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 16 April 2026 has been entered in full. Claims 1, 45, 52, 55, 126, 133, and 134 are amended. Claims 2-22, 24-44, 46-51, 53, 54, 56-125, 127, 130-132, 135-138 are cancelled. Claims 139-144 are added.
Claims 23, 133, and 134 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species and invention, there being no allowable generic or linking claim.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, 45, 52, 55, 126, 128, 129, and 139-144 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 April 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The replacement drawings were received on 16 April 2026. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objections to the drawings as set forth at pages 3-4 of the previous Office Action of 16 January 2026 are withdrawn in view of the submission of replacement drawings on 16 April 2026.
2. The Sequence Listing Requirement deficiencies set forth at pages 4-6 of the previous Office Action of 16 January 2026 are withdrawn in view of Applicant’s amendment to the instant specification and submission of replacement drawings (16 April 2026).
3. The objections to claims 1 and 80 as set forth at pages 6-7 of the previous Office Action of 16 January 2026 are withdrawn in view of the amended and cancelled claims (16 April 2026).
4. The rejection of claims 2, 8, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 7-10 of the previous Office Action of 16 January 2026 are withdrawn in view of the amended and cancelled claims (16 April 2026).
5. The rejection of claims 2, 5, 7, 8, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al. (US 2021/0260163 or WO 2019/173832) as set forth at pages 16-18 of the previous Office Action of 16 January 2026 is withdrawn in view of the amended and cancelled claims (16 April 2026). Specifically, Yu et al. do not teach a cytokine prodrug comprising a VHH masking moiety.
6. The rejection of claims 1, 2, 5, 7, 8, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 2021/0260163 or WO 2019/173832) and Karow et al. (US 2021/0002343 or WO 2020/069398) as set forth at pages 19-20 of the previous Office Action of 16 January 2026 is withdrawn in view of the amended and cancelled claims (16 April 2026). Specifically, Yu et al. and Karow et al. do not teach a cytokine prodrug comprising a VHH masking moiety.
7. The rejection of claims 2, 5, 7-9, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 2021/0260163 or WO 2019/173832) and Mazor et al. (mAbs 7(2): 377-389, 2015) as set forth at pages 20-22 of the previous Office Action of 16 January 2026 is withdrawn in view of the amended and cancelled claims (16 April 2026). Specifically, Yu et al. and Mazor et al. do not teach a cytokine prodrug comprising a VHH masking moiety.
New 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.
8. Claims 1, 45, 52, 55, 126, 128, 129, and 139-144 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.
8a. Claims 1, 45, 52, 55, 126, 128, 129, and 139-144 are rejected as being indefinite because claim 1 recites the limitation "or a fragment thereof" in lines 8 and 10. Claim 52, line 5 also recites the limitation "or a fragment thereof" in line 5.
There is insufficient antecedent basis for this limitation in the claims. The claim amendments of 16 April 2026 deleted the first recitation of “or a fragment thereof” in claim 1, line 3. Therefore, deletion of the remaining limitations of "or a fragment thereof" in claims 1 and 52 would overcome this issue.
Maintained 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.
9. Claims 1, 45, 52, 55, 126, 128, 129, and 139-144 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. The basis for this rejection is set forth for claims 1, 2, 5, 7-9, 14, 19, 45, 52, 55, 65, 68, 80, 126, 128, and 129 at pages 10-16 of the previous Office Action of 16 January 2026.
Amended claim 1, for example, is directed to a targeted cytokine comprising:
a) a PD-1 targeting moiety;
b) an IL-2 cytokine;
c) a VHH masking moiety; and
d) 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.
(i) At the top of page 11 of the Response of 16 April 2026, Applicant argues that without acquiescing to the allegations and solely to expedite prosecution, claim 1 has been amended to recite, in part, a targeted cytokine comprising: a) a PD1 targeting moiety; b) an IL-2 cytokine; c) a VHH masking moiety. Applicant asserts that as acknowledged by the Office, the instant specification describes 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)). Applicant submits that the subject matter of claim 1 and its dependent claims is fully supported by the specification.
Applicant’s claim amendments and arguments have been fully considered but are not found to be persuasive. Although claim 1 has been amended, subpart (c) simply recites “a VHH masking moiety” and the remainder of the claim recites “…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” (see claim 1, lines 4, 8-10).
The specification of the instant application filed 16 April 2026 teaches that the masking moiety comprises a VHH (single domain antibody) that binds to a cytokine (page 3, [0012]; page 93, [0342]; pages 122-123, [0482-0484]). The specification discloses that the IL-2 masking moiety is an anti-IL2 VHH antibody, such as an anti-IL2 VHH having the amino acid sequence of SEQ ID NO: 168 (page 124, 0486-0487]). The specification continues to state that the masking moiety comprises an anti-IL-2 VHH having a hCDR1 of SEQ ID NO: 169, a hCDR2 of SEQ ID NO: 170, and a hCDR3 of SEQ ID NO: 171 (page 124, [0486-0487]). Examples 10-12 (at pages 184-194, in particular Table 8) of the specification disclose IL-2 constructs with IL-2-specific masking moieties, “VHH”, “SCFV1”, “QVQ_VHHv1”, “QVQ_VHHv2”, or “VHHv2”. The specification teaches that SCFV1 comprises the amino acid sequence of SEQ ID NO: 180 and is an scFv (not a VHH) (page 121; page 198, [0722]). However, the specification does not specifically define or identify, “VHH”, “QVQ_VHHv1”, “QVQ_VHHv2,” or “VHHv2”.
The specification of the instant application clearly 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 and the claims of the instant application are still broadly interpreted by the Examiner as reading upon a targeted cytokine that comprises any possible VHH masking moiety.
There is no identification of any particular sequence or structure of the VHH masking moiety that must be conserved in the claimed construct in order to provide the desired functions of binding the IL-2 cytokine and releasing IL-2 upon cleavage encompassed by the claims. Thus, the claims are drawn to a genus of targeted cytokines that comprise a genus of VHH masking moieties. In the instant case, the only factors present in the method claims are (i) a structural characteristic of a targeted cytokine that comprises any VHH masking moiety and (ii) functional characteristics of targeting, binding the IL-2 cytokine, and releasing IL-2 upon cleavage. There is no identification of any particular sequence or structure of the VHH 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 VHH masking moieties.
The description of a masking moiety comprising (i) an anti-IL2 VHH having the amino acid sequence of SEQ ID NO: 168 or (ii) an anti-IL-2 VHH having a hCDR1 of SEQ ID NO: 169, a hCDR2 of SEQ ID NO: 170, and a hCDR3 of SEQ ID NO: 171 (page 124, [0486-0487]) is not adequate written description of an entire genus of targeted cytokines that comprise a genus of VHH 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).
In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of targeted cytokines that comprise a genus of VHH 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 VHH masking moiety is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Therefore, only a target cytokine comprising
(a) a PD-1 targeting moiety;
(b) an IL-2 cytokine;
(c) an anti-IL2 VHH masking moiety comprising (i) the amino acid sequence of SEQ ID NO: 168 or (ii) the hCDR1 amino acid sequence of SEQ ID NO: 169, the hCDR2 amino acid sequence of SEQ ID NO: 170, and the hCDR3 amino acid sequence of SEQ ID NO: 171; and
(d) an Fc domain, but not the full breadth of the claims meets 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).
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
10. Claims 1, 45, 52, 55, 126, 128, 129 and new claims 139-144 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. The basis for this rejection is set forth in detail at pages 22-25 of the previous Office Action of 16 January 2026.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(i) At the bottom of page 13 of the Response of 16 April 2026, Applicant states that amended claim 1 requires, in part, a first or second linker that is a cleavable linker comprising one of the cleavable peptides as defined by SEQ ID NOs: 34 and 42, while the claims of the ‘234 application an attenuated IL-2 cytokine and only one linker comprising a cleavable peptide. Applicant argues that amended claim 1 and dependents therefrom are patentably distinct from the claims in co-pending Application 18/821,234.
Applicant’s arguments have been fully considered but are not found to be persuasive. Applicant is reminded that instant claim 1 recites in line 9 that “the first or the second linker is a cleavable linker” (emphasis added by the Examiner). There is no requirement in instant claim 1 that both linkers are cleavable or a requirement as to which specific linker is cleavable. Therefore, since claims 42 and 53 of the ‘234 application recite one cleavable linker, the cleavable linker limitation of instant claim 1 is met.
Additionally, claim 43 of the ‘234 application recites that the cleavable linker comprises MPYDLYHP (SEQ ID NO: 34), meeting the limitations of instant claim 1 (which recites the same cleavable linker amino acid sequence).
Lastly, regarding Applicant’s argument that the claims of the ‘234 application are directed to attenuated an IL-2 cytokine, it is noted that the amended claims of the instant application simply recite “an IL-2 cytokine”. Therefore, the masked cytokine comprising “an attenuated IL-2 polypeptide” of the ‘234 application is a species that anticipates the genus “IL-2 cytokine” recited in the claims of the instant application.
Conclusion
No claims are allowable.
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 BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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BEB
Art Unit 1647
26 June 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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