DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/21/2025 has been entered.
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
3. Claims 1-4 and 9-34 are pending. Claim 34 is new. Claims 5-8 are canceled. Claims 15-18 and 21-30 are withdrawn from consideration. Claims 1 and 31 are amended.
4. Claims 1-4, 9-14, 19-20 and 31-34 are under examination.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 11/21/2025 has been considered by the examiner.
Objections Withdrawn
6. The objection to claim 1 for missing SEQ ID NO for the sequences recited in the claim is withdrawn in view of applicant’s amendments.
Rejections Withdrawn
7. The rejection of claims 1-4, 9-14, 19-20 and 31-32 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of applicant’s amendments. The claims as currently written do not require the polypeptide to have a function, such as being fusogenic, as such meet the written description requirement.
8. All prior art rejections are withdrawn in view of applicant’s amendments. The combination of the prior art does not teach the limitation “wherein the amino acid sequence does not have 100% sequence identity to SEQ ID NO:3”. The FAST protein from Broome virus taught by Thalmann is 100% identical to instant SEQ ID NO:3.
Claim Rejections - 35 USC § 112
9. 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.
10. Claims 1-4, 9-14, 19-20, 31, 32 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an immune effector cell comprising a nucleotide sequence encoding a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 74, 82, 92, 98, 100 and 104 (corresponding to Mut 5, 9, 14, 17, 18 and 20 disclosed in the specification), and a nucleotide sequence encoding a cell-targeting molecule, does not reasonably provide enablement for any mammalian cell comprising a nucleotide sequence encoding a polypeptide comprising an amino acid sequence having at least 95% or 97% sequence identity to at least one sequence set forth in SEQ ID NOs: 74, 82, 92, 98, 100 and 104. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
''Factors to be considered in determining whether a disclosure would
require undue experimentation have been summarized by the board in Ex
parte Forman. They include (1) the quantity of experimentation necessary,
(2) the amount of direction or guidance presented, (3) the presence or
absence of working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the predictability
or unpredictability of the art, and (8) the breadth of the claims.''
The nature of the invention
Claims 1-4, 9-14, 19-20, 31 and 34 are drawn to a mammalian cell comprising a nucleotide sequence encoding a polypeptide comprising an amino acid sequence having at least 95% sequence identity to at least one sequence set forth in SEQ ID NOs: 74, 82, 92, 98, 100 and 104.
Claim 32 further limit claim 1, wherein the polypeptide comprising an amino acid sequence having at least 97% sequence identity to at least one sequence set forth in SEQ ID NOs: 74, 82, 92, 98, 100 and 104.
The nature of the claims is protein and cell engineering.
The invention is in a class of invention, which the CAFC has characterized as ''the unpredictable arts such as chemistry and biology.'' Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims
The claims recite a polypeptide comprising an amino acid sequence having at least 95% or 97% sequence identity to at least one sequence set forth in SEQ ID NOs: 74, 82, 92, 98, 100 and 104. Each of SEQ ID NOs: 74, 82, 92, 98, 100 and 104 is a reference polypeptide.
The claims encompass a genus of variants of a reference polypeptide, wherein the variants share 95% or 97% sequence homology with the reference polypeptide. Up to 5% or 3% of the amino acids in the reference polypeptide may be changed by substitution, addition, deletion or combination thereof at any positions. Note that the claims do not require the variants to have any function.
Quantity of experimentation
The quantity of experimentation in this area is extremely large in view of the breath of claims and unpredictability of protein/cell engineering. The function of each variant must be determined in order to know how to use a mammalian cell comprising the variant.
Working examples
The specification discloses that the function of p13 has not previously been characterized at the amino acid level. To determine which amino acids and domains are critical for fusion, an alanine scan of p13 was performed. The p13 protein was mutated with sequential stretches of 4 alanine residues, beginning at amino acid #1 and proceeding to amino acid #113, excluding the transmembrane domain, for a total of 23 unique proteins (SEQ ID NOs:67-111 and 151). Three mutations ablated fusion: (1) Mut 1, comprising mutations within the consensus myristoylation site (MYR: amino acids #1-#2); and (2) Mut 2 and Mut 3, comprising mutations in the critical N-terminus of p13 (FIG. 5). Six mutants, Mut 5, 9, 14, 17, 18, and 20 (which have SEQ ID NOs: 74, 82, 92, 98, 100 and 104, respectively), showed augmented fusion compared to p13 (WT) when expressed in CD19-targeting human T-cells targeting CD19+ human B-cells (FIG. 5). Two of these mutants comprise mutations in domains important for p13 function, the polybasic (PB) domain and the amphipathic helix (AH) (FIG. 5). Taken together, these data identified regions of p13 necessary for fusion, as well as alanine mutations capable of promoting fusion (e.g., between human T-cells and human B-cells) ([00448]). The specification further disclose testing combinations of two, three, four or all five mutations, six combinations, Mu5 5/17, Mut 5/18, Mut 5/20, Mut 9/17, Mut17/20, and Mut 5/17/20 showed significant augmented fusion compared to p13 (WT) (Example 2, and Fig. 9).
Applicant’s Figs. 5 and 9 (reproduced below) provide evidence of unpredictability of the effects of substitutions on the fusogenic function of a fusogen.
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Regarding claim 34, although the claims recites “the amino acid sequence comprises MGSGPSNFVNKVDGASA (which is amino acid residues 1-17 of SEQ ID NO: 3) and TEDKLVNPFI (which is amino acid residues 104-113 of SEQ ID NO:3), these sequences are insufficient to provide the function (being fusogenic). This is evidenced by Mut13 and Mut 15. Both Mut13 (SEQ ID NO: 90) and Mut 15 (SEQ ID NO: 94) comprise amino acid residues 1-17 and 104-113 of SEQ ID NO: 3 ([00675]-[00676], [00681]-[00682]). However, they did not induce cell fusion (see Fig. 5 above) (i.e. they are not fusogenic).
Furthermore, the disclosure limited to alanine scanning of fusogen p13 is not commensurate in scope with the claims which allows 5% or 3% change in any one of SEQ ID NOs: 74, 82, 92, 98, 100 or 104, such change includes substitution with any amino acids, deletion, addition and/or any combination thereof. The specification does not disclose the function of all the variants. Without knowing the function of the variants, one of ordinary skill in the art would not know how to use the invention as broadly claimed.
Guidance in the specification
The specification does not provide guidance on how to use the full scope of the invention.
While one of ordinary skill in the art know how to make all the variants and mammalian cells comprising each of the variants, the specification does not teach how to use the mammalian cells comprising each of the variants. The variants encompass those with no fusogenic function, and those whose functions remain to be determined.
The state of the art
Thalmann et al (Virology 2010, 402:26-40, PTO-892 dated 9/23/2024) teaches a novel fusion associated small transmembrane (FAST protein) identified from Broome virus which is responsible for syncytium formation in BroV-infected cells and comprises an amino acid sequence that is 100% identical to instant SEQ ID NO:3 (see sequence alignment below).
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The prior art does not teach any variants of instant SEQ ID NOs: 74, 82, 92, 98, 100 and 104, which are not 100% identical to instant SEQ ID NO:3.
The unpredictability of the art
Protein chemistry is probably one of the most unpredictable areas of biotechnology. It is known in the art that the relationship between the amino acid sequence of a protein (polypeptide) and its tertiary structure (i.e. its binding activity) are not well understood and are not predictable). There is no recognition in the art that sequence with identity predicts biological function. It is known in the art that even single amino acid changes or differences in a protein's amino acid sequence can have dramatic effects on the protein's function. Duncan et al. (Annu Rev Virol, 2019, 6:341-63, PTO-892 dated 9/23/2024) teaches that the rudimentary FAST protein ectodomains are all small, amphiphilic peptides. These domains in p10, p14, and p15 are sensitive to substitution and in liposome fusion assays induce robust lipid mixing, two characteristics of enveloped virus FPs. They do so, however, using remarkably diverse structures. While structurally distinct, these unusual viral FPs all appear to be dynamic structures, and all three contain a pair of apolar aromatic and beta-branched amino acids (e.g., Phe and Val) (page 352, last para). Proline residues are tolerant of substitution, but multiple substitutions that disrupt the helix structure ablate p15-induced syncytiogenesis (page 13, para 3). Despite the dramatic differences in their structures, the p15 ectodomain can be functionally replaced by that of p14, but the converse substitution is nonfusogenic, evidence that specific combinations of different ecto-, endo-, and TM domain motifs are needed to generate a functional FAST protein (page 13, para 13).
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the unpredictability of the art, the unpredictability of the function of the broadly encompassed variants, the lack of correlation between a function and a structure of the variants, the presence of working examples and guidance which are not commensurate in scope of the claims, balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the claimed invention.
Conclusion
11. Claims 1-4, 9-14, 19-20, 31-32 and 34 are rejected. Claim 33 is objected to as being dependent from a rejected claim.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1643