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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 21, 2025 has been entered.
Claim Status
Claim listing filed on October 21, 2025 is pending. Claims 2-4, 6-29, 31, 33-45, 49, and 51-54 are canceled. Claim 1 is amended. Claims 56-57 are new. Claims 47-48 and 50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species in the election made without traverse in the reply filed on November 20, 2024. Claims 1, 5, 30, 32, 46, and 55-57 are examined upon their merits.
Withdrawn Claim Rejections
Applicant’s cancelation of Claim 18 has rendered all previous rejections directed to this claim moot.
Claim Rejections - 35 USC § 112 (New)
Claims 1, 5, 30, 32, 46, and 55-56 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.
Claim 1 recites wherein the modified human IFNα2 comprises SEQ ID NO: 6 or 7 and has a mutation at position R149. The specification teaches that SEQ ID NO: 6 is the human wild-type IFNα2a allele and SEQ ID NO: 7 is the human wild-type IFNα2b allele which only differs from IFNα2a by a R23K substitution (pages 7-8). However, SEQ ID NO: 7 as listed in the specification and the sequence listing has a tryptophan (W) residue at position 142 instead of two valine (VV) residues at positions 141-142 as in SEQ ID NO: 6 (as evidenced in the sequence alignment below wherein the top line is SEQ ID NO: 6 and the bottom line is SEQ ID NO: 7). Because UniProt Biodata Resource (of record in the non-final office action filed 12/19/2024) teaches that the sequence of human wild-type IFNα2b comprises the double valine (VV), Examiner believes there is typographical error in instant SEQ ID NO: 7 (a tryptophan (W) instead of a double valine (VV)).
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Therefore, the claims are rejected for indefiniteness because the correct structure of SEQ ID NO: 7 is unclear. For the purpose of compact prosecution, it is interpreted that SEQ ID NO: 7 comprises double valines (VV) at residues 141-142 instead of a tryptophan (W) at residue 142. Note, without this interpretation a 112(d) rejection would be appropriate for Claim 55 because SEQ ID NO: 9 does not comprise SEQ ID NO: 7 with the tryptophan (W) at residue 142; instead, SEQ ID NO: 9 comprises SEQ ID NO: 7 with the double valines (VV) at residues 141-142.
Should Applicant need to correct the sequence listing, Applicant must provide:
A "Sequence Listing" part of the disclosure, as described in 37 CFR 1.821(c) as well as:
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5). Correcting a typographical error does not constitute new matter; and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to 37 CFR 1.821(c), Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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. Correcting a typographical error does not constitute new matter;
If the "Sequence Listing" part of the disclosure is submitted according 37 CFR 1.821(c), Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to 37 CFR 1.821(e).
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 1, 5, 30, 32, 46, and 57 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 is maintained. The rejection of record applies to newly added Claim 57.
Amended Claim 1 is no longer directed to a genus of IFNα2 variants and instead comprises IFNα2 comprising SEQ ID NOs: 6 or 7 with a mutation at position R149. It is interpreted that R149 can be substituted with any other naturally occurring or non-naturally occurring amino acid. Because R149 is known to be in the IFNα2 receptor binding site, and R149A reduces binding affinity to the IFNα2 receptor as compared to wild-type IFNα2 (as evidenced by Tavernier US 9,492,562; of record; Example 2), it is reasonable that any mutation made at R149 would disrupt the binding site and confer reduced affinity to the IFNα2 receptor. There is proper written description, from the specification and the state of the art prior to filing, for the claimed modified human IFNα2.
However, Claim 1 is still directed to a genus of possible targeting moieties comprising a single copy of the extracellular domain of FLT3L or a portion thereof. The specification defines the FLT3L extracellular domain to comprise SEQ ID NO: 2 (page 3), but “a portion thereof” is not defined and the broadest reasonable interpretation is any fragment of two or more consecutive amino acids of SEQ ID NO: 2. Further, Claim 5 recites wherein the targeting moiety comprises at least 98% identity to one of SEQ ID NOs: 2-5, and Claim 46 recites wherein the chimeric protein comprises at least 95% identity to SEQ ID NO: 9. Claim 5 encompasses 2% amino acid variation in the targeting moiety, and Claim 46 encompasses 5% variation in the targeting moiety. The specification teaches the full-length FLT3L extracellular domain (SEQ ID NO: 2) and three variants thereof (SEQ ID NOs: 3-5) (pages 3-4). However, four species is not a “representative number of species” to adequately represent the variation in the claimed genus of targeting moieties. The genus of targeting moieties as claimed can have substantial structural variation comprising portions thereof and amino acid alterations thereof. In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of targeting moieties, the specification does not provide adequate written description of the claimed genus.
Applicant's arguments filed October 21, 2025 have been fully considered but they are not persuasive. Applicant argues that the recitation that the targeting moiety comprises a single copy of the extracellular domain of FLT3L conveys sufficient information with respect to the written description requirement. Examiner maintains that the claims encompass a single copy of the extracellular domain of FLT3L or a portion thereof (Claim 1) in addition to the amino acid variations in Claims 5 and 46 for which there is not proper written description for the reasons outlined above. Note, there is proper written description for FLT3L comprising one of SEQ ID NOs: 2-5.
The rejection of Claims 1, 5, 30, 32, 46, and 57 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification, while being enabling for the specific species of chimeric proteins comprising SEQ ID NOs: 2, 6, and 9 and the R149A IFNα2 mutation, does not reasonably provide enablement for the genus of chimeric proteins comprising FLT3L portions thereof or amino acid variations thereof (Claims 1, 5, and 46). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The rejection of record applies to newly added Claim 57.
The claims are directed to a genus of chimeric proteins comprising various FLT3L extracellular domains (Claim 1: portions thereof; Claim 5: 98% identity to one of SEQ ID NOs: 2-5; and Claim 46: 95% identity to SEQ ID NO: 9).
Applicant's arguments filed October 21, 2025 have been fully considered but they are not persuasive. Applicant argues that enablement for the claims is provided in the chimeric protein used in Example 1 of the specification. The chimeric protein in Example 1 comprises SEQ ID NO: 9 which comprises a FLT3L extracellular domain comprising SEQ ID NO: 3 (page 38). While the specification is enabled for a FLT3L extracellular domain comprising one of SEQ ID NOs: 2-5 (pages 3-4), the specification is not enabled for the genus of FLT3L extracellular domains comprising portions thereof and amino acid alterations thereof as there is no guidance pertaining to truncations and amino acid alterations that can be made such that the targeting function is preserved. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the variant FLT3L domains encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims. This amount of experimentation is undue, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (Modified, necessitated by amendment)
Claims 1, 5, and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Ma US PGPub 2005/0232931 (of record), and further in view of Tavernier US 9,492,562 (of record) as evidenced by UniProt Biodata Resource IFNα2 (of record) and UniProt Biodata Resource FLT3L.
The 103 rejection of record in the non-final office action filed 12/19/2024 is maintained and modified to address Applicant’s amendments. Amended Claim 1 recites “wherein the reduced affinity or bioactivity is restorable by attachment to the targeting moiety” which was previously the limitation of canceled Claim 18 and has been addressed on the record from the teachings of Tavernier. Note, the broadest reasonable interpretation of “reduced affinity and/or bioactivity” is any decrease in binding affinity or bioactivity for the IFNα2 receptor, even a non-significant change. Similarly, the broadest reasonable interpretation of “restorable” is any increase in binding affinity of bioactivity for the IFNα2 receptor, even a non-significant change.
It is of record that Ma teaches a chimeric protein comprising a FLT3L extracellular domain linked to a tumoricidal agent. The amino acid sequence of human wild-type FLT3L sequence has been known in the art as early as 1996 as evidenced by the UniProt Biodata Resource FLT3L (sequence and history attached as non-patent literature) and comprises 100% sequence identity to SEQ ID NO: 2 which reads on new Claim 56.
It is of record that Tavernier teaches a chimeric protein comprising a human IFNα2 comprising a R149A mutation linked to a targeting construct. It is of record that the human wild-type IFNα2 sequence has been known in the art as early as 1988 (UniProt Biodata Resource structure and history). This UniProt sequence entry specifically teaches the sequence for the IFNα2b allele which comprises 100% identity to instant SEQ ID NO: 7 and reads on amended Claim 1. The UniProt Biodata Resource also teaches that the IFNα2a allele differs from the IFNα2b allele by a R23K substitution wherein position 23 is in reference to the numbering of instant SEQ ID NO: 7 (UniProt P01563 variant document attached as non-patent literature). The IFNα2a allele sequence as evidenced by UniProt comprises 100% identity to instant SEQ ID NO: 6 which reads on amended Claim 1 and new Claim 57.
Applicant's arguments filed October 21, 2025 have been fully considered but they are not persuasive. Applicant argues that none of the cited references teach or suggest a chimeric protein comprising (i) a targeting moiety which comprises a single copy of the extracellular domain of FLT3L; (ii) one or more flexible linkers; and (iii) a modified human IFNα2 comprising SEQ ID NO: 6 or 7 and having a mutation at position R149. It is of record that Ma teaches a chimeric protein comprising a FLT3L extracellular domain linked to a tumoricidal agent, and Tavernier teaches a chimeric protein comprising a human IFNα2 comprising a R149A mutation linked to a targeting construct. One cannot show nonobviosuness by attacking references individually where the rejections are based on combinations of references (MPEP § 2145.IV).
Applicant argues that Ma teaches chimeric proteins containing a FLT3L and a peptidyl tumoricidal agent selected from an anti-p230 antibody, and anti-CD20 antibody, an anti-Her2 antibody, and anti-Her3 antibody, an anti-Her4 antibody, and an anti-EGFR antibody, and there is no reason for a person skilled in the art to read this list of tumoricidal agents and believe an attenuated cytokine could or should be substituted into the chimeric protein. Ma teaches that FLT3L is an activator of dendritic cells and when bound to a tumoricidal agent, the resulting chimeric protein can reduce tumor burden by directly inducing the apoptosis of tumor cells while also targeting and activating dendritic cells to infiltrate tumor tissues (paragraph [0008]). Tumor antigens released by the dying tumor cells then can be processed and presented by the activated dendritic cells that then serve as antigen-presenting cells for a specific anti-tumor immune response (paragraph [0008]). These new sections of Ma are referenced, not as a new grounds of rejection, but solely in reply to Applicant’s arguments to demonstrate how one of ordinary skill would understand that any tumoricidal agent could be linked to the FLT3L to achieve the desired anti-tumor mechanism. IFNα2 is an obvious choice of tumoricidal agent because Tavernier teaches that IFN acts not only to engage the processes of tumor rejection (i.e. tumoricidal) but also to break the immune tolerance against the tumor (col. 2, lines 1-4), and type I IFNs specifically activate dendritic cells (col. 1, lines 58-64). Thus, IFNα2 can act as both a tumoricidal agent and a pro-inflammatory agent that promotes dendritic cells which are the mechanisms by which the chimeric protein of Ma exerts its anti-tumor effects. The new sections of Tavernier are referenced, not as a new grounds of rejection, but solely in reply to Applicant’s arguments. One of ordinary skill would understand that Ma lists examples of tumoricidal agents but the teachings are not strictly limited to these agents. Applicant’s arguments have been considered, but they are not persuasive and the rejection is maintained.
The rejection of Claims 30 and 32 under 35 U.S.C. 103 as being unpatentable over Ma US PGPub 2005/0232931 (of record) in view of Tavernier US 9,492,562 (of record) as applied to Claims 1, 5, and 56-57 above, and further in view of Tsapogas et al. Int J Mol Sci. 2017 (of record) is maintained.
Applicant's arguments filed October 21, 2025 have been fully considered but they are not persuasive. Applicant argues that Tsapogas does not teach a FLT3L targeting moiety in chimeric protein format. Ma is relied upon to teach a FLT3L targeting moiety in chimeric protein format, and one cannot show nonobviosuness by attacking references individually where the rejections are based on combinations of references (MPEP § 2145.IV). Further, Ma teaches that the FLT3L ligand in the chimeric protein format maintains binding to the FLT3L receptor (paragraph [0094] relied upon solely in response to Applicant’s arguments and not as a new grounds of rejection).
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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