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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2020/050851, filed on 09/15/2020, which claims domestic benefit to US provision application 62/901,198, filed 09/16/2019.
Claim Status
The Amendment, filed on 12/17/2025, is acknowledged in which:
Claim 9 and 11 are canceled.
Claims 1 and 7 are currently amended.
Claims 8, 16-19, 22-24, and 27-29 were previously presented.
Claims 2-6, 12-15, 20-21, 25-26, and 30-32 are original.
Claims 1-8, 10, and 12-32 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements filed 12/17/2025 and 01/06/2026 fail to comply with the provisions of 37 CFR 1.97(a) because it lacks the appropriate size fee assertion and appropriate size fee set forth in 37 CFR 1.17(v)(3) “filing an information disclosure statement that causes the cumulative number of applicant-provided or patent owner-provided items of information to exceed 200”. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Withdrawn Objections and Rejections
In the office action dated 10/01/2025,
The specification was objected to for a typographical error in the text (pg 2). Applicant’s submission of an amended specification with appropriate correction has overcome the objection and the objection is withdrawn.
All claim objections and/or rejections regarding claims 9 and 11 are rendered moot in view of claim cancellations
Claim 7 was rejected under 35 USC 112(b) for reciting unclear claim limitations “as compared to SEQ ID NO:4.” Applicant’s amendment to recite a sequence comprising SEQ ID NO:4 with specific amino acid substitutions has overcome the rejection and the rejection is withdrawn.
Claims 1-8, 10, 12-20, and 22-31 were rejected under 35 USC 102(a)(1) as being anticipated by Vallera Applicant’s amendment to the claim to recite specific scFv sequences for the targeting domain of the claimed compound (i.e. previous limitations of claim 11) has overcome the rejection and the rejection is withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Specification
The use of the terms as noted in the office action dated 10/01/2025, which are trade names or marks used in commerce, has been noted in this application. While applicant has submitted replacement paragraphs for amendments to specification for capitalization of terms, they do not include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Therefore, the objection is maintained.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8, dependent on claim 1, recites that the targeting domain is an antibody or a binding fragment thereof defined in the specification to include various antibody formats in addition to scFv (e.g. Fab, F(ab’)2, Fv, sdAbs; pg 7, ¶ 2). This effectively broadens the scope of the base claim which recites the antibody targeting domain comprises an scFv with specific amino acid sequences (i.e. restricted format). Claim 10 does not fix this issue as the claim further recites Fab monoclonal antibody species or functional variants thereof.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 1-8, 10, 12-20, and 22-31 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/062604 A1 (herein Vallera) and WO 2014/018572 A2 (herein Dixit).
Regarding claim 1, 4-5, 7-10, 12-15, Vallera teaches killer engager (bi-, tri-, and tetra-specific) molecules comprising an NK cell engaging domain that selectively binds CD16 (anti-CD16 scFv), an NK activating domain operably linked to the NK cell engaging domain comprising IL-15, and various targeting domains that selectively binds to a target cell and is operably linked to the NK activating domain and the NK engaging domain (claim 1). Vallera teaches that any scFv can be inserted into the generalized TriKE structural platform of 1615X (i.e. replacing the anti-CD33 scFv in the 161533 TriKE shown in Figure 1A and encoded by SEQ ID NO:1 (partially annotated alignment shown below indicates flanking sequences that anticipate instant claims 12-15 and an IL-15 domain identical to SEQ ID NO:4 with N72D mutation according to instant claim 7) and teaches exemplary TriKE molecule 1615Her2, which enhances ADCC, expansion, and activation of NK cells in vitro (page 27, lines 8-11; Table 3). While the amino acid sequence for this TriKE is not disclosed, Vallera teaches the anti-HER2 can be derived from HER2 antibodies trastuzumab or pertuzumab (page 14, lines 26-27).
Instant SEQ ID NOs: 4 aligned with Vallera SEQ ID NO:1 (partial)
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While Vallera teaches known HER2 targeting antibodies (trastuzumab and pertuzumab) Vallera does not teach specific amino acid sequences for the disclosed TriKE with HER2 scFv targeting domain (e.g. selected from SEQ ID NOs:6 or 15-27).
Dixit teaches an anti-HER2 single chain Fab (i.e. scFv) derived from antibody 4D5 obtained from the 1N8Z structure Herceptin® (brand name for trastuzumab) Fab (¶ [00203]; page 75 table, Variant 656, SEQ ID NO:2) identical to instant SEQ ID NO:16 (see alignment below). This variant was observed to retain parent Fab (Variant 695) like antigen binding affinity (Fig 8A; Table 10).
Instant SEQ ID NOs: 16 (Qy) aligned with Dixit SEQ ID NO:2 (Db)
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that a known HER2 scFv derived from trastuzumab as taught by Dixit can be substituted for the CD33 scFv within 161533 construct to form a 1615Her2 TriKE as taught by Vallera with a reasonable expectation of success because Vallera teaches that any scFv can be inserted into the generalized TriKE structural platform of 1615X and that HER2 targeting TriKEs improve NK cell function.
Regarding claim 2, the combined teaching of Vellera and Dixit teach claim 1 as discussed above. Vallera further teaches an NK engaging domain that selectively binds CD16 can comprise CD16a specificity (claim 8) to engage NK cells while avoiding neutrophils (page 14, lines 11-15) (i.e. anti-CD16a scFv encoded in 16a1538; SEQ ID NO:16).
Regarding claims 3 and 5-6, the combined teaching of Vellera and Dixit teach claim 1 and 4 as discussed above. Vallera further teaches that the CD16 scFv within the 161533 humanized TriKE molecule can be replaced with llama anti-CD16 (camelid-VHH) without hindering specificity (Page 31, ¶ 2; Figure 22). This construct (SEQ ID NO:14) comprises sequences identical to instant SEQ ID NOs: 2 and 4, respectively (see alignments below).
Instant SEQ ID NOs: 2 and 4 aligned with Vallera SEQ ID NO:14
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Regarding claim 16-17, the combined teaching of Vellera and Dixit teach claim 1 as discussed above. Vallera further teaches the compound can comprise a second targeting domain (e.g. 1615EpCAM133 - SEQ ID NO:9; Figure 13), second activating domain, or second NK engaging domain (claims 24-26; page 2, lines 7-8).
Regarding claim 19-20, 22-31, the combined teaching of Vellera and Dixit teach claim 1 as discussed above. As discussed above Vallera teaches 1615Her2 enhances ADCC, expansion, and activation of NK cells in vitro, suggesting effectiveness as a in vivo cancer therapeutic (Table 3). Vallera further teaches the TriKEs as described above may be formulated with a pharmaceutically acceptable carrier (page 36, ¶ 5) and administered to a subject to induce NK-mediated killing of target cells (claim 49) wherein the target cells are cancer (claims 51, 54, 64). Vallera further teaches TriKE molecules or compositions thereof may be administered with one or more additional therapeutic agents before, after, and or/coincident to the administration of a TriKE molecule (claim 57 and 67; page 38, ¶ 6). Vallera teaches exemplary therapeutic agents including species recited in instant claim 31 as chemotherapeutics (claim 58 and 68; page 39, ¶ 2)
Claims 20-21, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Vallera and Dixit as applied to claims 19 and 29 above, and further in view of US 11,291,721 B2 (herein Loew).
The combined teachings of Vallera and Dixit teach claims 19 and 29 as discussed above.
However, neither reference teaches additional therapeutic/immunotherapeutic agents that target HER2, HER3, or HER2/HER3 heterodimer.
Loew teaches multispecific molecules that include (i) a first and (ii) second tumor-targeting moiety comprising antibody molecules that bind to cancer antigens, (iii) a third antibody that binds to NKp30 or NKp46 (i.e. NK cell engager); and (iii) a cytokine molecule selected from a group consisting of cytokines including IL-15 or a functional variant thereof (claim 1). Loew teaches that the first or second cancer antigen is selected from a group including Her2/neu (claim 6). Loew also teaches exemplary alternative NK cell engagers including CD16 (e.g. CD16a, CD16b, or both) (column 9, lines 45-56). Loew teaches a method of treating cancer in a subject by administering the multispecific molecules according to claim 1 (claim 19) and teaches this method can further comprise a second therapeutic treatment comprising a therapeutic agent, radiation, or surgery (claim 20). Loew defines therapeutic agent to include biologics (page 23, line 51), and teaches biologics known in the art as useful in the treatment of cancers including HER2 targeting Herceptin® (trastuzumab) (column 248, lines 55-58) and pertuzumab (column 249, line 66).
One of ordinary skill in the art would recognize that the multispecific molecule as taught by Loew is analogous to a TriKE as taught by the combined teachings of Vallera and Dixit. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the 1615Her2 TriKE as taught by Vallera would have a reasonable expectation of success as a method for treating cancer in combination with additional FDA approved biologics (i.e. immunotherapy) that target HER2 as taught by Loew.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 12/17/2025 have been fully considered in so far as they apply to the modified rejection above, but they are not persuasive.
Applicant states:
“Applicant submits that claim 1 is patentable under 35 U.S.C. § 103 over the combination
of Vallera and Dixit because, at a minimum, Applicant's specification establishes that the
compound of claim 1 provides a surprising result that is not predictable from the combination of Vallera and Dixit.” (Remarks, pg 15, ¶ 4)
“Dixit describes generating and characterizing scFv antibody fragments derived from
trastuzumab. Dixit, paragraph [0203]. Dixit lacks any teaching of in vivo activity of any
compound that includes a trastuzumab-derived scFv. In contrast, Applicant's specification
provides data explicitly demonstrating the in vivo efficacy of a 1615HER2 TriKE molecule in, for example, reducing tumor size in a mouse model (FIG. 10) and improving survival (FIG.
11D).” (Remarks pg 15-16 spanning ¶)
“Applicant respectfully submits that Dixit does not provide any reasonable expectation
that a HER2 targeting TriKE compound having a trastuzumab-derived scFv would have the antitumor properties of the compound recited in claim 1. It is well established in the art that in vitro experiments are not necessarily an indication of the efficacy of a compound in vivo. Thus, the compound recited in claim 1 provides a surprising result that is not predictable from the combined teachings of Vallera and Dixit.” (Remarks, pg 16, ¶ 2)
In response to applicant’s argument that Dixit fails to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., in vivo efficacy) are not recited in the rejected claims 1-8, 10, and 12-21, which are drawn to a compound and composition comprising said compound (i.e. product). Although the claims are interpreted in light of the specification, limitations (or intended uses) from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding claims 22-32, which recite methods of treatment using the compound of claim 1 (i.e. implicit in vivo efficacy), as discussed above the VH/VL domains in the scFv as taught by Dixit are identical to VH/VL domains of the monoclonal antibody Herceptin® (trastuzumab), which was known in the prior art to be effective in treating HER2 positive cancers (e.g. breast cancer in 1998) as evidenced by The Antibody Society (Approved antibodies - The Antibody Society. The Antibody Society. Published 2018. Accessed February 21, 2026). Therefore, one of ordinary skill would recognize that an scFv comprising these domains, which has similar binding activity to the parent Fab in vitro as taught by Dixit, would have a reasonable expectation of also maintaining binding affinity in vivo. Further, the MPEP dictates a reasonable expectation of success (e.g. in vivo functionality) doesn't require absolute predictability of success ("Obviousness does not require absolute predictability of success." Id. at 903, 7 USPQ2d at 1681.)
Applicant states:
“Each of claims 20, 21, 30, and 32 ultimately depends from claim 1. Claim 1 is amended
herein to include subject matter previously recited in claim 11. Claim 11 is not subject to
rejection as being obvious in view of the combined teachings of Vallera and Loew. Thus,
Applicant submits that claims 20, 21,30, and 32 are nonobvious in view of the combination of
Vallera and Loew for at least all of the reasons that claim 11 was not included in the rejection.” (Remarks, pg 16, ¶ 5)
Applicants argument regarding the rejections for claim 20, 21, 30 and 32 in view of Vallera and Loew, are not persuasive because the scope of independent claim 1 has changed with amendments and the rejection of claim 1 has been modified to include Dixit (previously relied on to determine obviousness of claim 11) as discussed above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647