DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
The amendment of 08 December 2025 has been entered in full. Claim 8 is amended. Claims 3, 4, 6, 10-13, 15-18, 20-22, 24-44, 46-51, 53, 54, 56-64, 66, 67, 69-79, 81-125, 127, 130-132, and 135-138 are cancelled..
Claims 1-2, 5, 7-9, 14, 19, 23, 45, 52, 55, 65, 68, 80, 126, 128, 129, 133, and 134 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 2, 5, 7-9, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129, drawn to a targeted cytokine comprising (a) a targeting moiety, (b) a cytokine, (c) a masking moiety, and (d) an Fc fragment, in the reply filed on 08 December 2025 is acknowledged.
Applicant’s election without traverse of the single domain antibody (VHH) as the species of masking moiety, in the reply filed on 08 December 2025 is also acknowledged. However, it is noted that after further consideration of the prior art, the restriction requirement among species of masking moiety as set forth at pages 6-8 of the Restriction requirement of 10 September 2025, is hereby withdrawn.
Claims 23, 133, and 134 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species and invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08 December 2025.
Claims 1, 2, 5, 7-9, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are under consideration in the instant Office Action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08 December 2025; 15 August 2025; 16 October 2024; and 14 November 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
It is noted that on the IDS of 14 November 2023, the Kuen reference (#C59) has been crossed off because it was cited in duplicate (see the IDS of 16 October 2024).
Drawings
1. The replacement drawings were received on 24 July 2023. These drawings are not acceptable. Specifically, the drawing sheets are not labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d).
Additionally, it is noted to Applicant that 37 C.F.R. § 1.84(U)(1) states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Replacement Figures 2A, 2B, 6A, 7B, 8B, 10B, and 11F, for example, are presented on 2-3 separate pages, with the second and third pages only labeled as “ Fig. XX (Continued)”.
If Applicant submits new replacement drawings, the sheets/pages for Figures 2A, 2B, 6A, 7B, 8B, 10B, and 11F should be relabeled with the figure number and consecutive capital letters (and not “Continued”). For example, the second and third pages of Figure 2A should be relabeled as “FIG. 2B” and “FIG. 2C”.
Applicant is reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicant is required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
2A. Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See page 3, [0010]; page 12, [0034]; page 87, [0322, 0323]; page 88, [0324, 0326]; page 90, [0332]; pages 139-140, [0563]; pages 184-186, Table 8 cleavage peptides; page 191, Table 14.
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.
2B. Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Please see Figures 10A and 10C; See also Figure 10B headings “MPYDLYHP” and “VPYSLYSG”.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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 Objections
3. Claims 1 and 80 are objected to because of the following informalities:
3a. In claim 1, line 2, subpart “a)” is not recited. Therefore, in lines 2-5, subparts “b)”, “c)”, “d)”, and “e)” should be relabeled as “a)”, “b)”, “c)”, “d)”.
3b. In claim 80, line 4, the word “antibodies” should be “antibody” (i.e., “a Fab-like bispecific antibody”).
Appropriate correction is required.
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.
4. Claims 2, 8, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 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.
4a. Claims 2, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are indefinite because claim 2 recites “Table 1” in line 12. The claims are reading limitations from the specification into the claims. MPEP § 2173.05(s) states that “[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claims. Incorporation by reference is a necessity doctrine, not for applicant's convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." Please note that this issue could be overcome by amending claim 2 to refer to the specific SEQ ID NOs presented in Table 1.
4b. Claim 8 is rejected as being indefinite because line 4 recites “a masking moiety comprising CD122 or a fragment thereof comprising one or more mutations selected from the group consisting of…”. It is not clear if CD122 comprises one or more mutations or if a fragment of CD122 comprises one or more mutations. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
4c. Claim 45 is rejected as being indefinite because line 3 recites that the targeting moiety comprises “an agent that specifically binds to the cytokine or the fragment thereof”. However, the specification of the instant application teaches that the targeting moiety comprises an antigen-binding moiety that binds to an antigen expressed on the surface of a target cell (page 55, [0195]). Therefore, since the claimed cytokine of claim 2 (from which claim 45 depends) comprises the cytokine, it is not clear how a targeting moiety that comprises an agent that binds to the cytokine would bind to the surface of a target cell as intended. The targeting moiety agent as recited in line 3 of claim 45 would seemingly just generate a cytokine aggregate with itself. Therefore, the metes and bounds of claim 45 cannot be determined.
4d. 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 45 recites the broad recitations “peptide”, “polypeptide”, and “protein”, and the claim also recites “a ligand” and “one or more antigen binding domains” which are the narrower statements of the limitations. The claim is 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.
4e. Claim 52 recites the limitations "first antigen binding domain" in line 2 and “second antigen binding domain” in line 6. There is insufficient antecedent basis for these limitations in the claim. Claim 2, from which claim 52 depends, does not recite a “first antigen binding domain” or a “second antigen binding domain”.
4f. Claim 65 is rejected as being indefinite because lines 5-6 recite “or MSP or a fragment thereof”. It is not clear if the “fragment” recitation is a fragment of MSP or a fragment of any one of the previously recited cytokines. Furthermore, line 2 already recites “a fragment thereof”. Thus, are lines 5-6 also intending to encompass a fragment of a fragment? Please note that this issue could be overcome, for example, by deleting the phrase “or a fragment thereof” from lines 5-6.
4g. 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 80 recites the broad recitation “an antibody”, and the claim also recites “a single domain antibody”, “a Fab-like bispecific antibody”, and “a single-domain antibody” which are the narrower statements of the limitation. The claim is 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.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1, 2, 5, 7-9, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1, for example, is directed to a targeted cytokine comprising:
b) a targeting moiety;
c) a cytokine or a fragment thereof;
d) a masking moiety; and
e) an Fc domain comprising a first Fc polypeptide linked to the cytokine or a fragment thereof through a first linker and a second Fc polypeptide linked to the masking moiety through a second linker,
wherein the masking moiety binds to the cytokine or a fragment thereof,
wherein the first or the second linker is a cleavable linker such that the masking moiety releases the cytokine or a fragment thereof upon cleavage,
wherein the cleavable linker comprises MPYDLYHP (SEQ ID NO: 34) or VPLSLYSG (SEQ ID NO: 42) and
wherein the targeting moiety is linked to the Fc domain through one or both of the first and second Fc polypeptides.
The specification of the instant application teaches that the present invention is based on the discovery that a targeting masked cytokine specifically targets a cell of interest for effective treatment of cancer without causing undesired side effects. Specifically, the targeting cytokines specifically bind the target cells of interest, accumulate in tumor, and are activated by tumor proteases (page 2, [0005]).
The specification teaches that the targeted cytokine of the present invention can comprise any cytokine or a variant thereof (page 67, [0236] through page 92). The specification provides specific cytokine sequences for IL-2, IL-15, and IL-12 (pages 68-92).
The specification also discloses that the masking moiety binds to the cytokine moiety and inhibits the biological activity of the cytokine. Upon cleavage, the masking moiety is released from the cytokine, activating the function of the cytokine in a target of interest (page 93, [0340]). The specification states that the masking moiety comprises an agent, a peptide, or a polypeptide that binds the cytokine (page 93, [0341]). The specification further explains that the masking moiety may comprise a Fab, a single chain Fv (scFv), a single domain antibody (VHH), one or more CDRs, a variable heavy chain (VH), a variable light chain (VL), a Fab-like bispecific antibody, a single-domain antibody linked-Fab, an antibody, a receptor of the cytokine, a fragment of a receptor, an extracellular domain of a receptor (page 93). At pages 94-124, the specification lists specific cytokines and masking moieties.
Lastly, the instant specification teaches the generation of a targeted cytokine comprising (a) a PD-1 targeting moiety; (b) IL-2 (cytokine); (c) CD122 (masking moiety); and two Fc polypeptides (pages 167-168, [0647]; see constructs “TC3”, “TC4”, “TC5”; Figures 3, 5A; Examples 4-5, pages 173-179). See also Examples 10 and 12 (at pages 184-186 and 192-194) of the specification for IL-2 constructs with alternative IL-2-specific masking moieties, SCFV1, QVQ_VHHv2, or VHHv2.
Therefore, the claims of the instant application are broadly interpreted by the Examiner as reading upon a targeted cytokine that comprises a) a targeting moiety; b) any possible cytokine or fragment thereof; (c) any possible masking moiety that binds to the cytokine or fragment thereof; and (d) an Fc domain comprising a first and second Fc polypeptide (as well as nucleic acids encoding such, host cells, and methods of making).
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the only factors present in the method claims are (i) a structural characteristic of a targeted cytokine that comprises any cytokine fragment and any masking moiety and (ii) functional characteristics of targeting and being active (see for instance, claim 7). There is no identification of any particular sequence or structure of the cytokine fragment and masking moiety that must be conserved in the claimed construct in order to provide the desired functions encompassed by the claims. Thus, the claims are drawn to a genus of targeted cytokines that comprise a genus of cytokines/cytokine fragments and a genus of masking moieties.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of cytokine fragments and the genus of masking moieties and the functions of targeting and being active. The specification of the instant application clearly also teaches that the masking moiety binds to the cytokine moiety and inhibits biological activity of the cytokine (page 93, [0340]). After cleavage, the masking moiety is released from the cytokine, allowing activation of the function of the cytokine (page 93, [0340]). Therefore, the cytokines and masking moieties are intended to interact and bind each other. However, the specification does not teach a structure which results in targeted cytokine constructs that comprise cytokines/cytokine fragments and masking moieties with the claimed required characteristics of targeting and being active. The description of a targeted IL-2 cytokine comprising (a) a PD-1 targeting moiety; (b) IL-2 (cytokine); (c) IL-2-specific masking moieties of CD122, “SCFV1”, “QVQ_VHHv2”, or “VHHv2”; and two Fc polypeptides (pages 167-168, [0647]; see constructs “TC3”, “TC4”, “TC5”; Figures 3, 5A; Examples 4-5, pages 173-179; Examples 10 and 12 (at pages 184-186 and 192-194)) is not adequate written description of an entire genus of targeted cytokines that comprise a genus of cytokines/cytokine fragments and a genus of masking moieties.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states 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). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). 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). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of targeted cytokines that comprise a genus of cytokines/cytokine fragments and a genus of masking moieties, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The specific cytokine/cytokine fragment and masking moiety are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), 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). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
6. Claims 2, 5, 7, 8, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al. (US 2021/0260163 or WO 2019/173832; both cited on the IDS of 14 November 2023). It is noted that US 2021/0260163 and WO 2019/173832 have the same disclosure. Thus, for brevity, relevant portions of US 2021/0260163 will be cited below.
Yu et al. teach targeted anti-claudin 18.2-IL-2 prodrugs and anti-PDL1-IL-2 prodrugs (page 17, Example 4). It is noted that Yu et al. state that claudin 18.2 and PD-L1 are antigens on the surface of tumor cells (page 6, [0075]). Specifically, Yu et al. disclose that the IL-2 prodrugs comprise:
a) an antibody against either claudin 18.2 (“589”) or PDL-L1 (atezolizumab) [targeting moiety];
b) IL-2 [cytokine]; and
c) IL-2Rβ [mask] (also known as CD122);
wherein one Fc domain of the antibody is linked to IL2 and the other Fc domain of the antibody is linked to IL-2Rβ via a cleavable linker, meeting the limitations of instant claims 2, 5, 7, 8, 19, 45, 52, 65, and 68 (page 1, [0004]; page 6, [0064]; page 17, [0147-0151]; Table 5 (pages 16-17); Figure 3; Tables 6 and 8 (page 17)). It is noted that the cleavable linker amino acid sequences of SEQ ID NOs: 18, 34, 35, 63, and 217 of Yu et al. (see Tables 6 and 8) comprise the sequence “LSGRSDNH” of SEQ ID NO: 232 of the instant application (as recited in instant Table 1).
Yu et al. teach that “knob-into-hole” mutations are made to promote the formation of the antibody heavy chain Fcs, meeting the limitations of instant claim 55 (see page 6, [0071]).
Yu et al. also disclose that the masking moiety in the IL-2 prodrug constructs may comprise an antagonist of IL-2, such as antibody, scFv, a Fab, a single chain antibody, meeting the limitations of instant claim 80 (page 5, [0062-0063]).
Yu et al. disclose polynucleotides encoding the IL-2 prodrugs, host cells comprising the polynucleotides, and a method of producing the prodrugs, meeting the limitations of instant claims 126, 128, and 129 (page 3, [0021]; page 9, [0103]; page 13, embodiments 56-60).
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.
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.
7. Claims 1, 2, 5, 7, 8, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 2021/0260163 or WO 2019/173832; both cited on the IDS of 14 November 2023) and Karow et al. (US 2021/0002343 or WO 2020/069398 (cited on the IDS of 14 November 2023)). It is noted that Karow et al. US 2021/0002343 or WO 2020/069398 have the same disclosure. Thus, for brevity, relevant portions of US 2021/0002343 will be cited below.
The teachings of Yu et al. are set forth directly above.
Yu et al. do not teach that the cleavable linker comprises “MPYDLYHP” (SEQ ID NO: 34) or “VPLSLYSG” (SEQ ID NO: 42) (instant claim 1).
Karow et al. teach a masked cytokine comprising: a) a cytokine or functional fragment thereof; b) a first linker; c) a masking moiety; d) a second linker; and e) a half-life extension domain (page 1-2, [0010-0013]). Karow et al. disclose that a proteolytically cleavable linker links the cytokine to the masking moiety, links the cytokine to the half-life extension domain, and/or links the masking moiety to a half-life extension domain (page 7, [0071-0072]; page 21, [0208]; pages 33-34, [0271-0274]; pages 35-39, Table 1). In particular, Karow et al. teach cleavable linkers, “MPYDLYHP” and “VPLSLYSG” (Table 1, page 35, 37; SEQ ID NOs: 96 and 315, respectively).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the IL-2 prodrugs comprising: a) an antibody against claudin 18.2 (“589”) or an antibody against PDL-L1 (atezolizumab); b) IL-2; and c) IL-2Rβ;
wherein one Fc domain of the antibody is linked to IL2 and the other Fc domain of the antibody is linked to IL-2Rβ via a cleavable linker as taught by Yu et al. by substituting Yu et al.’s cleavable linker sequence “LSGRSDNH” with one of Karow et al.’s cleavable linker sequences, “MPYDLYHP” and “VPLSLYSG”. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the linker sequences, “MPYDLYHP” and “VPLSLYSG” of Karow et al. are also known cleavable peptide sequences and the simple substitution of one known equivalent element for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her 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 International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
8. Claims 2, 5, 7-9, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 2021/0260163 or WO 2019/173832; both cited on the IDS of 14 November 2023) and Mazor et al. (mAbs 7(2): 377-389, 2015).
The teachings of Yu et al. are set forth directly above.
Yu et al. do not teach that antibody against either claudin 18.2 (“589”) or PDL-L1 (atezolizumab) of the targeting moiety comprise a CH3 domain that comprises a modification that reduces or eliminates binding to Protein A and a CH3 domain that binds to Protein A (instant claim 9).
Mazor et al. teach new technology for enhanced cognate heavy chain (HC) and light chain (LC) pairing for making IgGs. (abstract). Mazor et al. explain that a significant problem in the production of bispecific IgGs is the formation of by-products and difficulties removing them (page 386, column 1, 1st paragraph). Mazor et al. disclose that mutations are introduced into a “hole” half-IgG containing CH3 to facilitate selective purification of correctly assembled antibodies (page 386, column 1, 1st paragraph). Specifically, Mazor et al. indicate that histidine 435 is mutated to arginine (H435R) because this mutation is known to ablate protein A binding (page 386, column 1, 1st paragraph). As arginine 435 co-occurs with phenylalanine 436, Mazor et al. also teach that the tyrosine at position 436 is changed to phenylalanine (Y436F) to minimize potential immunogenicity (page 386, column 1, 1st paragraph).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the IL-2 prodrugs comprising: a) an antibody against claudin 18.2 (“589”) or an antibody against PDL-L1 (atezolizumab); b) IL-2; and c) IL-2Rβ;
wherein one Fc domain of the antibody is linked to IL2 and the other Fc domain of the antibody is linked to IL-2Rβ via a cleavable linker as taught by Yu et al. by introducing the H435R and Y436F modifications into the CH3 domains of Yu et al.’s antibody Fc domains, as taught by Mazor et al. The person of ordinary skill in the art would have been motivated to make that modification because the two mutations (H435R and Y436F), referred to as “RF”, enable easy removal of hole-hole homodimers and hole half-IgG byproducts during protein A purification (see Mazor et al., page 386, column 1, 1st paragraph). The person of ordinary skill in the art reasonably would have expected success because H435R and Y436F CH3 modifications in Fc proteins were already being successfully performed at the time the invention was made (see Mazor et al.). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her 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 International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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9. Claims 1, 2, 5, 7, 9, 14, 19, 45, 52, 55, 65, 80, 126, 128, and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7, 8, 11, 17, 20, 27, 28, 38, 40-42, 53, and 61-68 of copending Application No. 18/821,234. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a targeted/masked cytokine comprising the same elements, namely a targeting moiety, a cytokine, a masking moiety, an Fc domain, and two linkers (wherein one is cleavable), and wherein the targeting moiety is linked to the Fc domain through one or both of the first and second Fc polypeptides.
Claim 1 of the instant application, for example, is directed to a targeted cytokine comprising: (i) a targeting moiety; (ii) a cytokine or fragment thereof; (iii) a masking moiety; and (iv) an Fc domain comprising a first Fc polypeptide linked to the cytokine through a first linker and a second Fc polypeptide linked to the masking moiety through a second linker,
wherein the masking moiety binds to the cytokine,
wherein the first or the second linker is a cleavable linker such that the masking moiety releases the cytokine upon cleavage,
wherein the cleavable linker comprises MPYDLYHP (SEQ ID NO: 34) or VPLSLYSG (SEQ ID NO: 42) and
wherein the targeting moiety is linked to the Fc domain through one or both of the first and second Fc polypeptides.
Claim 19 of the instant application recites that the targeting moiety specifically binds PD-1.
Claim 45 of the instant application recites that the targeting moiety comprises one or more antigen binding domains.
Instant claim 65 recites that the targeted cytokine is IL-2.
Instant claim 80 recites that the masking moiety comprises a single domain antibody (VHH) (elected species).
Meanwhile, claim 42 of the ‘234 application, for example, recites a masked cytokine comprising three polypeptides:
(a) a first polypeptide comprising a variable heavy chain of an anti-PD1 targeting moiety, a first Fc polypeptide, a non-cleavable linker, and an attenuated IL-2 polypeptide;
(b) a second polypeptide comprising a variable heavy chain of an anti-PD1 targeting moiety, a second Fc polypeptide, a cleavable linker, and a VHH masking moiety; and
(c) a third polypeptide comprising a variable light chain of an anti-PD1 targeting moiety.
Claim 43 of the ‘234 application recites that the cleavable linker comprises MPYDLYHP (SEQ ID NO: 34).
Regarding the Fc polypeptide limitations instant claim 9 (i.e., comprising a CH3 domain that comprises a modification that reduces or eliminates binding to Protein A; and a CH3 domain that binds to Protein A), the Fc sequences of SEQ ID NO: 20 and 21 recited in claim 53 of the ‘234 application comprise such modifications (see page 50 of the ‘234 specification).
Claims 126, 128, and 129 of the instant application and claims 61-64 of the ‘234 application recite a nucleic acid encoding the targeted/masked cytokine, a host cell comprising the nucleic acid, and a method of producing the targeted/masked cytokine.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Blackler et al. (WO 2021/189139, published 30 September 2021; cited on the IDS of 16 October 2024). Blackler et al. teach a masked interleukin 12 (IL12) fusion protein comprising: (a) an Fc domain comprising a first Fc polypeptide and a second Fc polypeptide; (b) a masking moiety (MM); and (c) an IL12 polypeptide, wherein the masking moiety is fused to the first Fc polypeptide by a first linker; and optionally, wherein the masking moiety further comprises a second linker, wherein the IL12 is fused to the second Fc polypeptide by a third linker, wherein at least one of the first, second, or third linkers is protease cleavable (page 3, lines 11-17).
Blackler et al. also disclose that the masked IL12 fusion proteins further comprise a targeting domain (page 5, CC; page 55, lines 12-23 through page 58). However, Blackler et al. do not teach that the targeting moiety is linked to the Fc domain through one or both of the first and second Fc polypeptides.
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BEB
Art Unit 1647
07 January 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647