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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/21/2026 has been entered.
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 05/21/2026, is acknowledged in which:
Claim 8-11 are canceled.
Claims 1 is currently amended.
Claims 7, 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 33-34 are new
Claims 1-7 and 12-34 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/06/2026 has been considered by the examiner
Withdrawn Objections and Rejections
In the office action dated 2/25/2026,
The specification was objected to for tradenames or marks used in commerce without appropriate symbols. As discussed in the advisory action, applicant’s reference to MPEP 608.01(v)(II) has overcome the objection and the objection is withdrawn.
All claim objections and/or rejections regarding claims 8 and 10 are rendered moot in view of claim cancellations
Claims 1-7, 12-20, and 22-31 were rejected under 35 USC 103 as being unpatentable over Vallera and Dixit. Applicant’s amendment to the claim to limit the targeting to SEQ ID NO:6 has overcome the rejection and the rejection (as previously stated) is withdrawn. However, upon further consideration, new grounds of rejection are made in view of newly found prior art as discussed below.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims. Please note, 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 Rejections - 35 USC § 103 (Modified)
Claim 1-7, 12-20, 22-31, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/062604 A1 (herein Vallera) and US 7,754,211 B2 (herein Rosenblum).
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 with identity to SEQ ID NOs:6.
Rosenblum teaches an anti-c-erbB-2 (also known as HER2) scFV (scFv23), identical to instant SEQ ID NO:6, conjugated to an immunotoxin gelonin (SEQ ID NO: 13) (see alignment below).
Instant SEQ ID NOs: 6 (Qy) aligned with Rosenblum SEQ ID NO:13 (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 as taught by Rosenblum 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 Rosenblum 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 Rosenblum 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 Rosenblum 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 Rosenblum 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 Rosenblum 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 Rosenblum 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 Rosenblum. 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 5/21/2026 have been fully considered but they are not persuasive.
Applicant states:
“…neither Vallera nor Dixit describes a compound having a targeting domain that includes an scFv that includes the amino acid sequence of SEQ ID NO:6… Since the combination of Vallera and Dixit fails to establish that every feature recited in claim 1 was known, the combination of Vallera and Dixit cannot render claim 1 obvious.” (Remarks, pg 11, ¶ 1 and 3)
“The deficiencies of the combination of Vallera and Dixit with respect to the subject matter of claim 1, as amended herein, are addressed immediately above. Loew neither teaches nor suggests and scFv that includes the amino acid sequence of SEQ ID NO:6. Therefore, Loew fails to cure the deficiencies of the combination of Vallera and Dixit with respect to the subject matter of claim 1.” (Remarks, pg 11-12, page spanning ¶)
Applicant’s argument regarding the combination of Vallera and Dixit is not persuasive because the scope of the respective claims have been amended to exclude previous embodiments referenced in the prior art of record. As applicant has altered the scope of the claims, new ground of rejection are made in view of newly found prior art reference Rosenblum, which teaches a known anti-HER2 scFv (identical to instant SEQ ID NO:6) which be a suitable alternative within the TriKE molecules as taught by Vallera as discussed above.
Subsequent arguments regarding the deficiencies of Vallera in combination with Dixit and Loew (i.e. pg 11-12 spanning ¶) are therefore also considered not persuasive.
Claim Rejections - 35 USC § 103 (New)
Claims 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Vallera and Rosenblum as applied to claims 1 and 19 above, and further in view of Tóth (PLoS One. 2014;9(3):e90896) and NCBI (The Genetic Codes. Updated Jan 7, 2019).
Vallera and Rosenblum teach claims 1 and 19 above (i.e. amino acid residues 3-501 of instant SEQ ID NO:1). Vallera further teaches that synthesis of the compound was generated from a fully-assembled polynucleotide with a 5’ NcoI restriction site comprising an ATG initiation codon, which translates to methionine (M) (i.e. first residue of SEQ ID NO:1) as evidenced by NCBI, followed by the sequences encoding the VH and VL regions of the CD16 targeting domain (Example 3).
Vallera however, does not teach the nucleotide sequence for this construct, nor does Vallera explicitly teach the second amino acid residue, glutamic acid (E), between the start codon (M) and the starting amino acid residue of the CD16 VHH (Q) within SEQ ID NO:1.
Tóth teaches that using a 5’ NcoI restriction site within a vector comprising nucleotides “C’CATG_G” generates a single nucleotide overhang upon NcoI digestion, limiting the second position to codons starting with a G (Figure 7A).
NCBI teaches a limited number of amino acids that translate from codons starting with G: valine (V), alanine (A), aspartic acid (D), glutamic acid (E), and glycine (G) (Table 1).
One of ordinary skill in the art would recognize that the construct as described by Vallera requires two extra nucleotides downstream the 5’ NcoI start codon to prevent frameshift caused by the single residue overhang as taught by Tóth, and would recognize a limited number of candidate amino acids as taught by NCBI (i.e. codons starting with G). Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to arrive at the instantly claimed sequence SEQ ID NO:1, comprising amino acid residues “ME” in positions 1 and 2, because that the base construct as taught by Vallera is disclosed to start with methionine (i.e. amino acid residue 1 of SEQ ID NO:1) generated from NcoI restriction site. Furthermore, as the NcoI restriction site generates a single nucleotide “G” overhang, limiting the second residue to a finite number of 5 possible amino acids (V, A, D, E, or G) as taught by Tóth and NCBI, it would be well within the purview of those skilled in the art to arrive at the instantly claimed sequence comprising a glutamic acid (E) as the second residue to prevent frameshift of the subsequent encoded anti-CD16 VHH. This rationale aligns with choosing from a finite number of identified, predictable solutions with a reasonable expectation of success; see MPEP 2143(I)(E).
Double Patenting (New)
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.
US 11,098,100 B2
Claims 1, 3-7, 12-15, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-9, and 19 of U.S. Patent No. 11,098,100 (herein US’100) in view of US 7,754,211 B2 (herein Rosenblum). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter.
Claim 1 of US’100 claims a compound comprising (a) an NK engaging domain comprising amino acid residues 19-140 of SEQ ID NO:14, which are identical to instant SEQ ID NO:2 of instant claim 3 and defined as within scope of an NK engaging domain that selectively binds to CD16 by nature of claim dependency and also defined as a camelid antibody within scope of instant claims 4-5 (instant specification, pg 13, lines 7-8); (b) an NK activating domain comprising the amino acid sequence of SEQ ID NO:15 (identical to instant SEQ ID NO:4 as recited in instant claim 6), or the amino acid sequence of SEQ ID NO:15 comprising an N72D amino acid substitution or an N72A amino acid substitution (i.e. as recited in instant claim 7); (c) a first linker linking the NK engaging domain to the NK activating domain (i.e. claim 12); (d) a targeting domain that selectively binds to a target antigen; and (e) a second linker linking the NK activating domain to the targeting domain (i.e. claims 13-14 and C- to N- terminal format as described in instant claim 15) (see alignments below, which share identity to amino acid residues 3-265 of instant SEQ ID NO:1, a construct within scope of the compound of instant claim 1). Claim 6 of US’100 claims the targeting domain comprises a moiety that selectively binds to a tumor cells. Claim 7 of US’100 claims the targeting moiety comprises an antibody or a binding fragment thereof. Claim 8 of US’100 claims the antibody fragment comprises an scFv. Claim 9 of US’100 claims a composition of the compound with a pharmaceutically acceptable carrier (i.e. instant claim 19). Claim 19 of US’100 claims the target antigen is selected from a group including HER2 (claim 19, line 3).
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While US’100 claims 6-9 and 19 imply an anti-HER2 scFv is within scope of the antigen targeting domain genus of US’100 claim 1. US’100 does not claim a HER2 targeting domain comprising SEQ ID NO:6.
Rosenblum teaches an anti-HER2 specific scFv (SEQ ID NO: 13) identical to instant SEQ ID NO:6.
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 HER2 targeting compound genus as claimed in US’100 when substituted with a known anti-HER2 scFv as taught by Rosenblum would arrive at the instantly claimed invention (i.e. species within). While the compound of US’100 does not by itself render the instantly claimed invention obvious, it would be within the technical grasp of one of ordinary skill in the art to pursue known options (i.e. substituting equivalents known for the same purpose) such as the known anti-HER2 scFv as taught by Rosenblum to obtain predictable results of HER2 targeting. Therefore, the indicated claims are not patentably distinct.
US 12,606,604 B2
Claims 1, 3-7, 12-15, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, and 13-15 of U.S. Patent No. 12,606,604 (herein US’604) in view of US 7,754,211 B2 (herein Rosenblum). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter.
Claim 1 of US’604 claims a compound comprising (a) an NK engaging domain comprising an antibody or binding fragment thereof (b) an NK activating domain comprising the amino acid sequence of SEQ ID NO:15 (identical to instant SEQ ID NO:4 as recited in instant claim 6), or the amino acid sequence of SEQ ID NO:15 comprising an N72D amino acid substitution or an N72A amino acid substitution (i.e. as recited in instant claim 7); (c) a first linker linking the NK engaging domain to the NK activating domain (i.e. claim 12) with various sequences; (d) a targeting domain that selectively binds to a target antigen; and (e) a second linker linking the NK activating domain to the targeting domain with various sequences (i.e. claims 13-14 and C- to N- terminal format as described in instant claim 15) (see alignments below, which share identity to instant SEQ ID NO:1 within scope of the compound of instant claim 1). Claim 5 of US’604 claims the targeting domain comprises a moiety that selectively binds to a tumor cells. Claim 6 of US’604 claims the targeting moiety comprises an antibody or a binding fragment thereof. Claim 7 of US’604 claims the antibody fragment comprises an scFv. Claim 13 of US’604 claims the target antigen is selected from a group including HER2. Claim 14 of US’604 claims the NK engaging domain comprises amino acid residues 19-140 of SEQ ID NO:14, which are identical to instant SEQ ID NO:2 of instant claim 3 and defined as within scope of an NK engaging domain that selectively binds to CD16 by nature of claim dependency and also defined as a camelid antibody within scope of instant claims 4-5 (instant specification, pg 13, lines 7-8). Claim 15 of US’604 claims a composition of the compound with a pharmaceutically acceptable carrier (i.e. instant claim 19).
While US’604 claims 5-7 and 13 imply an anti-HER2 scFv is within scope of the antigen targeting domain genus of US’604 claim 1. US’604 does not claim a HER2 targeting domain comprising SEQ ID NO:6.
Rosenblum teaches an anti-HER2 specific scFv (SEQ ID NO: 13) identical to instant SEQ ID NO:6.
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 HER2 targeting compound genus as claimed in US’604 when substituted with a known anti-HER2 scFv as taught by Rosenblum would arrive at the instantly claimed invention (i.e. species within). While the compound of US’604 does not by itself render the instantly claimed invention obvious, it would be within the technical grasp of one of ordinary skill in the art to pursue known options (i.e. substituting equivalents known for the same purpose) such as the known anti-HER2 scFv as taught by Rosenblum to obtain predictable results of HER2 targeting. Therefore, the indicated claims are not patentably distinct.
Conclusion
No claims are currently allowed. 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
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