;
(GlySerSerGly)n where n= 1-5;
GSGGSSGG (SEQ ID NO: 820);
GSSSGSGSGSSG (SEQ ID NO: 821);
GSSSGSGSGSSGG (SEQ ID NO: 822);
GGSSGG (SEQ ID NO: 823);
GGSSGGSGGSSSG (SEQ ID NO: 824);
GSSSGSGSGGSSSGSGSG (SEQ ID NO: 825);
GGSSGGSSGGGSSGGSSG (SEQ ID NO: 826); and GSSSGS (SEQ ID NO:827),
c) a linker that comprises a GS linker and the sequence EPKSCDKTHCPPCP, corresponding to residues 219-233 of SEQ ID NO: 26,
d) a linker that that comprises a GS linker and the sequence SCDKTH, corresponding to residues 212-223 of SEQ ID NO: 26, and
e) a linker that comprises a GS linker and all or a portion of the hinge sequence of nivolumab, corresponding to residues 212-223 of SEQ ID NO:29”.
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.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 contains a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In this case:
claim 1 recites the broad limitation “modified Fc”, and the claim also recites “modified Fc that has one or more of a) a modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling; and c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody- dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP), which is a narrower statement of the range/limitation.
b) The recitation of “a linker that comprises all or a portion of the hinge sequence of trastuzumab SCDKTH…or at least 5, 6, 7, 8, 9, 10, or 11 contiguous residue thereof” in claim 1 is indefinite because a linker that comprises all of SCDKTH is just 6 contiguous residue in length. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
c) The recitation of “a GS linker selected from among linker comprising” in claim 1 (b) is indefinite because the term “comprising” is open ended. It expands the GS linker to include linkers that are not recited in the claim. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention. Amending the claim to recite “a GS linker selected from the group consisting of” would obviate this rejection.
Claim 12 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Duffields et al (of record, WO2010094720 publication, published August 26, 2010; PTO 892).
Regarding claim 12, the WO2010094720 publication teaches a tumor necrosis factor receptor 1 (TNFR1) antagonist, e.g., anti-TNF alpha receptor 1 (TNFR1, p55) immunoglobulin single variable domain antibody comprising the amino acid sequence of SEQ ID NO: 53, which is at least 98% sequence identity to the claimed SEQ ID NO: 704, see entire document, reference SEQ ID NO: 53, sequence alignment below:
Query Match 97.8%; Score 1253; Length 244;
Best Local Similarity 98.0%;
Matches 239; Conservative 2; Mismatches 1; Indels 2; Gaps 1;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFDKYSMGWVRQAPGKGLEWVSQISDTADRTYY 60
||||||||||||||||||||||||||||| ||||||||||||||||||||||:|||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYY 60
Qy 61 AHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVS-- 118
||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSSA 120
Qy 119 SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAP 178
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAP 180
Qy 179 KLLILWNSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKV 238
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KLLILWNSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKV 240
Qy 239 EIKR 242
||||
Db 241 EIKR 244
Thus, the reference teachings anticipate the claimed invention.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 11, 14, 17 and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 19/554,453. Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims anticipate instant claims. In particular, the copending claims limits the particular combination of Fc mutations to knob-into-holes, increase or enhance neonatal Fc receptor (FcRn) recycling or reduce or eliminating effector function (species) whereas instant claims are generic with the Fc modification (genus).
Copending claim:
A construct that is a tumor necrosis factor receptor 1 (TNFR1) antagonist, comprising two polypeptide chains that are the same or different; wherein: each chain has the formula 1:
(TNFR1 inhibitor)n-linkerp-(activity modifier)n, wherein each of n and q is an integer, where n is 0 or 1, and q is 1;p is 0, 1, 2 or 3; at least one chain comprises a TNFR1 inhibitor molecule; the TNFR1 inhibitor molecule binds TNFR1 to inhibit (antagonize) TNFR1;
a linker increases flexibility of the construct, and/or moderates or reduces steric effects of the construct or its interaction with a receptor, and/or increases solubility of the construct in aqueous medium;
the TNFR 1 inhibitor comprises a domain antibody (dAb); the dAb comprises a sequence set forth in any of SEQ ID NOs: 55-84, 86-88, 450, 495-498, which each bind to the same epitope on TNFR1 as the dAb of SEQ ID NO:59; and an activity modifier is a moiety that modulates or alters the activity or the pharmacological property of the construct compared to the construct in the absence of the activity modifier; the activity modifier is a modified Fc;
the modified Fc comprises one or more of a)-d):
one or more amino acid mutations to increase serum half-life, and, when the construct has one TNFR1 inhibitor and q =2, the Fc has modification(s) to introduce knobs-into-holes;
b) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling;
c) a modification(s) to reduce or eliminate immune effector functions, selected from among one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody- dependent cell-mediated phagocytosis (ADCP), which corresponds to instant claim 1. The copending application teaches the claims SEQ ID NO: 54-83.
2. The construct of claim 1, wherein the dAb binds to the domain 3 of the TNFR1 extracellular domain (ECD) with an affinity of about 300-500 pM as measured by SPR.
3. The construct of claim 1, wherein n is I on each chain, whereby the construct is bivalent; or for one chain, n is 0 and the modified Fc comprises a knob or hole, and for the other chain n is 1, and the Fc comprises a knob or hole whereby construct forms two chains with a single dAb, which corresponds to instant claim 1.
4. The construct of claim 1, wherein the modified Fc comprises the mutations designated YTE (M252Y,S254T,T256E with reference to SEQ ID NO:1503) to extend half-life, and the mutations designed LALAPG (L234A,L235A,P329G with reference to residue positions in SEQ ID NO: 1503) to minimize its in vivo Fc effector function (species), which anticipates instant claim 1 (genus with respect to the Fc modification).
5. The construct of claim 3 that is designated EN-1206 bivalent or EN- 1206, wherein the constructs comprise the dAb of SEQ ID NO:59 and do not have TNFR t agonist activity.
6. The construct of claim 1, that comprises two chains, wherein for one chain n is 1, and for the other chain n is 0, whereby the resulting construct comprises one chain that contains the dAb and modified Fc, and the other chain is a modified Fc, whereby the resulting construct is monovalent.
7. The construct of claim 1, wherein n is 1 for each chain, whereby the construct is bivalent; and the resulting the construct does not have TNRF 1 agonist activity.
8. A polypeptide chain for forming a construct of claim 1, wherein a chain is selected from:
a) SEQ ID NO:1488, which is an Fc only comprising, by EU numbering, T366S, L368A,Y407V to form a hole, M252Y, S254T, T256E for increased half-life, L234A, L235A, P329G for minimizing, eliminating, or reducing Fc effector function, and includes a leader sequence, MGWSCILFLVATATGVHS (SEQ ID NO:1509), that is cleaved off in a cell in which the polypeptide is expressed and comprises the sequence:
MGWSCILFLVATATGVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWIFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK;
SEQ ID NO:1489, which comprises a dAb and Fc, where the Fc comprises the modifications, by EU numbering, T366W to form a knob, M252Y, S254T, T256E for increased half-life, and L234A, L235A, P329G for minimizing, reducing, or eliminating Fc effector function, and the chain includes a leader sequence, MGWSCILFLVATATGVHS (SEQ ID NO:1509) that is cleaved off in a cell in which is the polypeptide is expressed:
MGWSCILFLVATATGVHSEVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;
c) SEQ ID NO:1505, which is an Fc with the modifications, by EU numbering, T366S, L368A, Y407V to form a hole, M252Y, S254T, T256E for increased half-life, L234A, L235A, P329G for minimizing, reducing, or eliminating Fc effector function, and comprises the sequence:
DKTHTCPPCPAPEAAGGPSVELFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK; and
d) SEQ ID NO:1506, which comprises a dAb and Fc, where the Fc comprises the modifications, by EU numbering, T366W to form a knob, M252Y, S254T, T256E for increased half-life, and L234A, L235A, P329G for minimizing, reducing, or eliminating Fc effector function, and comprises the sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGPWFDYWGQG
TLVTVSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
9. A chain for forming the construct of claim 1that is a monovalent construct comprising two chains, where one chain comprises EN 1206 and the Fc with hole, and the other chain comprises EN1206 and the Fc with knob, wherein: each chain, when expressed in a cell, comprises the leader sequence MGWSCIILFLVATATGVHS that is cleaved when expressed in a cell and is not present in the resulting construct; and each chain, when expressed in a cell, comprises the leader sequence and comprises the sequences:
a) the first chain is an Fc with modified residues, by EU numbering, T366S,L368A,Y407V to form a hole, M252Y, S254T, T256E for increasing half-life and L234A, L235A, P329G for minimizing, reducing, or eliminating Fc effector function and having the sequence (SEQ ID NO:1488): MGWSCIILFLVATATGVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITR EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, wherein MGWSCIILFLVATATGVHS (SEQ ID NO:1509) is a leader sequence present when the chain is expressed, but is not present in the two chain monovalent construct; and
b) the second chain comprises the dAb and a modified Fc with T366W to form a knob, M252Y, S254T, T256E for increasing half-life, and L234A, L235A, P329G minimizing, reducing, or eliminating Fc effector function and having the sequence (SEQ ID NO:1489):MGWSCIILFLVATATGVHSEVQLLESGGGLVQPGGSLRLS CAASGFTFAHET MVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVSSDKTHTCPPCPAPEAAG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK, wherein MGWSCIILFLVATATGVHS (SEQ ID NO:1509) is a leader sequence present when the chain is expressed, but is not present in the two chain construct.
10. The construct of claim 1, comprising two chains, wherein: a) the construct is a monovalent construct designated EN 1206-MV, wherein:
i) chain 1 in the construct comprises the polypeptide of SEQ ID NO:1505 that is a modified Fc with modifications numbered by reference to SEQ ID NO:1503 by EU numbering: T366S, L368A,Y407V, to form a hole; YTE (M252Y,S254T,T256E), for increased half-life, and LALAPG (L234A,L235A,P329G), for minimized in vivo Fc effector function; wherein the resulting chain comprises the sequence: DKTHTCPPCPAPEAAGGPSVFLFPPKFNWYVDGVEVHNAKTKPREEQ SNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLS CAVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK; and
ii) chain 2 comprises a monovalent dAb with an Fc knob (T366W) by EU numbering, and is modified for increased half-life and minimized Fc effector function including, respectively, YTE (M252Y,S254T,T256E, by EU numbering), and LALAPG (L234A,L235A,P329G, by EU numbering), wherein the chain comprises the polypeptide of SEQ ID NO:1506: EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIP PDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGP WFDYWGQGTLVTVSSDKTHTCPPCPAPEAAGGPSVFLFPPVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK; or b) the construct is a bivalent construct, designated EN1206-BV, comprising identical chains, wherein each chain comprises the dAb and Fc with modifications - YTE (M252Y,S254T,T256E, by EU numbering) LALAPG (L234A,L235A,P329G, by EU numbering), wherein each chain comprising the sequence, (SEQ ID NO:1507): EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIP PDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGP WFDVTC LHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
11. A polypeptide chain for forming a construct of claim 1 selected from:
a) SEQ ID NO:1488, which is an Fc only comprising T366S, L368A,Y407V, by EU numbering, to form a hole, M252Y, S254T, T256E, by EU numbering, for increased half-life, L234A, L235A, P329G, by EU numbering, for minimizing, eliminating, or reducing Fc effector function, and includes a leader sequence, MGWSCIILFLVATATGVHS (SEQ ID NO:1509), that is optional and is cleaved off in a cell in which is the polypeptide is expressed and comprises the sequence: MGWSCIILFLVATATGVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITR EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;
b) SEQ ID NO:1489, which comprises a dAb and Fc, where the Fc comprises the modifications T366W to form a knob, M252Y, S254T, T256E, by EU numbering, for increased half-life, and L234A, L235A, P329G, by EU numbering, for minimizing, reducing, or eliminating Fc effector function, and the chain includes a leader sequence, MGWSCIILFLVATATGVHS (SEQ ID NO:1509) that is optional and is cleaved off in a cell in which is the polypeptide is expressed: MGWSCIILFLVATATGVHSEVQLLESGGGLVQPGGSLRLS CAASGFTFAHET MVWVRQAPGKGLEWVSHIPPDGQDPFYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYHCALLPKRGPWFDYWGQGTLVTVS SDKTHTCPPCPAPEAAG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK;
c) SEQ ID NO:1505, which is an Fc with T366S, L368A, Y407V, by EU numbering, to form a hole, M252Y, S254T, T256E, by EU numbering, for increased half-life, L234A, L235A, P329G, by EU numbering, for minimizing, reducing, or eliminating Fc effector function, and comprises the sequence: DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRV VS VLTVLHQD WLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLS CAVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK; and
d) SEQ ID NO:1506, which comprises a dAb and Fc, where the Fc comprises, by EU numbering, T366W to form a knob, M252Y, S254T, T256E, by EU numbering, for increased half-life, and L234A, L235A, P329G, by EU numbering, for minimizing, reducing, or eliminating Fc effector function, and comprises the sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIP PDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGP WFDYWGQGTLVTVS SDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
12. A chain for forming a construct of claim 1, comprising the sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHIP PDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRGP WFDYWGQGTLVTVS SDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:1507).
13. A construct of claim 1, comprising two chains, wherein:
a) one chain comprises the polypeptide of SEQ ID NO:1505; and
b) the second chain comprises the polypeptide of SEQ ID NO: 1506, whereby the construct comprises a dAb of SEQ ID NO:59 linked to the Fc comprising a knob, T366W, by EU numbering, and is modified to have increased half-life and reduced or eliminated Fc effector function as in the first chain.
14. A construct of claim 1, comprising a dAb of any of SEQ ID NOs: 55- 59, 60-84, 86-88, 450, or 495-498linked directly or via a linker to a modified Fc that comprises M252Y, S254T, T256E, by EU numbering, for increasing half-life and L234A, L235A, P329G by EU numbering, for minimizing, reducing, or eliminating Fc effector function.
15. A TNFRl antagonist construct of claim 1, comprising a dAb, an optional linker, and a modified Fc, wherein the dAb is DOMlh-131-206 SEQ ID NO:59: EVQLLESGGGLVQPGGSLRLSCAASGFTFAHETMVWVRQAPGKGLEWVSHI PPDGQDPFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCALLPKRG PWFDYWGQGTLVTVSS, which corresponds to instant claims 1, 11.
16. The construct of claim 1 that comprises a linker, wherein the linker is selected from among a chemical linker, a polypeptide linker, and combinations thereof, which corresponds to instant claim 1.
17. The construct of claim 16 that comprises a linker between the dAb and Fc portions, wherein the linker is selected from among:
a) a linker that comprises all or a portion of the hinge sequence of trastuzumab, SCDKTH (corresponding to residues 222-227 of SEQ ID NO:26) or up to the full sequence of the hinge region of trastuzumab, that contains or has the sequence EPKSCDKTHTCPPCP (corresponding to residues 219-233 of SEQ ID NO:26), or at least 5, 6, 7, 8, 9, 10, or 11 contiguous residues thereof, or residues ESKYGPPCPPCP, set forth as residues 212-223 of SEQ ID NO:29, or a sequence having at least 98%or 99% sequence identity thereto that is a linker;
b) a linker that is or comprises a glycine-serine (GS) linker;c) a GS linker selected from among (GlySer)n, where n= 1-10; (GlySer2);(Gly4Ser)n, where n= 1-10; (Gly3Ser)n, where n= 1-5; (SerGly4)n, where n= 1-5; (GlySerSerGly),, where n= 1-5; GSGGSSGG; GSSSGSGSGSSG; GSSSGSGSGSSGG; GGSSGG; GGSSGGSGGSSSG; GSSSGSGSGGSSSGSGSG; GGSSGGSSGGGSSGGSSG; and GSSSGS;
d) a linker that comprises a GS linker and all or a portion of the hinge sequence of trastuzumab, corresponding to residues EPKSCDKTHTCPPCP, set forth as residues 219-233 of SEQ ID NO:26;
e) a linker that comprises a GS linker and comprises the sequence SCDKTH, corresponding to residues 217-222 of SEQ ID NO:31; and
f) a linker that comprises a GS linker and all or a portion of the hinge sequence of nivolumab, corresponding to residues 212-223 of SEQ ID NO:29, which corresponds to instant claim 1.
18. The construct of claim 1, wherein a chain comprises a modified Fc, wherein:
the unmodified Fc is an IgG1 or IgG4 Fc;
the IgG1 Fc is selected from the IgG1 Fc of human IgG1, set forth in SEQ ID NO:10, or the IgG1 Fc of trastuzumab, set forth in SEQ ID NO:27;
the IgG4 Fc is selected from the IgG4 Fc of human IgG4, set forth in SEQ ID NO:16, or the IgG4 Fc of nivolumab, set forth in SEQ ID NO:30; and optionally, the Fc includes one or more modifications to introduce knobs-into-holes, and/or increase or enhance neonatal Fc receptor (FcRn) recycling, and/or reduce or eliminate immune effector functions.
19. The construct of claim 1, wherein the Fc is selected from among: a) an Fc that comprises knobs-into-holes modifications, wherein: the knob mutation is selected from among one or more of S354C, T366Y, T366W, and T394W by EU numbering; and the hole mutation is selected from among one or more of Y349C,T366S, L368A, F405A, Y407T, Y407A, and Y407V by EU numbering; b) an Fc that comprises modifications to increase or enhance FcRn recycling that is/are selected from among one or more of:T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L,M428L/N434S, V259I/V308F, V259I/V308F/M428L, E294del/T307P/N434Y, and T256N/A378V/S383N/N434Y, by EU numbering ;c) an Fc that comprises modifications to immune effector functions that are selected from among one or more of complement-dependent cytotoxicity (CDC),antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell- mediated phagocytosis (ADCP);d) a construct that comprises modification(s) in the Fc to reduce or eliminate immune effector functions, wherein the Fc and modifications are selected from among one or more of :in IgG1: L235E, L234A/L235A, L234E/L235F/P331S, L234F/L235E/P331S, L234A/L235A/P329G, L234A/L235A/G237A/P238S/H268A/A330S/P331S,G236R/L328R, G237A, E318A, D265A, E233P, N297A, N297Q, N297D, N297G, N297G/D265A, A330L, D270A, P329A, P331A, K322A, V264A, and F241A, by EU numbering; and in IgG4: L235E, F234A/L235A, S228P/L235E, and S228P/F234A/L235A, by EU numbering;
e) an Fc that is an IgG Fc that comprises one or more of the following modifications:
i) a modification(s) to introduce knobs-into-holes, wherein: the knob mutation is selected from among one or more of S354C, T366Y, T366W, and T394W by EU numbering; and the hole mutation is selected from among one or more of Y349C,T366S, L368A, F405A, Y407T, Y407A, and Y407V by EU numbering;
ii) a modification(s) to increase or enhance neonatal Fc receptor (FcRn) recycling, wherein the modification is selected from among one or more of:T250Q, T250R, M252F, M252W, M252Y, S254T, T256D, T256E, T256Q, V259I, V308F, E380A, M428L, H433K, N434F, N434A, N434W, N434S, N434Y, Y436H, M252Y/T256Q, M252F/T256D, M252Y/S254T/T256E, H433K/N434F/Y436H, N434F/Y436H, T250Q/M428L, T250R/M428L,M428L/N434S, V2591/V308F, V2591/V308F/M428L,E294de1/T307P/N434Y, and T256N/A378V/S383N/N434Y, by EU numbering; and
iii) a modification(s) to increase or enhance immune effector functions, wherein: the immune effector functions are selected from among one or more of CDC, ADCC and ADCP; and the modification(s) to increase or enhance immune effector functions is selected from among one or more of: in IgGl: S239D; 1332E; S239D/I332E; S239D/A330L/I332E;S298A/E333A/K334A; F243L/R292P/Y300L/V305I/P396L; L235V/F243L/R292P/Y300L/P396L; F243L/R292P/Y300L;L234Y/G236W/S298A in the first heavy chain and S239D/A330L/I332E in the second heavy chain;L234Y/L235Q/G236W/S239M/H268D/D270E/S298A in the first heavy chain and D270E/K326D/A330M/K334E in the second heavy chain; A327Q/P329A; D265A/S267A/H268A/D270A/K326A/S337A; T256A/K290A/S298A/E333A/K334A; G236A; G236A/I332E; G236A/S239D/I332E; G236A/S239D/A330L/I332E; introduction of a biantennary glycan at residue N297; introduction of an afucosylated glycan at residue N297; K326W; K326A; E333A; K326A/E333A; K326W/E333S; K326M/E333S; K222W/T223W; K222W/T223W/H224W; D221W/K222W; C220D/D221C;C220D/D221C/K222W/T223W; H268F/S324T; S267E; H268F;S324T; S267E/H268F/S324T; G236A/I332E/S267E/H268F/S324T; E345R; and E345R/E430G/S440Y, by EU numbering; an
f) an Fc that is modified to increase binding to the inhibitory Fcγ receptor (FcyR) FcγRIIb; and
g) combinations of a)-f).
20. The construct of claim 1 that comprises the dAb of SEQ ID NO:59or a variant thereof having at least 95% sequence identity thereto and binding to the same epitope as SEQ ID NO:59 linked directly or indirectly via a linker to the modified Fc.
21. The construct of claim 1, comprising two of polypeptide chains of SEQ ID NOs:1505-1507 linked, whereby they form monovalent or divalent constructs, or comprising variants of the chains of SEQ ID NOs:1505-1507 having at least 95% sequence identity thereto and that bind TNRF 1, have anti-TNFR 1 antagonist activity, and retain the half-life of constructs.
22. A pharmaceutical composition, comprising a construct of claim 1.
Conclusion
Construct that is a tumor necrosis factor receptor 1 (TNFR1) antagonist comprising the amino acid sequence of SEQ ID NO: 704, 705, 710-725, 729-740, 1475 or residues 20-732 of SEQ ID NO: 1475 or at least 95% identical to SEQ ID NO: 705, 710-725, 729-740, 1475 or at least 99% identical to SEQ ID NO: 704 is free of prior art.
Claims 14 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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