DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response to restriction requirement filed on February 12, 2026 have been received and entered. Claim 7 has been amended, while claims 18-22 is newly added.
Claims 1-22 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 7-11 (group II) in the reply filed on February 12, 2026 is acknowledged. Applicant’s election of YLR3 intracellular domain species of TLR intracellular domain cancer antigen as species of the target factor and cancer as specie of target disease in the reply filed on February 12, 2026 is also acknowledged. Upon further consideration election of species requirement is hereby withdrawn and all the non-elected species are rejoined with the elected invention.
Claims 1-6, 12-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 12, 2026.
Priority
This application is a 371 of PCT/JP2021/043978 filed on11/30/2021, which claims priority from foreign application JP 2021-005337 filed on 01/15/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/14/2023 and 01/22/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 7-11, 18-21 and 22 are under consideration.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 7-11, 20-21 and 22 are rejected under 35 U.S.C. 102 (a)(1) /102(a) (2) as being anticipated by Shen et al (WO2020/210816, dated 10/15/2020, EFD, 4/12/2019).
Claims are directed to a polynucleotide encoding a chimeric target factor receptor of comprising a target factor-binding domain, a transmembrane domain, and an intracellular domain containing a TLR intracellular domain.
With respect to claims 7 and 20, Shen teaches a nucleic acid encoding single-chain variable fragment (scFv), targeting EpCAM on a cancer cell surface, a CD8 transmembrane domain and an intracellular domain containing TLR4 intracellular domain and CD40 intracellular domain in tandem (see para. 120-122, fig. 3B).
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Regarding claims 8-11, Shen teaches a dendritic cell comprising a nucleic acid encoding single-chain variable fragment (scFv), targeting EpCAM on a cancer cell surface, a CD8 transmembrane domain and an intracellular domain containing TLR4 intracellular domain (see fig. 3B). Shen teaches that said CAR DCs have anti-tumor potential in tumor model and therefore, CAR-DC disclosed in Shen is a pharmaceutical composition as it is capable to treat tumor (see para. 106, 143, 149).
With respect to claim 21 and 22, Shen teaches that polynucleotide comprises a target factor binding domain that is single chain antibody (scFv), targeting EpCAM (a cancer antigen).
Accordingly, Shen anticipates claims 7-11, 20-21 and 22.
Claims 7-8, 11, 18 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Corey et al (WO2019067328, dated 04/04/2019).
Claims are directed to a polynucleotide encoding]a chimeric target factor receptor comprising a target factor-binding domain, a transmembrane domain, and an intracellular domain containing a TLR intracellular domain.
Regarding claim 7, Corey teaches a nucleic acid molecule encoding chimeric engulfment receptor (CER) comprising an extracellular domain comprising a binding domain; a transmembrane domain and an engulfment intracellular signaling domain that comprises a toll-like receptor (TLR) signaling domain (see fig. 1A and 1B).
With respect to claims 8 and 11, Corey teaches a pharmaceutical composition comprising host cell comprising CER comprising an extracellular domain comprising a binding domain; a transmembrane domain and an engulfment intracellular signaling domain that comprises a toll-like receptor (TLR) signaling domain (see claim 31 of ‘328, page 98, lines 19-29) and a pharmaceutically acceptable carrier (claims 69 of ‘328).
Regarding claims 18, 19, Corey teaches signaling domain that comprises a toll-like receptor (TLR) signaling domain selected from group consisting of TLR1, TLR2, TLR3 and TLR9 (see page 52, lines 15-19, example 5, lines 9-13, 21-24, claims 1, 14, 23).
Accordingly, Corey anticipates claims 7-8, 11, 18 and 19.
Claim Rejections - 35 USC § 112-written description
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.
Claims 7-11, 18-21 and 22 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.
MPEP 2163 states “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). "A representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
The claims 7-8 and 22 embrace a polynucleotide encoding a chimeric target factor receptor comprising a target factor-binding domain, a transmembrane domain, and an intracellular domain containing a TLR intracellular domain, wherein the target factor is at least one selected from the group consisting of cancer antigens, cytokine receptors, and cell growth factor receptors. Thus, the claims encompass function of receptor is to bind specifically to a genus of cancer antigen, cytokine receptors, or any cell growth factor receptors (target factor). Dependent claim limits the target factor binding domain having any single chain antibody structure. Claims are also directed to genus of host cells comprising the polynucleotide of the invention subsequently limiting to a dendritic cells.
The specification contemplates to provide a chimeric target factor receptor capable of activating antigen- presenting cells, such as dendritic cells, in a target-factor- specific manner (see para. 6 of the specification). The specification contemplates target factors include cancer antigens, various receptors (e.g., cytokine receptors such as interleukin receptors, and cell growth factor receptors), cell adhesion factors, and membrane proteins of bacteria or viruses. Specific examples of target factors include CD19, GD2, GD3, CD20, CD37, CEA, HER2, EGFR, type III mutant EGFR, CD38, BCMA, MUC-l, PSMA, WTl, cancer testis antigens (e.g., NY-ESO-1, and MAGE-A4), mutation peptides (e.g., k-ras, h- ras, and p53), hTERT, PRAM, TYRP1, mesothelin, PMEL, mucin, IL- 12R, IL-4R, IL-13R, IL-6R, IL-23R, CTLA4, EGFR806, PSCA, Claudin, EpCAM, VEGFR2, Nectin4/FAP, LewisY, Glypican-3, IL-13Ra2, CD171, MUC16, AFP, AXL, CD80/86, c-MET, DLL-3, DR5, EpHA2, FR-a, gp100, MAGE-A1/3/4, and LMP1. The specification contemplates domain containing all or part of a cytokine or cell growth factor (a cytokine or cell growth factor domain), and a domain containing all or part of a cell adhesion factor (a cell adhesion factor domain). A domain containing one or more CDRs of an antibody or T-cell receptor typically has one or more, preferably two, three, four, five or more, more preferably all six of the CDRs of the antibody or T-cell receptor against a target factor (e.g., if the CDRs of an antibody are the case, heavy-chain CDR1, heavy-chain CDR2, heavy-chain CDR3, light-chain CDR1, light-chain CDR2, and light-chain CDR3) (see para. 36). The specification exemplifies a nucleic acid encoding a chimeric target factor receptor construct containing the following disposed in this order from the N-terminus to C-terminus comprises signal peptide of SEQ ID NO: 19 or 20, anti-Her2 scFv domain of SEQ ID NO: 1 or 9, CD29 transmembrane domain of SEQ ID NO:2 or 10 and intracellular domain as set forth in SEQ ID NO: 3, 4, , 5, 6 or 7 and further comprising CD40. The specification further teaches a chimeric target factor receptor construct containing a nucleic acid encoding signal sequence of SEQ ID NO: 19, anti-mesothelin scFV as set forth in SEQ ID NO: 17, CD 28 transmembrane domain and TLR1 to TLR9 intracellular domain. Example 2 and 3 teaches dendritic or macrophage cell expressing the chimeric target factor receptor as discussed above. The results indicate that the use of the intracellular domain of TLR for the intracellular domain can increase the expression of MHC class I and MHC class II in response to the target factor. In particular, the degree of activation was found to be high when TLR2, TLR3, or TLR9 was used (Fig. 9).
The state of the prior art summarized by the reference of Fujiwara et al (BBRC, 2020, 527, 2, 350-357) reported that the Fv structure affects CAR expression efficiency and stability on T cells and not all scFvs can be expressed as a chimeric antigen receptor (CAR) on T cells (see highlight and page 368). The teaching of Fujiwara shows that not all target factor binding domain would work due to lack of predictability across claimed genus. Xu et al (Mol Immunol. 2020 Oct:126:56-64 ) reported that CAR activity impacted by ligand-binding domai, compared to other construct components (abstract). It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of a given antibody. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites. Rudikoff et al (Proc Natl Acad Sci USA 1982 Vol 79 page 1979-1983) teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Hasegawa (MAbs, 2017 Apr 5;9(5):854-873) supports the assertion of Rudikoff stating "Single amino acid substitution within the complementarity-determining region (CDR) and framework region can have dramatic effects Hasegawa continue to teach "examples of harmful single amino acid substitution that affect the specificity and the affinity of antigen binding are well documented. Another class of deleterious amino acid substitutions increases aggregation propensity of immunoglobulin proteins by affecting folding stability. Other disadvantageous amino acid substitution are known to impair the secretion of immunoglobulins" (see page 854, col. 2, para. 2 and references therein). A skilled artisan cannot fully describe genus, visualize or recognize the identity of the members of the genus that exhibit the structural and functional properties of the claims. There is insufficient guidance and direction as to the written description of the claimed target factor receptor comprising any cancer antigens-binding domain or cytokine receptors-binding domain or cell growth factor receptors-binding domain and any transmembrane domain in any host cell as broadly encompassed by the claimed invention.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (Biochemical and Biophysical Research Communications Vol. 307, pp 198-205, 2003) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (See entire document). Casset et al also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.). Vajdos et al (Journal of Molecular Biology Vol. 320, pp 415-428, 2002) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left column). Wu et al (Journal of Molecular Biology Vol. 294, pp 151-162, 1999) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity dues in part to large conformational change in antibodies that accompany antigen binding (page 152, left column) but certain residues have been identified as important for maintaining conformation.
In the instant case, the specification lacks written description for making and using a functional polynucleotide encoding a genus of chimeric target factor receptor comprising any target factor-binding domain, any transmembrane domain, and an intracellular domain containing any TLR intracellular domain in any host cells as broadly encompassed by claims 7 and 8. As stated before, claims encompass a broad genus of target factor binding domain in any host cell . The guidance provided in the specification is limited to species anti Her2 scFv domain set forth in SEQ IDNO 9 and anti-mesothelin scFV as set forth in SEQ ID NO: 17 and CD28 transmembrane domain in antigen presenting cells.
Vas-Gath Inc. v. Mahurkar, 19 USPQ2d 111, clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed."
The genus of a polynucleotide encoding any chimeric target factor receptor comprising any cancer antigens-binding domain or cytokine receptors-binding domain or cell growth factor receptors-binding domain and any transmembrane domain in any host cell, other than the sequence as set forth in 1 or 9 (anti Her2 scFV) and 17 or 18 (anti-mesothelin scFV) and CD28 transmembrane domain (SEQ ID NO 2 or 10) in antigen presenting cells, encompassed within the genus have not been disclosed. The specification does not provide a representative number of species of chimeric target factor receptor comprising any cancer antigens-binding domain or cytokine receptors- binding domain or cell growth factor-receptors-binding domain and any transmembrane domain. The possible structural variations are limitless. The claims lack written description because there is no disclosure of a correlation between function and structure of the different species of beyond those specifically disclosed in the examples in the specification. The specification lacks sufficient variety of species to reflect this variance in the genus showing contemplated biological activity.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of chimeric target factor receptor comprising any cancer antigens -binding domain or cytokine receptors binding domain or cell growth factor receptors-binding domain and any transmembrane domain in any host cell, other than the sequence as set forth in 1 or 9 (anti Her2 scFV) and 17 or 18 (anti-mesothelin scFV) and CD28 transmembrane domain (SEQ ID NO 2 or 10) in antigen presenting cell like dendritic cells. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Lim et al (PLoS One, 2012, 7(9) , e45185, 1-8, IDS) provide data into the effect of co stimulatory molecule in regulating APC:T cell interactions.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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