DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Priority
The instant application, filed 12/21/2023, is a 371 filing of PCT/EP2022/067236, filed 06/23/2022, and claims foreign priority to EP22163748.1, filed 03/23/2022, and EP21181271.4, filed 06/23/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 08/16/2024 is acknowledged. Claims 3 and 5-14 are amended, and claims 18-20 are new. Claims 1-20 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/21/2023 and 08/25/2025 (3) are in compliance with the provisions of 37 CFR 1.97, except where noted below. Accordingly, the information disclosure statements have been considered by the examiner.
The IDS submitted 08/25/2025, Foreign patent document 1 is WO 2017112528 A1. A copy of the reference was not identified in the file wrapper as required by 37 CFR 1.97. The reference has been lined through on the IDS and has not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification recites amino acid sequences without corresponding SEQ ID NOs in the following locations:
Page 25, line 34: “GGGGS”; and
Pages 91-92, Table 41, sequences recited in the right column of the table.
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 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-4, 11-17, and 19-20 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 3, part c, recites the limitation “IgG2 (IgG2a or IgG2b)” and “(IgG2 amino acids 118 to 260 and the IgG4 amino acids 261 to 447)”. The use of parentheticals in the claim renders the claim indefinite as it is unclear if the limitations within the parenthesis are limiting features of the claimed invention or exemplary embodiments. This is particularly the case as the limitations in the parenthesis are narrower embodiments of the preceding limitations. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3c recites the broad recitations IgG2 and IgG2 and IgG4 hybrid, and the claim also recites “(IgG2a or IgG2b)” and “(IgG2 amino acids 118 to 260 and the IgG4 amino acids 261 to 447)” which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claim 4 is rejected by virtue of its dependency on claim 3 as it does not resolve the ambiguity discussed above.
Claims 11 and 19 recite the limitation “IL-15 (SEQ ID NO: 2)” in claim 11, part c, and claim 19 lines 2-3 and line 4. The inclusion of “SEQ ID NO: 2” in parentheticals renders the claims indefinite as it is unclear if the IL-15 claimed is limited to SEQ ID NO: 2 or if SEQ ID NO: 2 is an exemplary embodiment. This is particularly the case as SEQ ID NO: 2 is a narrower embodiment of IL-15 as it claims a particular sequence for the IL-15. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recite the broad recitation “IL-15”, and the claims also recite “(SEQ ID NO: 2)” which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claim 12 is rejected by virtue of its dependency on rejected claim 11 as it does not resolve the ambiguity discussed above.
Claim 13 part (d), as amended, recites “wherein the immunomodulatory antibody inhibits an immunosuppressive receptor antagonists.” It is unclear if the word “antagonists” in the last line of the claim was unintentionally left in the claim during amendment, for instance if appears that “PD-1 antagonists” was intended to be removed, or if the claim is drawn to an antibody that inhibits antagonists. As the scope of the claim is unclear, the claim is indefinite.
Appropriate clarification/correction is required.
In the instant office action, the claim is interpreted as being drawn to antibodies that inhibit an immunosuppressive receptor.
Claims 14-17 and 20 recite the limitation “the cytokine domain.” There is insufficient antecedent basis for this limitation in the claims. The instant claims are dependent on claim 1, which does not recite “a cytokine domain” that could be being referenced.
Appropriate correction is required.
In the instant office action, reference to “the cytokine domain” is interpreted as referring to the conjugate recited in claim 1.
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, 10, 13, and 18 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2018/0312560 A1 (Morisseau, S.D., et al) 01 Nov 2018.
US’560 teaches an immunocytokine comprising (a) a conjugate, and (b) an antibody or a fragment thereof directly or indirectly linked by covalence to said conjugate, wherein said conjugate comprises (i) a polypeptide comprising the amino acid sequence of the interleukin 15 or derivatives thereof, and (ii) a polypeptide comprising the amino acid sequence of the sushi domain of the interleukin 15R alpha (IL-15Rα) or derivatives thereof (abstract). US’560 further teaches that, preferably, the conjugate is a fusion protein and the amino acid sequence of the conjugate is in a C-terminal position relative to the amino acid sequence of the antibody, most preferably C-terminal to the amino acid sequence of at least one of the heavy chain constant regions of the antibody (page 8, [0135]).
US’560 exemplifies the construction of IL-15 based immunocytokines using anti-CD20 (rituximab) and anti-CD2-O-acetylated immunocytokines. Expression plasmids were used for encoding the antibody IgG light chains. The chimeric IgG heavy chain sequences were designed to be fused in 3’term with or without a linker of 22-amino acid, SEQ ID NO: 16, to IL-15 (page 11, [0197]-[0198]). The plasmids were transfected into CHO cells, cultured, and supernatant was collected. Obtained immunocytokines were tested (page 12, [0199]-page 13, [0219]).
US’560 exemplifies the construction of RL1-based immunocytokines, specifically anti-CD20 and anti-GD2-O-acetylated immunocytokines and teaches that they were constructed as previously described but that the IL15 homo sapiens sequence was replaced by the sequence of SEQ ID NO: 17 (page 13, [0226]-[0228]). US’560, SEQ ID NO: 17 comprises an IL-15Rα sushi domain, a linker, and IL-15. The IL-15 in US’560, SEQ ID NO: 17 comprises instant SEQ ID NO: 2 as well as the linker SGGSGGGGSGGGSGGGGSGG, which is 20 amino acids long. The alignment of US’560, SEQ ID NO: 17 and instant SEQ ID NO: 2 is shown below.
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Thus, US’560 anticipates instant claims 1, 10, 13, and 18.
Claims 1-2 and 13 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020.
US’512 teaches PD-1 targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein (abstract). US’512 provides schematics of the disclosed structures including Figs. 28E and F, which are duplicated below for convenience.
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As shown, the structures in both Fig. 28E and 28F comprise an anti-PD-1 antibody with a heterodimeric Fc domain and a conjugate comprising an IL-15 and the sushi domain of IL-15Rα which is indirectly fused to the C-terminus of one of the antibody heavy chains, meeting the limitations of instant claim 1.
US’512 teaches that Fig. 28E is the “mAb-scIL-15/Rα” format and comprises a VH fused to the N-terminus of a first and second heterodimeric Fc, with IL-15 fused to IL15Rα sushi which is then further fused to the C-terminus of one of the heterodimeric Fc-region, while the corresponding light chains are transfected separately so as to form a Fabs with the VHs (page 5, [0059]).
Fig. 28F is a “mAb-ncIL-15/Rα” format and comprises a VH fused to the N-terminus of a first and second heterodimeric Fc, with IL-15Rα sushi fused to the C-terminus of one of the heterodimeric Fc-region, while corresponding light chains are transfected separately so as to form a Fabs with the VH, and while IL-15 is transfected separately so that a non-covalent IL-15/Rα complex is formed (page 5, [0059]).
US’512 teaches that it can be either the IL-15 domain or the sushi domain that is covalently linked to the Fc domain, generally using an optional domain linker (pages 19-20, [0258]).
Thus, US’512 anticipates instant claims 1-2 and 13.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-8, 10-13, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020.
The teachings of US’512 are as discussed above.
US’512 further teaches that the IL-15 or IL-15Rα protein can be attached to an Fc domain via a linker or can be directly attached to the Fc domain such as without a linker (page 26, [0350]).
US’512 further teaches that the heterodimeric fusion proteins include two different Fc domains (one on each of the first and second monomers) that include modifications that facilitate the heterodimerization of the first and second monomers and/or allow for ease of purification of heterodimers over homodimers, collectively referred to as heterodimerization variants. Heterodimerization variants can include skew variants, e.g., variants that skew the formation of heterodimers over homodimers, as well as pI variants that facilitate the separation of homodimers away from heterodimers. US’512 also teaches mechanisms for heterodimerization including “knobs in holes” (“KIH”), “electrostatic steering” or “charge pairs” (pages 21-22, [0289]-[0291]).
In some embodiments, the skew variants advantageously and simultaneously favor heterodimerization based on both the “knob and holes” mechanism as well as the “electrostatic steering” mechanism. In some embodiments, the fusion proteins include one or more sets of such heterodimerization skew variants. US’512 teaches exemplary skew variants on page 22, paragraph [0296], including T366S/L368A/Y407V:T366W, which meets the instant claim 6 limitation of KiH according to the definition in the instant specification, page 24, Table 3. US’512 also teaches that the variant can optionally including a bridging disulfide as T366S/L368A/Y407V/Y349C:T366W/S354C, which meets the instant claim 6 limitation of KiHs-s based on the instant specification, page 24, Table 3. US’512 teaches that the variants come in pairs of sets. That is, one set of the pair is incorporated into the first monomer and the other set into the second monomer. US’512 teaches that the pairs can form an interface between the two monomers that encourages heterodimer formation and discourages homodimer formation, allowing for the percentage of heterodimers that spontaneously form under biological conditions to be over 90%, rather than the expected 50% (page 22, [0296]). US’512 also teaches that the modifications outlined are shown relative to IgG1, but that all isotypes can be altered this way, we well as isotype hybrids (page 23, [0311]).
US’512 teaches effector functions as including a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, ADCC, ADCP, and CDC (page 16, [0203]). US’512 teaches methods increasing effector function (page 24, [0315]) and also teaches ablation variants that ablate FcγR binding, sometimes referred to as knock outs or “KO” variants (page 3, [0031]).
US’512 further teaches that the variants can include a N297A mutation (page 3, [0036]; page 4, [0040]). It is noted that, while US’512 does not directly state that this mutation provides reduced ADCC, this outcome would flow naturally from the substitution. See MPEP 2145 II.
US’512 also teaches that there are additional substitutions that find use in increasing binding to the FcRn receptor and increasing serum half-life, including, but not limited to 434S, 434A, 428L, 308F, 259I, 428L/434S, 259I/308F, 436I/428L, 436I, or V/434S, 436V/428L and 258I/308F/428L (page 25, [0333]). US’512 teaches specific substitutions including M428L/N434S or M252Y/S254T/T265E substitutions (page 25, [0343]).
US’512 further teaches that there are a number of useful Fc substitutions that can be made to alter binding to one or more of the FcγR receptors. Substitutions that result in increased binding as well as decreased binding can be useful. For example, it is known that increased binding to FcγRIIIa results in increased ADCC, which is antibody dependent cell-mediated cytotoxicity; the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target and subsequently cause lysis of the target cell. Particular variants that find use include, but are not limited to, 239D, 239D/332E, 332E/330L, and 239D/332E/330Y (page 25, [0331]).
US’512 further teaches that for all constant region positions discussed in the disclosure, numbering is according to the EU index as in Kabat (page 38, [0525]).
US’512 further teaches that, in some embodiments, the human IL-15 protein has the amino acid sequence set forth in NCBI Ref. Seq. No. NP_00576.1 or SEQ ID NO: 1, which is the precursor sequence. In some cases, the coding sequence of human IL-15 is as set forth in NCBI Ref. Seq. No. NM_00585. An exemplary IL-15 protein of the Fc fusion heterodimeric protein outlined can have the amino acid sequence of SEQ ID NO: 2 (mature IL-15), which corresponds to amino acids 49-162 of SEQ ID NO: 1. US’512, SEQ ID NO: 1, is identical to instant SEQ ID NO: 2, as shown in the ABSS alignment below.
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US’512 further teaches that, in some embodiments, the IL-15 domain has been engineered to include amino acid substitutions (page 18, [0232]). The IL-15 human protein is engineered to confer decreased potency and that the reduction in potency in the heterodimeric fusion proteins can enhance both pharmacodynamics and pharmacokinetics in subjects that are administered the proteins. Similarly, the variants can expand lymphocyte counts for a greater duration compared to wild-type fusion proteins. In addition, the reduction in potency of IL-15 can improve the therapeutic index, i.e., enable higher dosing with less toxicity (page 18, [0233]).
US’512 teaches that the amino acid substitution(s) may be isosteric substitutions at the IL-15:IL-2β and IL-15:common gamma chain interface (page 18, [0238]). US’512 teaches a number of suitable IL-15 amino acid variants that confer reduced potency and increased pharmacokinetics including variant IL-15 proteins comprising amino acid substitutions selected from the group of: N1D; N4D, D8N; D30N; D61N; E64Q; N65D; Q108E; and combinations thereof (page 18, [0237]).
US’512 teaches that, in some embodiments, the IL-15 protein and the IL-15Rα protein are attached together via a linker, e.g., in a scIL-15/Rα format (page 26, [0350]). In some embodiments, the linker is a “domain linker”, used to link any two domains and predominantly includes Gly, Ser, Ala, or Thr. The linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. The linker can be about 1 to 50 amino acids in length, preferably about 1 to 30 amino acids in length (page 26, [0352]). The linker length of 1 to 30 amino acids disclosed by US’512 encompasses the instantly claimed range of 18 to 22 amino acids recited in instant claims 10 and 18, rendering the instant ranges obvious as it would be obvious to use any length disclosed by US’512 with a reasonable expectation of success, including 18-22. See MPEP 2144.05 I.
US’512 teaches that the heterodimeric proteins are generally isolated or recombinant. Isolated means a polypeptide that has been identified and/or recovered from a cell or cell culture from which it was expressed. Ordinarily the isolated polypeptide will be prepared by at least one purification step (page 17, [0213]).
Although US’512 does not exemplify immunocytokines meeting each of the instant claim limitations, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to arrive at the instantly claimed invention as US’512 teaches the claimed substitutions and formats for use in the production of immunocytokines that comprise a conjugate comprising a polypeptide comprising an IL-15 or derivative thereof and the sushi domain of IL-15Rα or a derivative thereof fused directly or indirectly to the C-terminus of one of the antibody heavy chains. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 3-4, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020 as applied to claim 1 above, and in further view of WO 2020/086758 A1 (Cheung, A.F., et al) 30 April 2020.
US’512 teaches the immunocytokine of claim 1 as discussed in detail above.
As discussed above, US’512 teaches Fc heterodimers and teaches exemplary skew variants including KiH.
US’512 also teaches the ablation of ADCC, or antibody dependent cell-mediated cytotoxicity (page 12, [0163]; page 25, [0335]) and further teaches that the antibody can be an IgG4 antibody (page 3, [0036] and [0038]; page 4, [0042]).
US’512; however, does not disclose that the IgG4 antibody or functional variant thereof comprises a L235E mutation.
WO’758 teaches Fc-fused protein constructs that have a higher serum half-life compared to a native/natural molecule, and are; therefore, advantageous for achieving higher titers of the proteins during production, higher stability during storage, and improve efficacy when used as a therapeutics. The Fc-fused protein constructs also have mutations in the Fc region that reduce effector functions (abstract).
WO’758 teaches that effector function includes ADCC and teaches that the Fc domain polypeptides can include IgG1 or IgG4 Fc domains (page 2, [0009]; page 140, [0220]).
WO’758 teaches that the amino acid substitution in the first Fc domain replaces the original amino acid with a larger amino acid and the substitution in the second antibody Fc domain replaces the original amino acid with a smaller amino acid, such that the larger amino acid substitutions (a protuberance) fits into the surface of the smaller amino acid substitutions (a cavity). For example, one antibody Fc domain polypeptide can incorporate a T366W substitution and the other can incorporate three substitutions including T366S, L368A, and Y407V (page 140, [0219]), which is the same skew substitutions disclosed by WO’758 and the KiH substitutions instantly claimed. WO’758 further teaches that the amino acid substitutions are all numbered according to the EU index as in Kabat (page 139-140, [0218]).
WO’758 teaches that the Fc domain polypeptides are human IgG4 Fc domain polypeptides and that the first and/or second Fc domains comprise one or more mutation(s) at 235 and/or 239 under EU numbering. In some embodiments, the mutation(s) are selected from L235E and P329A (page 3, [0011]). WO’758 teaches that the mutation reduces an effector function of the Fc (page 3, [0014]).
WO’758 further teaches that the fusion protein constructs can exhibit improved yield during production (page 17, [0067]). To achieve the highest yield of the protein, different ratios of the first and second expression vectors can be explored to determine the optimal ratio of transfection into the host cells. Clones can be cultured under conditions suitable for bioreactor scaleup and maintained expression of the proteins. The proteins can be isolated and purified using methods known in the art (page 155, [0279]-[0280]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the IgG4 KiH heterodimerized Fc fusion proteins disclosed by US’512 to further include a L235E substitution as disclosed by WO’758. It would have been obvious to include a L235E substitution as WO’758 demonstrates that a L235E substitution in IgG4 Fc heterodimerization domains results in reduced effector function of the Fc. An ordinarily skilled artisan would have had a reasonable expectation of success as US’512 teaches that the antibody can be an IgG4 Fc, can have KiH heterodimerization mutations, and can have modifications leading to reduced effector function. Additionally, WO’758 also teaches heterodimer fusion proteins comprising IgG4 Fc domains with KiH heterodimerization modifications.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020 as applied to claim 1 above, and in further view of Pereira, N.A., et al (2018) The “less-is-more” in therapeutic antibodies: afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity MABS 10(5); 293-711.
It is noted that claim 5 was rejected above as being obvious over US’512. The claim is rejected again here to demonstrate further obviousness, including the alternative limitation in part (b), in view of the prior art.
US’512 teaches the immunocytokine of claim 1 as discussed above.
As discussed above, US’512 teaches that it is known that increased binding to FcγRIIIa results in increased ADCC, which is antibody dependent cell-mediated cytotoxicity; the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target and subsequently cause lysis of the target cell. Particular variants that find use include, but are not limited to, 239D, 239D/332E, 332E/330L, and 239D/332E/330Y (page 25, [0331]).
These modifications are further supported by the prior art.
US’512 also does not disclose that the antibody is an afucosylated IgG1, IgG2, or IgG4 antibody or functional variant thereof.
Pereira teaches that, in cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, ADCC, as the major mode of action to deplete tumor cells. It is well known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as NK cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic design. Pereira provides a review discussing the relevance of antibody core fucosylation to ADCC and strategies to produce afucosylated antibodies (abstract).
Pereira teaches that, in addition to glycoengineering of the Fc N-glycan, various strategies have been performed to engineer the Fc domain to improve the ADCC effector function. With the use of computational structure-based design and high-throughput screening a series of engineered Fc variants were generated. These Fc variants of either single, S239D or I332E; double, S239D/I332E; or triple S239D/I332E/A330L, mutations demonstrated up to 169-fold enhanced interaction with human FcγRIIIa (page 696, left column, paragraphs 2-3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the heterodimerized Fc fusion proteins disclosed by US’512 by substituting the antibody with an afucosylated antibody and/or using the Fc variants disclosed by Pereira. It would have been obvious to use an afucosylated antibody and/or the substitutions disclosed by Pereira as Pereira teaches that the absence of the core fucose on the Fc N-glycan enhances ADCC activity as does the substitutions disclosed. An ordinarily skilled artisan would have had a reasonable expectation of success as US’512 teaches that useful Fc substitutions can be made to alter binding to one or more of the FcγR receptors including increased binding and teaches substitutions that overlap with those of Pereira.
Claims 10 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020 as applied to claim 1 above, and in further view of US 2018/0312560 A1 (Morisseau, S.D., et al) 01 Nov 2018.
It is noted that claims 10 and 18 were rejected above as being obvious over US’512. The claims are rejected again here to demonstrate further obviousness in view of the prior art.
US’512 teaches the immunocytokine of claim 1 as discussed above.
US’512 does not explicitly disclose that the linker between the IL-15Rα sushi domain and IL-15 is 18 to 22 amino acids.
The teachings of US’560 are as discussed in detail above.
As discussed above, US’560 exemplifies a linker between IL-15 and the sushi domain of IL-15Rα that is 20 amino acids in length.
US’560 further teaches that the amino acid sequence of IL-15 or derivatives thereof and the amino acid sequence of the sushi domain of IL-15Rα or derivatives thereof may be separated by a first “linker” that is sufficient length to ensure that the fusion protein form proper secondary and tertiary structures. The length of the first linker amino acid sequence may vary without significantly affecting the biological activity of the fusion protein. Typically the linker comprises at least one, but less than 30 amino acids, e.g., a linker of 2-30 amino acids… most preferably 18-22 amino acids (page 5, [0098]-[0099]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the linker between IL-15 and the sushi domain of IL-15Rα in US’512 with the linkers disclosed by US’560. An ordinarily skilled artisan would have made this substitution with a reasonable expectation of success as US’560 teaches the use of the linkers in producing a conjugate comprising IL-15 and the sushi domain of IL-15Rα, which is the same elements of the conjugate disclosed by US’512.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0140512 A1 (Bernett, M., et al) 7 May 2020 as applied to claim 1 above, and in further view of WO 2008/143794 (Wong, H., et al) 27 Nov. 2008.
US’152 teaches the immunocytokine of claim 11 as discussed in detail above.
US’152; however, does not disclose that the substitution includes a N65A substitution or a combined substitution selected from D8N/N65A, D61A/N65A, or D61A/N65A/Q101D.
WO’794 teaches fusion protein complexes and IL-15 variants that have therapeutic and diagnostic use (abstract).
WO’794 teaches that the fusion protein comprises an IL-15 domain that is an IL-15 variant (also referred to as an IL-15 mutant). Preferably the amino acid substitutions/deletions are in the domains that interact with IL-15Rβ and/or γC. Preferably, the IL-15 variants comprise one or more than one amino acid substitutions/deletions at positions 8, 61, 65, 72, 92, 101, 108, or 111 of the mature human IL-15 sequence; particularly D8N, D8A, D61A, N65A, N72R, or Q108A (page 26, lines 1-28). WO’794 also teaches a combination of D8N/N65A (Fig. 19C).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the heterodimerized Fc fusion proteins disclosed by US’512 by either substituting the IL-15 substitutions disclosed with those of WO’794 or to further include the IL-15 substitutions disclosed by WO’794, including D8N, N65A, or D61A. It would have been obvious to substitute or further include these substitutions as WO’794 identifies the positions as being in the domains that interact with IL-15Rβ and/or γC and the specific substitutions are identified as preferable substitutions for modifying the mature human IL-15 sequence. An ordinarily skilled artisan would have had a reasonable expectation of success as US’512 teaches substitutions in the mature human IL-15 sequence in the fusion proteins for the same purpose.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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