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 .
Application Status
Claims 93-112 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous objections to the specification are withdrawn in view of amendment.
Previous rejection of claim 110 under 35 U.S.C. 112(b) is withdrawn in view of claim amendments.
Previous rejection of claim 110 under 35 U.S.C. 112(a) is withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 112(a)
New Rejection Necessitated by Amendment
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 93-109 and 111-112 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The teachings of the specification and the claimed invention:
Regarding claim 93: The nature and scope of the claimed invention at issue is a modular chimeric receptor comprising a first synthetic transmembrane domain with at least 40% sequence identity to SEQ ID NO: 16; wherein the lysine residue at position 9 of SEQ ID NO: 16 is replaced by a serine, threonine, or alanine; the threonine residue at position 13 is replaced by lysine and up to 8 of the residues are replaced by leucine residues and a second synthetic transmembrane domain with at least 80% sequence identity to SEQ ID NO: 26, wherein: the aspartic acid residue at position 9 of SEQ ID NO: 26 is replaced by an alanine or threonine; and the threonine at position 13 is replaced by aspartic acid.
SEQ ID NO: 16 is 19 amino acids in length, requiring 40% sequence identity only requires only 8 amino acids to align with the sequence, with 2 required substitutions (these substitutions can be within the 18 amino acids to achieve 80% sequence identity). This results in 11 undetermined amino acids, but the specific residues are not limited which would result in millions of possible sequences, which does not permit the ordinary artisan to predict which sequences would meet this limitation while still performing the function of a transmembrane domain. Note the limitation that “up to 8 of the residues are replaced by leucine” does not require any particular residue substitution or number of substitutions.
SEQ ID NO: 26 is 23 amino acids in length, requiring 80% sequence identity requires about 18 amino acids to align with the sequence, with 2 required substitutions (these substitutions can be within the 18 amino acids to achieve 80% sequence identity). This results in 5 undetermined amino acids, but the specific residues are not limited which would result in thousands of possible sequences, which does not permit the ordinary artisan to predict which sequences would meet this limitation while still performing the function of a transmembrane domain.
Regarding claims 94, 96, 98-109, and 111-112: These claims depend from claim 93 without correcting the issue.
Regarding claims 95 and 97: The claims are directed to specific variant sequences of SEQ ID NOs: 16 and 26 but they only resolve the issue identified above for one of the synthetic transmembrane domains.
The instant specification teaches: That transmembrane refers to a sequence of amino acids (usually between 15-25 amino acids, mostly hydrophobic) from a protein that forms a single alpha helix that is inserted in the lipid bilayer of a cell (page 20, lines 12-14). Wherein the first positively charged amino acid and first negatively charged amino acid are positioned so that the electrostatic interactions between the first synthetic transmembrane domain and the second synthetic transmembrane domains in the target immune cell membrane are stronger than the electrostatic interactions with the native transmembrane domain from the immune receptor and/or native transmembrane domain from the immune cell signaling protein (page 19, lines 30-34). Stronger electrostatic interactions mean that the ability of the first synthetic TM and the second synthetic TM to bind to each other (i.e. to assemble) in the target immune cell membrane is better than their ability to bind to the native TM from the immune receptor and/or native TM from the immune cell signaling protein. Since modular immune receptors require assembly in the cell membrane for expression at the cell surface, the ability of the modules (synthetic or native) to bind to each other (i.e. to assemble) in the cell membrane may be assessed by measuring the level of expression of the modular receptors at the cell surface (as shown in the Examples below), with a higher surface expression of the entirely synthetic modules (i.e. comprising the first and second synthetic transmembrane domains) relative to modules comprising a native TM indicating stronger electrostatic interactions between the first and second synthetic transmembrane domains. It is to be understood that the electrostatic interactions between the first synthetic transmembrane domain and the second synthetic transmembrane domains in the target immune cell membrane must be sufficient to allow the assembly and cell surface expression of the synthetic receptor and synthetic signaling modules (page 19, last para- page 20 1st para). The skilled person would understand that the first and second synthetic transmembrane domains may be variants of TMs of native (or endogenous) immune receptors, and are designed based on the sequences, and more particularly the position of the positively and negatively charged residues, of the native TMs (page 20, lines 27-30).
The instant specification further teaches: Positively charged (or basic) amino acids include lysine (K), arginine (R) and histidine (H). Preferably, the positively charged amino acid is arginine or lysine. In an embodiment, the positively charged amino acid is arginine. In another embodiment, the positively charged amino acid is lysine. Negatively charged (or acidic) amino acids include aspartic acid (D) and glutamic acid (E). In an embodiment, the negatively charged amino acid is aspartic acid. In another embodiment, the negatively charged amino acid is glutamic acid (page 20, lines 20-26).
The instant specification teaches 31 predicted transmembrane domain sequences of native immune receptors and associated immune receptor signaling proteins in table 1 with the charged residues represented by capital letters. This indicates that not every position within the native sequence can be substituted so that the transmembrane domain would still function as necessary to embed in the cell membrane and so that the first and second synthetic transmembrane domains interact with each other stronger than with the native transmembrane domain.
The instant specification teaches: SEQ ID NO: 16 and SEQ ID NO: 26 as seen in Table 1 both with a single capitalized residue, which correspond to KI2S5 and DAP12 respectively (pages 21-22). In an embodiment, the T residue at position 5 of SEQ ID NO:16 is replaced by a positively charged amino acid. In an embodiment, the T residue at position 13 of SEQ ID NO: 16 is replaced by a positively charged amino acid. In an embodiment, the amino acid(s) located 4 residues Nterminal and/or C-terminal of the positively charged amino acid is/are threonine. In an embodiment, one or more of the residues at positions 1, 9, 13 and 17 of SEQ ID NO: 16 are threonine residues. In an embodiment, at least 1, 2, 3, 4, 5, 6, 7 or 8 of the residues in SEQ ID NO: 16 are replaced by leucine residues. In an embodiment, the first synthetic transmembrane domain comprises the amino acid sequence VLIGTSWLLPFKILLFFLL (SEQ ID NO:32), VLIILLVGTSWKLLLFFLL (SEQ ID NO:33), VLIGTSVVTLPFKILLFFLL (SEQ ID NO:34), VLILLLLLLLLLKLLLFFLL (SEQ ID NO:35), VLILLLLGLLLLKLLLFFLL (SEQ ID NO:36), VLILLLLLALLLKLLLFFLL (SEQ ID NO:37) or VLILLLLLTLLLKLLLFFLL (SEQ ID NO:38) (page 33, lines 10-20). In an embodiment, the I residue at position 5 of SEQ ID NO:26 is replaced by a negatively charged amino acid. In an embodiment, the T residue at position 13 of SEQ ID NO:26 is replaced by a negatively charged amino acid. In an embodiment, the A residue at position 17 of SEQ ID NO:26 is replaced by a negatively charged amino acid. In an embodiment, the amino acid(s) located 4 residues N-terminal and/or C-terminal of the negatively charged amino acid is/are threonine. In an embodiment, one or more of the residues at positions 9, 13 and 21 of SEQ ID NO:26 are threonine residues. In an embodiment, at least 1, 2, 3, 4, 5, 6, 7 or 8 of the residues in SEQ ID NO:26 are replaced by leucine residues. In an embodiment, the second synthetic transmembrane domain comprises the sequence VLAGIVMGALVLDVLITLAVYFL (SEQ ID NO:39). In another embodiment, the second synthetic transmembrane domain comprises the sequence VLALAVLGIVMGDVLITLAVYFL (SEQ ID NO:40). In another embodiment, the second synthetic transmembrane domain comprises the sequence VLAGDVMGTLVLIVLIALAVYFL (SEQ ID NO:41) (page 39, lines 9-21).
As the instant specification teaches that the modular immune receptors require assembly in the cell membrane for expression at the cell surface, the ability of the modules (synthetic or native) to bind to each other (i.e. to assemble) in the cell membrane may be assessed by measuring the level of expression of the modular receptors at the cell surface (as shown in the Examples below), with a higher surface expression of the entirely synthetic modules (i.e. comprising the first and second synthetic transmembrane domains) relative to modules comprising a native TM indicating stronger electrostatic interactions between the first and second synthetic transmembrane domains but there was no testing done on the variants of SEQ ID NO: 16 and 26.
Therefore the instant specification does not disclose the minimum structure required for the sequence to function as a transmembrane domain, and only teaches 7 variant sequences of the millions possible for SEQ ID NO: 16 and 3 variant sequences of the thousands possible for SEQ ID NO: 26, before even considering the 40% and 80% minimum sequence identity required respectively.
Claim Analysis:
Regarding claim 93: The nature and scope of the claimed invention at issue is a modular chimeric receptor comprising a first synthetic transmembrane domain with at least 40% sequence identity to SEQ ID NO: 16; wherein the lysine residue at position 9 of SEQ ID NO: 16 is replaced by a serine, threonine, or alanine; the threonine residue at position 13 is replaced by lysine and up to 8 of the residues are replaced by leucine residues and a second synthetic transmembrane domain with at least 80% sequence identity to SEQ ID NO: 26, wherein: the aspartic acid residue at position 9 of SEQ ID NO: 26 is replaced by an alanine or threonine; and the threonine at position 13 is replaced by aspartic acid.
As detailed by the teachings of the prior art and the instant specification the ordinary artisan would not be able to envision the entire genus of sequences comprising 40% or 80% sequence identity to SEQ ID NOs: 16 and 26 that would retain the function of forming a transmembrane domain, wherein the variant domains interact with one another through electrostatic interactions.
Regarding claims 94, 96, 98-109, and 111-112: These claims depend from claim 93 without correcting the issue.
Regarding claims 95 and 97: These claims depend from claim 93 but only partially correct the issue.
State of the Art:
Wang (Cancer Immunol Res, 2015 July, 3(7): 815-826; IDS entered December 7, 2022) teaches a chimeric antigen receptor comprising KIR2DS2 and DAP12 that associate through electrostatic interaction (page 6, last para) with enhanced antitumor activity in vivo (page 9, 1st para). However the DAP12 and KIR2DS2 of Wang are wild type sequences from PBMCs and not engineered variants.
Beatty (US 2017/0260268 A1; cited in OA 09/17/2025) teaches a natural killer cell CAR comprising a transmembrane domain (claim 1), wherein the encoded transmembrane domain comprises an NKR transmembrane domain comprising a transmembrane domain of protein KIR2DS2 (claim 7), wherein the encoded transmembrane domain comprises at least one, two, or three modifications but not more than 5 modifications of the amino acid sequence of SEQ ID NO: 357 (claim 8), with 100% sequence identity to the instant claimed SEQ ID NO: 16. Modification of 5 amino acids would fall within the 40% sequence identity requirement but Beatty does not teach the specific residue substitutions as recited in instant claim 93. Beatty further teaches the nucleic acid molecule further comprises a nucleic acid sequence that encodes an adaptor molecule or intracellular signaling domain that interacts with said NKR-CAR, the encoded adaptor molecule comprises a functional signaling domain of DAP12 (Para 0037),the amino caid sequence of DAP 12 is SEQ ID NO: 368 with 100% sequence identity to the instant claimed SEQ ID NO: 26. As seen in Figure 1B of Beatty the DAP12 and KIR2DS2 interact together Beatty further teaches that The non-covalent association of natural KIR2DS2 and DAP12 depends upon the electrostatic interactions between an aspartic acid residue in the KIR transmembrane (TM) domain and a lysine residue in the DAP12 TM domain (para 1015). Beatty does not teach the specific residue substitutions to a first or second synthetic transmembrane domain that would result in functional transmembrane domains that interact with each other electrostatically more than the native sequence.
Feng (PLoS Biol, 2006 May, 4(5):e142; IDS entered December 7, 2022) teaches that DAP12 interaction with KIR is dependent upon a properly placed lysine residue within a hydrophobic sequence for electrostatic interaction in the transmembrane domains (Figure 2a; page 0770, col 1, para 2). Feng further teaches that previous experiments had demonstrated that assembly of KIR involved both TM aspartic acids of the DAP12 dimer and that conservative substitution of a single aspartic acid (D) by asparagine (DN combination) impaired assembly, while less conservative changes of one aspartic acid to serine or alanine (DS and DA combinations) reduced it to very low levels and further that substantial changes in the surrounding TM sequence did not alter the interaction of the KIR lysine with the DAP12 aspartic acid pair (page 0770, last para-page 0771, 1st para). Feng further teaches that in vitro translation system, metabolic labeling of transfectants, and FACS analysis of transfectants demonstrated specific assembly of the KIR-pVal protein with DAP12 and that large changes in the TM domain thus do not prevent assembly or transport of the KIR receptor to the cell surface (page 0773, col 1, para 1). Feng further teaches that steric hindrance between incompatible extra-membranous domains was identified as another important determinant of assembly specificity (page 0769, col 2, para 1).
There is no prior art that teaches the specific variant sequences recited in claims 95, 97, and 110, or that the synthetic transmembrane domains would interact together preferentially over the native sequences.
While there is some guidance in the prior art about which residues can be altered while still facilitating interaction between KIR and DAP12 in the transmembrane domain it is not sufficient. The variation encompassed by the present claims is large and the specification does not establish that the species described are representative of the claimed genus(es). Neither does the disclosure provide sufficient evidence of the structure function relationship to provide the claimed function(s).
It is noted that, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added). In this case, a skilled artisan cannot visualize the subgenus of antibodies that would bind to TCRβ V12 by the disclosure of a partial antibody sequence as the instant claim broadly claimed.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Response to Arguments
Applicant's arguments filed 2/11/2026 have been fully considered but they are not persuasive.
Applicant Submits: If a skilled artisan would have understood the inventor to be in possession of the claimed invention at the time of filing, even if every nuance of the claim is not explicitly described in the specification, then the requirement for an adequate written description is met.
The claims as amended now recite sufficiently complete and/or partial structures. In addition, the specification discloses a correlation between structure and function, sufficiently detailed, relevant identifying characteristics, and a representative number of species to provide evidence that the applicant was in possession of the claimed invention.
The claims recite a sufficiently complete and/or partial structures to allow one of skill in the art to instantly be able to envision the genus of sequences.
Amended claim 93 now recites specific and narrowly constrained synthetic transmembrane domains: Accordingly, 15 of the 19 amino acids of the first synthetic transmembrane domain are defined, noting that five leucine residues are already fixed in SEQ ID NO: 16.
Regarding the second synthetic transmembrane domain: 80% identity allows for four substitutions of which two are defined. Thus, one of skill in the art would instantly be able to envision the limited genus of the second synthetic transmembrane domain sequences as recited in amended claim 93.
In Response: As detailed in the updated 112a rejection above, there is not sufficient written description in claim 93. SEQ ID NO: 16 is 19 amino acids in length, requiring 40% sequence identity only requires only 8 amino acids to align with the sequence, with 2 required substitutions (these substitutions can be within the 18 amino acids to achieve 40% sequence identity).. This results in 11 undetermined amino acids, but the specific residues are not limited which would result in millions of possible sequences, which does not permit the ordinary artisan to predict which sequences would meet this limitation while still performing the function of a transmembrane domain. Note the limitation that “up to 8 of the residues are replaced by leucine” does not require any particular residue substitution or number of substitutions. The interpretation that the applicant is submitting in argument is only one possible interpretation of claim 93 as written and therefore does not overcome the 112a rejection. Therefore 15 of the 19 amino acid residues are not clearly defined or limited and the written description requirement has not been met.
Regarding the second transmembrane domain SEQ ID NO: 26 is 23 amino acids in length, requiring 80% sequence identity requires about 18 amino acids to align with the sequence, with 2 required substitutions (these substitutions can be within the 18 amino acids to achieve 80% sequence identity). This results in 5 undetermined amino acids, but the specific residues are not limited which would result in thousands of possible sequences, which does not permit the ordinary artisan to predict which sequences would meet this limitation while still performing the function of a transmembrane domain.
Applicant submits: The claims and specification provide a correlation between structure and function.
The specification provides sufficiently detailed, relevant identifying characteristics.
The specification provides a representative number of species.
In response: As detailed in the original 112 a in the OA mailed 09/17/2025 and the updated 112a above while there is some structural information provided it is not sufficient to provide the ordinary artisan with the ability to envision the entire genus of transmembrane domains recited in the scope of claim 93 that would retain the function claimed therein.
Allowable Subject Matter
Claim 110 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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