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 .
Election/Restrictions
Applicant’s election of Group I, and SEQ ID NO: 27 (from claim 29) in the reply filed on 10/20/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Accordingly, claims 40-46 are withdrawn from consideration for being directed to non-elected subject matter. Claims 26-39 are currently under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/16/2025 has been considered by the examiner except for the lined through references that do not have a publication year.
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). There are amino acid sequences on page 184, no.105, and in paragraph [00661] and [00664] not identified by sequence identifier.
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 Objections
Claim 26-39 are objected to because of the following informalities:
Claim 26 recites the term “MOD” in (v). It is suggested to spell out the full name when first mentioned in the claim. Claim 26 recites “more than on MOD sequences in tandem” on line 17, it is suggested to amend it to “more than one” for clarity.
Claim 30 recites “wt. or variant.” It is suggested to spell out the full name when first mentioned in the claim. Claim 30 recites “selected from wt. or variant,” it is suggested to amend “or” to “and” because there would not be a selection if members are recited in alternative.
Claim 33 recites “each chemical conjugation is selected from: a) amino acid chemical conjugation sites…and/or e) IgG nucleotide binding sites.” It is suggested to amend “and/or” to “and” because there would not be a selection if members are recited in alternative.
Dependent claims are objected to for same reason as applied to the above claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 26-39 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.
Regarding claim 26, the recitation of “wherein the MHC-H polypeptide comprises cysteine substitutions at positions 84 and 139 that form an intrachain disulfide bond, based on the numbering of any one of SEQ ID NO: 39, 47, 57 and 58” renders the claim indefinite because it is unclear whether the claimed MHC-H polypeptide comprises any one of the SEQ ID NO: 39, 47, 57 and 58. It is unclear how does “based on the numbering of any one of the SEQ ID NO: 39, 47, 57 and 58” limits the position of the cysteine substitution within the MHC-H if the amino acid sequence encoding said MHC-H differs in length and/or structure from the amino acids identified by SEQ ID NO: 39, 47, 57 and 58.
Regarding claim 27, the recitation of “wherein the unconjugated T-Cell-MP comprises at least one MOD sequence as part of element (i) or (ix)” renders the claim indefinite because it contradicts the recitation in (i) and (ix). (i) and (ix) starts with the word “optionally” so that entire (i) and (ix) are optional, and not required by the claim, so that no MOD is required for the T-Cell-MP claimed in claim 27, this contradicts with the “wherein” clause at the end.
Regarding claim 31, the recitation of “wherein, based on the numbering of SEQ ID NO: 106, the variant IL-2 MOD sequences comprise an animo acid at position 16 other than His and an amino acid at position 42 other than Phe” renders the claim indefinite because it is unclear whether the claimed IL-2 MOD sequences comprises SEQ ID NO: 106. It is unclear how does “based on the numbering of SEQ ID NO: 106” limits the position of the amino acid substitution within the IL-2 variant if the amino acid sequence encoding said IL-2 variant differs in length and/or structure from the amino acids identified by SEQ ID NO: 106.
Regarding claim 32, the recitation of “wherein the variant IL-2 MOD sequences comprise F42A and H16A or T substitutions” renders the claim indefinite because it is unclear where the T substitution is at. Does it mean T substitution at F42, H16A, both position or anywhere in the variant IL-2 MOD?
Regarding claim 35, the recitation of “wherein the cysteine is at position 43, 44 or 45 of the mature β2M polypeptide sequence, based on the numbering of SEQ ID NO:61, wherein the nature β2M polypeptide sequence does not comprise the 20 amino acid signal sequence MSRSVALAVLALLSLSGLEA of SEQ ID NO: 61” the claim indefinite because whether the claimed T-Cell-MP comprises SEQ ID NO: 61, a mature β2M polypeptide sequence thereof without the 20 amino acid sequence. It is unclear how does “based on the numbering of SEQ ID NO: 61” limits the position of the amino acid substitution within the T-Cell-MP amino acid sequence encoding said T-Cell-MP differs in length and/or structure from the amino acids identified by SEQ ID NO: 61. It is even more confusion whether the numbering is based on SEQ ID NO:61, or a sequence when the 1st 20 amino acids are removed. Since the amino acid at 43, 44 or 45 when the 1st 20 amino acids are removed (the mature version) will be Gly, Glu and Arg, it is inconsistent to the limitation based on cysteine at these positions.
Regarding claim 37, the term “a 7.8.60 polypeptide” renders the claim indefinite because it is unclear what the claim is referring to. Since the specification does not provide a limiting definition for a 7.8.60 polypeptide, the structure and/or function of the polypeptide” cannot be determined.
Claims dependent on claim 26 and other claims discussed above are rejected for same reason because they recite same limitation but does not remedy the indefiniteness as discussed above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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)(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.
Claim(s) 26-39 is/are rejected under 35 U.S.C. 102(a2) as being anticipated by Wu et al (WO2021/127495).
Claim 26 is drawn to a single chain, unconjugated T cell modulatory polypeptide (T-Cell-MP), comprising: (1) a β2M polypeptide sequence; (2) a class I MHC heavy chain (MHC-H) polypeptide sequence that comprises cysteine substitution; (3) a linker joining the β2M and class I MHC-H sequence; (4) a scaffold polypeptide and (5) one or more MOD, wherein the T-Cell-MP comprises a chemical conjugation site for epitope conjugation in (1) or (2). As discussed in the above 112b rejection, the recitation of “cysteine substitution at position 84 and 139..that based on the numbering of any one of SEQ ID NOS: 39, 47, 57 and 58” is indefinite because the position of the substitution cannot be determined if the claimed MHC-H differs from the MHC-H identified by SEQ ID NO: 39, 47, 57 and 58. As such, this claim limitation is interpreted as MHC-H comprise cysteine at any position.
Wu teaches a IL2 agonist that comprises an IL2 moiety, a multimerization moiety and a stabilization moiety and an optional tumor targeting moiety (paragraph [0015]). Wu teaches the targeting moiety may comprise a class I MHC heavy chain α polypeptide and a β2M polypeptide (paragraph [0190]). Wu teaches the MHC polypeptide and the β2M is linked to each other by a peptide linker (paragraph [0191], lines 1-4). Wu teaches the IL2 agonist can further comprise multimerization moiety that comprises Fc domains (paragraph [0206]), which meets the limitation of a scaffold polypeptide. Since the specification describes MOD or MOD polypeptide as immunomodulatory polypeptide (paragraph [0003]), the IL2 moiety taught by Wu meets this limitation. Since amino acids comprise sites for chemical conjugation, for example, cysteine, the wild type β2M amino acid sequence thus comprises chemical conjugation sites (see attached sequence). Therefore, the teaching from Wu anticipates the claimed polypeptide claimed in claim 26.
Regarding claim 27, Wu teaches the linker may be 10 to 25 amino acids in length (paragraph [0262]), which falls within the range of 10-50 aa as claimed.
Regarding claim 28, the β2M sequence comprises 100% sequence identity with amino acid 21-119 of SEQ ID NO: 61 (see attached alignment).
Regarding claim 29, Wu teaches the HLA-A sequence can be an HLA-A*0201 sequence (paragraph [0188]). Although Wu does not teach it comprises 200 contiguous aas of SEQ ID NO: 27, Wu incorporates the information from WO 2015/195531 (paragraph [0192]), which teaches MHC class I heavy chain sequence HLA-A02 (see attached alignment).
Regarding claim 30, Wu teaches IL-2 moiety, which meets the limitation of MOD.
Regarding claims 31 and 32, Wu teaches the IL-2 moiety is a full length IL-2 molecule, a human IL-2 molecule, or variants including deletion and substitution (paragraph [0138]-[0142]). Since the claim is indefinite as discussed above, the teaching from Wu anticipates the claimed invention because it is unclear where the amino acid substitution occurs.
Regarding claims 33-36, Wu teaches human β2M wild type sequence, which comprises at least two cysteine amino acids (see attached alignment), and it meets the limitation of amino acid conjugation sites. Since the claim is indefinite as discussed above, the teaching from Wu anticipates the claimed invention because it is unclear where the cysteine is located.
Regarding claim 37, Wu teaches the Fc region may be immunoglobulin heavy chain constant region from IgA, IgD and IgG (paragraph [0211]).
Regarding claims 38, Wu teaches the IL-2 agonists may be homodimers upon expression of the component monomers in a suitable cell line (paragraph [0083]).
Regarding claim 39, Wu teaches the IL-2 agonists may be heterodimers (paragraph [0094]).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 26-32, 37 and 38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5, 7, 8, 10, 14, 16 and 17 of copending Application No. 18/035,733 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the soluble T-Cell-MP claimed in claims 1 and 5 of ‘733 application anticipates the claimed single chain unconjugated T-Cell-MP claimed in claim 26 and claim 27 of present application.
Claim 7 of ‘733 application recites same limitation of β2M sequence as claim 28 of present application.
Claims 8 and 10 of ‘733 application recites same MHC-H sequence as claim 29 of present application.
Claim 14 of ‘733 application recites same IL2 MOD sequences as claim 30-32 of present application.
Claim 16 of ‘733 application recites same scaffold polypeptide sequence as claim 37 of present application.
Claim 17 of ‘733 application recites same duplex T-Cell-MP as claimed in claim 38 and 39 of present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637