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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 29, 2025 has been entered.
Application Status
The amended claims filed December 1, 2025 are entered. Claims 1-2, 9-10, 13-15, 17-19, 21, 26, and 28-31 are pending. Claims 5-6 and 27 were canceled. Claims 1, 9, and 26 are amended. Claims 2, 14-15, 17-19, and 21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 9-10, 13, 26, and 28-30 are under examination herein.
Notice Regarding Non-Compliant Claim Amendments
It is noted that claim 26, which is labeled as “(previously presented)” in the amended claims filed December 1, 2025, contains annotated amendments. Applicant also sets forth that the claim was amended in the Remarks filed December 1, 2025 at page 13.
In the interest of compact prosecution, the claims will be examined herein.
Applicant is advised to follow the rules of MPEP § 714 (in particular section (II)(C)) in future amendment submissions.
WITHDRAWN CLAIM REJECTIONS
All prior rejections of claims 5-6 and 27 are rendered moot by the cancelation of the claims.
The rejection of claims 1 and 13 under 35 U.S.C. § 102 as being anticipated by Baeuerle (WO 2017/156178 A1; cited in IDS) is withdrawn in view of Applicant's amendments to claim 1.
NEW AND MAINTAINED CLAIM OBJECTIONS AND REJECTIONS
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 1, 9-10, 13, and 30 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. This is a new rejection.
Regarding claim 1, 9-10, 13, and 30, the phrase “optionally” throughout the claims renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
It is noted that claim limitations which are designated as “optional” will not be considered required for the purposes of applying prior art under 35 U.S.C. §§ 102 and 103.
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.
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.
(1)
Claims 1, 9, 13, 26, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle (WO 2017/156178 A1; cited in IDS). This is a maintained rejection that has been updated for clarity and to address Applicant's claim amendments.
Baeuerle discloses conditionally activated polypeptide constructs comprising a protease-activated domain that binds to CD3, at least one half-life extension domain, and two or more target-binding domains (e.g., Abstract; Figure 3; ¶ 00151-00155, 00206-00227). Relevant to claims 1, 13, and 26, Figure 3 illustrates an exemplary agent which comprises a single polypeptide chain (i.e., a single molecule), wherein the agent comprises (i) a first targeting moiety (i.e., an antibody or antigen-binding fragment that binds to the tumor antigen EGFR), (ii) a first anti-CD3 scFv comprising an active VH domain, (iii) a second anti-CD3 scFv comprising an active VL domain, (iv) a first inert binding partner (anti-CD3 VL) that is comprised in the first anti-CD3 scFv and a second inert binding partner (anti-CD3 VH) that is comprised in the second anti-CD scFv, which act as masking moieties, (v) protease (enterokinase or EK) cleavage sites separating each of the first and second active anti-CD3 variable domains from the corresponding inert binding partners, and (vi) a second targeting moiety comprising a second antibody or antigen-binding fragment against a tumor antigen. Enterokinase is characterized by Baeuerle as protease which may be expressed by a variety of tumor or cancer cells as a type of diseased cells and tissues (e.g., ¶ 00221, 00256-00257; Table 1). Figure 3 also illustrates that a cleavable linker attaches the first and second inert binding partners. Further relevant to claim 26, Baeuerle teaches that the activity and efficacy of the polypeptide constructs of the invention shows little dependence on the orientation of the various domains and that the inert binding partners of the anti-CD3 scFvs can be upstream or downstream (N-terminal or C-terminal) (e.g., ¶ 00215).
Relevant to claims 9 and 28-29, Baeuerle teaches that the exemplary polypeptide constructs of the invention avoid the issue of renal clearance through the inclusion of the half-life extending moiety, and that upon reaching the desired target, the half-life extension domain is cleaved from the therapeutically active component so as to reduce its overall size and promote penetration into cells or tissues (e.g., ¶ 0009). Baeuerle teaches that in vivo half-life extension domains are preferably positioned to allow for removal of the domain once they have been delivered to the appropriate site (e.g., tumor) by placing the half-life extending moiety at a position in which it is separated from the therapeutically active component by a cleavable linker (e.g., ¶ 0008-0009, 00151, 00206-00217, 00227). In a particular embodiment, Baeuerle teaches that the half-life extension domain is joined to the inert VL or the inert VH (of the anti-CD3 scFvs) and that the half-life extension domain comprises an Fc domain (e.g., ¶ 00215-00216, 00260, 00271). See also ¶ 00228-00232 and Figure 53.
In view of the teachings of Baeuerle, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at single-molecule agent comprising a first tumor-targeting moiety, a first masked T-cell engaging domain, a second tumor-targeting moiety, and a second masked T-cell engaging domain, wherein the masking (inert) moieties are separated from the active domains of the T-cell engaging domains by protease cleavage sites and are attached to one another via a linker that further comprises a half-life extending moiety. The skilled artisan would have been motivated to do so because the conditionally active polypeptide constructs described by Baeuerle have improved pharmacokinetic properties due to the presence of the half-life extending domain, and also have increased therapeutic efficacy due to their smaller size at the target-binding site since the half-life extending moiety is cleaved upon exposure to proteases in the tumor microenvironment. There would have been a reasonable expectation of success because the exemplary constructs described by Baeuerle comprise a tumor-targeting moiety (which would be expected to have anti-tumor activity), a CD3-binding domain (which would be expected to specifically activate T cells upon conditional activation thereof in the tumor microenvironment), and a half-life extending moiety (e.g., an Fc domain) selected from art-recognized half-life extending domains (which are understood to extend serum half-life), thus comprising known elements that are respectively taught in the art to be useful for a specific purpose and combining them to form a composition that likewise is useful for these same specific purposes.
Response to Arguments
Applicant's arguments filed December 1, 2025 have been fully considered but they are not persuasive.
Applicant asserts that while Baeuerle contemplates the use of one or more half-life extending moieties, Baeuerle does not provide a teaching or motivation to incorporate a single half-life extending moiety that connects the two inert binding partners of the single molecule, as none of the exemplary constructs in Figure 53 comprise a ‘single’ half-life extending moiety connecting the two inert domains. Applicant further asserts that Baeuerle “only provides experimental data for single molecules that cleave into two components in serum or the tumor, where each component comprises a half-life extending moiety”, and only provides experimental data for agents comprising human serum albumin (HSA)-binding domains, in contrast to the single molecule described in the instant claims. See Remarks at pages 15-16. Regarding the specific structural configurations recited in claims 26 and 28, Applicant submits that the exemplary constructs in Figure 53 (highlighted in the previous Office actions) provide two separate half-life extending moieties on either side of the ‘regional linker’, one at the N-terminal end and one C-terminal to the regional linker, whereas the instantly claimed construct as set forth in claims 28 comprises a first half of an Fc domain attached to the first inert binding partner and a second half of an Fc domain attached to the second inert binding partner which recombine via covalent interactions to form a complete Fc domain at the N-terminus of the fusion protein. See Remarks at pages 17-18.
Applicant further argues that Baeuerle “teaches away from the use of large half-life extending moieties like Fc regions”, citing a portion of ¶ 0009 of Baeuerle. Applicant asserts that based on the disclosed experimental embodiments of Baeuerle, the skilled artisan would “not be motivated to use a ‘large’ half-life extension moiety, such as an Fc, to connect the two inert binding partners, because this half-life extending moiety would only dissociate from the molecule when the inert binding partners are also cleaved as depicted in instant Figure 5A”. See Remarks at page 17.
Regarding Applicant’s arguments with respect to the lack of working examples by Baeuerle of a conditionally activated polypeptide construct that expressly comprises an Fc domain situated between the inert binding partners, these arguments are not found persuasive because it is not necessary to reduce to practice a limitation in order to teach said limitation. It is held that Baeuerle clearly teaches that an Fc domain may be used a half-life extending moiety in the conditionally activated polypeptide constructs of the invention (e.g., ¶ 00216 and 00260). It is further noted that Baeuerle expressly conceives that “one or more” half-life extending moieties may be present in a polypeptide construct of the invention (e.g., ¶ 0015) and that the half-life extension domain may be present at different positions within the polypeptide construct (e.g., ¶ 00216). By virtue of positioning the half-life extending domain (“HED”) between the first inert anti-CD3 variable domain (which is separated from the first active anti-CD3 variable domain via a cleavable linker “CL1”) and the second inert anti-CD3 variable domain (which is separated from the second active anti-CD3 variable domain via a cleavable linker “CL2”), such as illustrated in Figure 53I or 53L, this format would necessarily result in a single-molecule construct in which the centrally positioned HED (together with the inert binding partners) is released upon cleavage of both inert binding partners in the tumor microenvironment, producing two activated molecules, analogous to the depiction illustrated in Figure 5A of the instant application. Furthermore, it is noted that the instant claims include open language (“comprises” and “comprising”) that does not preclude the presence of an additional half-life extending molecule at the N-terminus or C-terminus of the single-molecule agent.
Regarding Applicant's assertions with respect to Baeuerle “teaching away” from using Fc domains as the half-life extending domain, this is likewise found to be unpersuasive. MPEP § 2141.02 (VI) teaches, “[A] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983).” When the teachings of Baeuerle at ¶ 0009 are considered in their entirety, it is seen that Baeuerle teaches that a half-life extending domain (including a large half-life extending domain) of the invention is placed at a position in the molecule where it is separated from the therapeutically active component by a cleavable linker upon protease cleavage in the target microenvironment, thus reducing the size of the therapeutic component specifically at the site of action and promoting its penetration into tissues or uptake by cells. Until the polypeptide construct reaches the desired site of action, the polypeptide construct retains the HED, which prevents renal clearance. This mechanism of action mitigates any apparent issue described by Applicant as “teaching away” from use of a large HED, since the large HED would not be present in the therapeutically active component in the tumor microenvironment. Furthermore, Baeuerle does not at any point discourage or otherwise discredit the use of an Fc domain as the half-life extending moiety in a polypeptide construct of the invention, and Baeuerle does not teach that such a modification would render the polypeptide construct unsatisfactory for its intended purpose. MPEP § 2145 (X) states, “("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009))”. MPEP 2123 (II) states, “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).”
For at least these reasons, the rejection is maintained.
(2)
Claims 1, 9-10, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle (WO 2017/156178 A1; supra) as applied to claims 1, 9, 13, 26, and 28 above, and further in view of Wang (Protein Cell (2018) 9(1): 63-73; cited in PTO-892). This is a maintained rejection that has been updated for clarity and to address Applicant's claim amendments.
The teachings of Baeuerle are recited in the 35 U.S.C. § 103 rejection above.
However, Baeuerle does not expressly teach that the half-life extending Fc domain comprises one or more mutations as compared to a naturally occurring sequence.
Wang describes human antibody Fc modifications that modulate effector function and result in a variety of desirable enhancements to Fc characteristics, which are summarized in Table 1. Among these, Wang discloses the amino acid substitutions of M252Y/S254T/T256E (“YTE”) and M428L/N434S (e.g., Table 1; pages 69-70), pertinent to claims 10 and 30. Wang teaches that these mutations increase the binding of IgG for FcRn at pH 6.0, which results in extended half-life and increased anti-tumor efficacy based on preclinical studies (e.g., pages 69-70).
Based on the further teachings of Wang, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the conditionally activated polypeptide constructs described by Baeuerle, which may comprise an Fc domain as the half-life extending moiety, such that the Fc domain comprises either the M252Y/S254T/T256E (“YTE”) or M428L/N434S substitutions. The skilled artisan would have been motivated to do so because Wang sets forth that these mutations confer the specific advantage of further extending the half-life of antibody constructs comprising such a modified Fc domain and can increase the anti-tumor activity of said antibody constructs. There would have been a reasonable expectation of success because incorporating either of these sets of substitutions into the Fc domain would constitute the use of a known technique in a known product ready for improvement to yield a predictable result, as these substitutions were known by those in the art to confer half-life extending properties.
Response to Arguments
Applicant's arguments filed December 1, 2025 have been fully considered but they are not persuasive.
Applicant traverses the rejection on the grounds that Wang does not remedy the deficiencies of Baeuerle, which Applicant states “does not teach or suggest the use of a single half-life extending moiety connecting the two inert binding domains of the single molecule agent of claim 1” and “teaches against the use of an Fc region for tumor penetration” as summarized for the rejection above. See Remarks at page 19.
The response to Applicant's arguments regarding deficiencies of Baeuerle are set forth in the Response above. With respect to the present rejection, it remains held that Baeuerle teaches Fc domains as being among the suitable alternatives which may be used to extend the half-life of a conditionally activate polypeptide construct of the invention, and Wang further sets forth a clear advantage for specific modifications to the Fc domain which further advance this goal.
For these reasons, the rejection is 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.
(1)
Claims 1, 9, 13, 26, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-32 of co-pending Application No. 19/699,398 in view of Baeuerle (WO 2017/156178 A1; supra). This is a new rejection.
The co-pending claims recite a kit or composition comprising two single-molecule components comprising the elements set forth in (i), (ii), (iii), (iv), (v), (vi), and (vii) of claims 1 and 26, wherein the first and second targeting moieties are an antibody or antigen-binding fragment thereof that target an antigen expressed by cancer cells (e.g., co-pending claims 21-24, 26-28), pertinent to claims 1, 13, and 26.
The co-pending claims do not expressly recite that the first and second inert binding partners are linked via a linker that comprises a half-life extending domain, e.g., an Fc domain. However, this deficiency is remedied by the teachings of Baeuerle as set forth in the 35 U.S.C. § 103 rejection above.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the construct recited in the co-pending claims such that the inert binding partners are linked to one another and comprise between them a half-life extending domain (e.g., an Fc domain) such as set forth by Baeuerle. The skilled artisan would have been motivated to do so because the HLE domain would prevent rapid clearance of the constructs outside of the site of action. Furthermore, the presence of a linker with a HLE domain would place the two active T-cell-binding domains in closer proximity to one another (to permit T cell activation) once the inert binding partners have been cleaved away at the protease cleavage sites. There would have been a reasonable expectation of success because Baeuerle provides a proof-of-concept for analogous constructs comprising first and second components as set forth in the co-pending claims, which are functionally equivalent to those set forth in the co-pending claims.
(2)
Claims 1, 9-10, and 28-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-32 of co-pending Application No. 19/699,398 in view of Baeuerle (WO 2017/156178 A1; supra) as applied to claims 1, 9, 13, 26, and 28 above, further in view of Wang (Protein Cell (2018) 9(1): 63-73; supra). This is a new rejection.
The teachings of the co-pending claims and Baeuerle are recited in the provisional non-statutory double patenting rejection and 35 U.S.C. § 103 rejection above, respectively.
The co-pending claims do not expressly recite a half-life extending domain which is an Fc domain having one or more mutations as compared to a naturally occurring sequence. However, these deficiencies are remedied by the further teachings of Wang as set forth in the 35 U.S.C. § 103 rejection above.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the constructs described in the co-pending claims such that the inert binding partners are linked to one another and comprise between them an Fc domain comprising either the M252Y/S254T/T256E (“YTE”) or M428L/N434S substitutions. The skilled artisan would have been motivated to do so because Wang sets forth that these mutations confer the specific advantage of further extending the half-life of antibody constructs comprising such a modified Fc domain and can increase the anti-tumor activity of said antibody constructs. There would have been a reasonable expectation of success because incorporating either of these sets of substitutions into the Fc domain would constitute the use of a known technique in a known product ready for improvement to yield a predictable result, as these substitutions were known by those in the art to confer half-life extending properties.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
