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.
Information Disclosure Statement
The references cited on the information disclosure statements were considered and have been made of record to the extent that each was provided.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See page 22, lines 6 and 7; page 24, line 8; page 25, line 21; pages 26, lines 9 and 33; page 27, line 19; page 28, lines 4 and 26; page 29, lines 11 and 32; page 30, line 17; page 31, line 22; page 32, lines 6 and 27; page 33, lines 9 and 35; page 34, line 18; page 35, lines 2 and 24; page 36, lines 9 and 32; page 37, lines 16 and 36; page 38, line 22; page 39, lines 8 and 36; page 40, line 23; page 41, lines 7 and 29; and page 42, line 15.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 110 is 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 93 is drawn to a modular chimeric receptor comprising a synthetic receptor module comprising an extracellular domain fused to a first synthetic transmembrane domain and a synthetic signaling molecule comprising an intracellular signaling domain fused to a second synthetic transmembrane domain.
Claim 110 depends from claim 93 is drawn to the synthetic receptor module comprises an extracellular domain that binds to CD19, a transmembrane domain comprising an amino acid sequence of SEQ ID NO: 38 and an intracellular domain comprising a CD28 costimulatory domain; and the synthetic signaling module comprises a transmembrane domain comprising and amino acid sequence of SEQ ID NO: 39 and a CD3 zeta intracellular domain.
It is unclear form the language used in claim 110 if the transmembrane domain comprising SEQ ID NO: 38 the transmembrane domain comprising SEQ ID NO: 39 are the first and second synthetic transmembrane domain respectively required by claim 93.
Claim Rejections - 35 USC § 112(a)
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 93-112 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 an uncharged amino acid residue; and (i) at least one of: the glycine residue at position 4, the threonine residue at position 5, or the serine residue at position 6 of SEQ ID NO: 16 is replaced by a positively charged amino acid; and/or (ii) at least one of: the phenylalanine residue at position 12, the threonine residue at position 13, or the isoleucine residue at position 14 of SEQ ID NO: 16 is replaced by a positively charged amino acid and a second synthetic transmembrane domain with at least 40% sequence identity to SEQ ID NO: 26, wherein: the aspartic acid residue at position 9 of SEQ ID NO: 26 is replaced by an uncharged amino acid residue; and (i) at least one of: the glycine residue at position 4, the isoleucine residue at position 5, or the valine residue at position 6 is replaced by a negatively charged amino acid; (ii) at least one of: the leucine residue at position 12, the threonine residue at position 13, or the valine residue at position 14 is replaced by a negatively charged amino acid; and/or (iii) at least one of: the isoleucine residue at position 16, the alanine residue at position 17, or the leucine residue at position 18 is replaced by a negatively charged amino acid residue.
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. 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.
Considering only the required substitutions of 1 position with an uncharged residue (15 possibilities) and 6 residues with a positively charged residue (3 options) required results in almost 11,000 possible sequences
SEQ ID NO: 26 is 23 amino acids in length, requiring 40% sequence identity only requires only 10 amino acids to align with the sequence, with 1 required substitution. 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.
Considering only the required substitutions of 1 position with an uncharged residue (15 possibilities) and 9 residues with a negatively charged residue (2 options) required results in over 7,600 possible sequences
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 as they only resolve the issue identified above for one of the synthetic transmembrane domains.
Regarding claim 110: In view of the 112(b) issue identified above it is unclear if claim 110 resolves the issue identified above in claim 93, and is therefore included in this rejection.
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 to for the sequence to function as a transmembrane domain, and only teaches 7 variant sequences of the more than 11,000 possible for SEQ ID NO: 16 and 3 variant sequences of the more than 7,600 possible for SEQ ID NO: 26, before even considering the 40% minimum sequence identity required.
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 an uncharged amino acid residue; and (i) at least one of: the glycine residue at position 4, the threonine residue at position 5, or the serine residue at position 6 of SEQ ID NO: 16 is replaced by a positively charged amino acid; and/or (ii) at least one of: the phenylalanine residue at position 12, the threonine residue at position 13, or the isoleucine residue at position 14 of SEQ ID NO: 16 is replaced by a positively charged amino acid and a second synthetic transmembrane domain with at least 40% sequence identity to SEQ ID NO: 26, wherein: the aspartic acid residue at position 9 of SEQ ID NO: 26 is replaced by an uncharged amino acid residue; and (i) at least one of: the glycine residue at position 4, the isoleucine residue at position 5, or the valine residue at position 6 is replaced by a negatively charged amino acid; (ii) at least one of: the leucine residue at position 12, the threonine residue at position 13, or the valine residue at position 14 is replaced by a negatively charged amino acid; and/or (iii) at least one of: the isoleucine residue at position 16, the alanine residue at position 17, or the leucine residue at position 18 is replaced by a negatively charged amino acid residue.
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% 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.
Regarding claim 110: In view of the 112(b) issue identified above it is unclear if claim 110 resolves the issue identified above in claim 93.
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; PTO-892) 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.
Conclusion
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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