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 .
Status of the Claims
Claims 1 – 19, 22 – 26, 30 – 31, 33 and 35 – 44 were pending. Claims 1, 2, 4, 13 – 14, 18, 26, 33 have been amended, and claims 3, 5 – 12, 15 – 17, 22 – 24 have been canceled. Claims 1 – 2, 4, 13 – 14, 18, 25 – 26, 30 – 31, 33 and 35 – 44 are currently pending, with non-elected claims 39 and 41 – 43 withdrawn from consideration. Claims 1 – 2, 4, 13 – 14, 25 – 26, 30 – 31, 33, 35 – 38, 40, and 44 are the subject of this Office Action. This is the first Office Action on the merits of the claims.
Election/Restrictions
Applicant’s election of Group I (claims 1-19, 22-26, 30-31, 33 and 40; directed to an activatable proprotein homodimer) in the reply filed on 07/17/2026 is acknowledged. For the species, Applicant elects the following (see also claim 30): Fab: binds to PD-1, comprising CDRs of SEQ ID NOs: 3 (VH) and 4 (VL); Fc domain: SEQ ID NOs: 42 (IgGI hinge), 57 (IgGI CH2 domain with LALA-P329A mutations), and 58 (IgGI CH3 domain with delK); 1st linker: SEQ ID NO: 178, wherein x is 2 (stable linker) IL-15: SEQ ID NO: 79 (K86G and S162A mutations); linker: SEQ ID NO: 90 (cleavable linker); IL-15Ra: SEQ ID NO: 87 (sushi+ with T2A mutation); Homodimers: SEQ ID NOs: 146 and 147 (P53052037).
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)).
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 1 – 2, 4, 13 – 14, 25 – 26, 30 – 31, 33, 35 – 38, 40, and 44 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.
Claim 1 recites “a heavy chain variable (VH) region comprising VHCDR1, VHCDR2, and VHCDR3 regions set forth in SEQ ID NO: 3; and a light chain variable (VL) region comprising VLCDR1, VLCDR2, and VLCDR3 regions set forth in SEQ ID NO: 4”; however, the claims do not disclose the sequence of each CDR. Although, the sequences of the CDRs are underlined in the VH or VL sequences listed in Table P1, p. 24 of the specification, each claimed CDR having four or more amino acids requires a sequence identifier. See MPEP 2412.
Furthermore, claim 1 does not indicate the numbering system used to delineate the CDRs. Although the specification states that “[t]he structures and locations of immunoglobulin variable domains may be determined by reference to Kabat, E. A. et al., Sequences of Proteins of Immunological Interest. 4th Edition. US Department of Health and Human Services. 1987, and updates thereof” (p. 29, end of the second paragraph), the antibody numbering system or standardized frameworks used to label amino acid residues in the variable regions of antibodies should be expressly stated in claims reciting CDRs. However, this teaching is not considered a limiting definition for the numbering system encompassed by the claims. Thus, the CDRs encompassed by independent claim 1 could be according to Kabat, CDRs according to Chothia, or they could be numbered according to other CDR boundary definitions that may not strictly follow one of Kabat or Chothia, in which case, the CDRs would potentially encompass different amino acids within SEQ ID NOs: 3 and 4. See image, below.
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media_image1.png
397
513
media_image1.png
Greyscale
Because it is unclear what numbering system is being used, it is unclear what amino acid residues are required by the CDRs of the claims.
Claims 4 and 13 each depends from a canceled claim and thus the limitations are not clear.
Claim 30 recites the terms “optionally”, and although the term is considered acceptable alternative language, there must be no ambiguity as to which alternatives are covered by the claim. See MPEP 2173.05(h)(II). In this case, however, the placement of two of the “optionally” terms in present claim 30 results in some ambiguity, and it is not necessarily clear which limitations are optional and which limitations are required.
Claims 2, 14, 18, 25 – 26, 30 – 31, 33, 35 – 38, 40 and 44 depend from claim 1, either directly or indirectly, and thus inherit the deficiencies of claim 1.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WANG (WO 2021/032116 A1, published 02/25/2021; see PTO-892: Notice of References Cited) is cited to further show the general state of the art. WANG is directed to an immunocytokine of an antibody respectively fusing IL-15 and IL-15Ra on an antigen on the surface of a target cell, capable of effectively and specifically targeting a complex of IL-15 and IL-15Ra to a tumor microenvironment, activating relevant immune cells within or in the vicinity of a tumor, achieving the goal of specifically killing of the tumor, and at the same time, preventing immunotoxicity induced by the systemic hyperactivation of NK cells. See WANG (English translation) at the abstract.
WANG teaches the anti-PD-1 sequences of SEQ ID NOs: 3 and 4 with 100% identity. WANG’s SEQ ID NO: 76 teaches present SEQ ID NO: 3, and WANG’s SEQ ID NO: 78 teaches present SEQ ID NO: 4. See Appendix.
WANG also teaches the sequence of SEQ ID NO: 147 with 100% identity. See Appendix.
WANG teaches that in the tumor microenvironment, the IL-15/IL15Ra complex formed by the immune cytokine can activate the relevant immune cells in or near the tumor, and exert the specific killing effect of T cells or NK cells in the tumor microenvironment on the tumor At the same time, it can avoid the immune toxicity induced by systemic excessive activation of T cells or NK cells. See WANG at p. 2, last sentence, of the English translation.
However, WANG does not teach the sequence of present SEQ ID NO: 146 of present claim 1.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
APPENDIX
Alignment with SEQ ID NO: 3
AC BJA05258;
XX
DT 15-APR-2021 (first entry)
XX
DE Anti-PD-1 antibody heavy chain variable region, SEQ ID 76 #2.
XX
KW PD-1 protein; antibody; antiinflammatory; cancer; cytostatic;
KW heavy chain variable region; inflammatory disease; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 30..35
FT /label= CDR1
FT Region 47..66
FT /label= CDR2
FT Region 97..102
FT /label= CDR3
XX
CC PN WO2021032116-A1.
XX
CC PD 25-FEB-2021.
XX
CC PF 19-AUG-2020; 2020WO-CN109986.
XX
PR 19-AUG-2019; 2019CN-10764762.
XX
CC PA (SHAN-) SHANGHAI YICHEN BIOMED CO LTD.
XX
CC PI Wang F, Zheng H, Zhang Y;
XX
DR WPI; 2021-19445U/021.
XX
CC PT Immunocytokine in medicinal composition for treating inflammatory disease
CC PT or cancer in subject in need, comprises interleukin-15, interleukin-15
CC PT receptor a subunit and antibodies targeting treatment of related cell
CC PT surface antigens.
XX
CC PS Claim 11; SEQ ID NO 76; 39pp; Chinese.
XX
CC The present invention relates to a novel immunocytokine comprising an
CC interleukin-15 (IL-15), interleukin-15 receptor alpha subunit (IL-15Ra)
CC and antibodies targeting treatment of related cell surface antigens. The
CC IL-15 is connected to the N-terminus of a heavy chain variable (VH)
CC region of the antibody directly or through a connecting peptide, and the
CC IL-15Ra is connected to the N-terminus of a light chain variable (VL)
CC region of the antibody directly or through a connecting peptide or the IL
CC -15 is connected to the N-terminus of the VL region of the antibody
CC directly or through a connecting peptide, and the IL-15Ra is connected to
CC the N-terminus of the VH region of the antibody directly or through a
CC connecting peptide, or the IL-15 is connected to C-terminus of a light
CC chain constant (CL) region of antibody directly or through a connecting
CC peptide and the IL-15Ra is connected to C-terminus of a heavy chain
CC constant (CH) region of the antibody directly or through a connecting
CC peptide. The invention further claims: (1) a nucleic acid encoding the
CC immunocytokine; (2) a vector comprising the nucleic acid; (3) a host cell
CC comprising the vector; (4) a medicinal composition comprising the
CC immunocytokine and a carrier; and (5) a method for treating inflammatory
CC disease or cancer in a subject. The immunocytokine of the present
CC invention is useful in a medicinal composition for treating inflammatory
CC disease and cancer. Note: The present sequence is shown as SEQ ID NO: 76
CC in figure 5C of the specification, but it differs from the sequence
CC described as SEQ ID NO: 76 (see BJA05203) in the sequence listing.
XX
SQ Sequence 113 AA;
ALIGNMENT:
Query Match 100.0%; Score 602; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYY 60
Qy 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS 113
Alignment with SEQ ID NO: 4
BJA05259
ID BJA05259 standard; protein; 107 AA.
XX
AC BJA05259;
XX
DT 15-APR-2021 (first entry)
XX
DE Anti-PD-1 antibody light chain variable region, SEQ ID 78 #2.
XX
KW PD-1 protein; antibody; antiinflammatory; cancer; cytostatic;
KW inflammatory disease; light chain variable region; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 24..36
FT /label= CDR1
FT Region 46..56
FT /label= CDR2
FT Region 89..97
FT /label= CDR3
XX
CC PN WO2021032116-A1.
XX
CC PD 25-FEB-2021.
XX
CC PF 19-AUG-2020; 2020WO-CN109986.
XX
PR 19-AUG-2019; 2019CN-10764762.
XX
CC PA (SHAN-) SHANGHAI YICHEN BIOMED CO LTD.
XX
CC PI Wang F, Zheng H, Zhang Y;
XX
DR WPI; 2021-19445U/021.
XX
CC PT Immunocytokine in medicinal composition for treating inflammatory disease
CC PT or cancer in subject in need, comprises interleukin-15, interleukin-15
CC PT receptor a subunit and antibodies targeting treatment of related cell
CC PT surface antigens.
XX
CC PS Claim 11; SEQ ID NO 78; 39pp; Chinese.
XX
CC The present invention relates to a novel immunocytokine comprising an
CC interleukin-15 (IL-15), interleukin-15 receptor alpha subunit (IL-15Ra)
CC and antibodies targeting treatment of related cell surface antigens. The
CC IL-15 is connected to the N-terminus of a heavy chain variable (VH)
CC region of the antibody directly or through a connecting peptide, and the
CC IL-15Ra is connected to the N-terminus of a light chain variable (VL)
CC region of the antibody directly or through a connecting peptide or the IL
CC -15 is connected to the N-terminus of the VL region of the antibody
CC directly or through a connecting peptide, and the IL-15Ra is connected to
CC the N-terminus of the VH region of the antibody directly or through a
CC connecting peptide, or the IL-15 is connected to C-terminus of a light
CC chain constant (CL) region of antibody directly or through a connecting
CC peptide and the IL-15Ra is connected to C-terminus of a heavy chain
CC constant (CH) region of the antibody directly or through a connecting
CC peptide. The invention further claims: (1) a nucleic acid encoding the
CC immunocytokine; (2) a vector comprising the nucleic acid; (3) a host cell
CC comprising the vector; (4) a medicinal composition comprising the
CC immunocytokine and a carrier; and (5) a method for treating inflammatory
CC disease or cancer in a subject. The immunocytokine of the present
CC invention is useful in a medicinal composition for treating inflammatory
CC disease and cancer. Note: The present sequence is shown as SEQ ID NO: 78
CC in figure 5C of the specification, but it differs from the sequence
CC described as SEQ ID NO: 78 (see BJA05205) in the sequence listing.
XX
SQ Sequence 107 AA;
ALIGNMENT:
Query Match 100.0%; Score 553; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 107
Alignment with SEQ ID NO: 147
RESULT 16
BJA05213
ID BJA05213 standard; protein; 295 AA.
XX
AC BJA05213;
XX
DT 15-APR-2021 (first entry)
XX
DE IL-15Ra sushi-anti-PD-L1 antibody light chain fusion, SEQ ID 86.
XX
KW IL-15 receptor; IL-15Ra; Interleukin-15 receptor alpha subunit;
KW PD-L1 protein; antibody; antiinflammatory; cancer; cytostatic;
KW fusion protein; inflammatory disease; light chain; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Homo sapiens.
OS Unidentified.
OS Chimeric.
OS Synthetic.
XX
CC PN WO2021032116-A1.
XX
CC PD 25-FEB-2021.
XX
CC PF 19-AUG-2020; 2020WO-CN109986.
XX
PR 19-AUG-2019; 2019CN-10764762.
XX
CC PA (SHAN-) SHANGHAI YICHEN BIOMED CO LTD.
XX
CC PI Wang F, Zheng H, Zhang Y;
XX
DR WPI; 2021-19445U/021.
DR N-PSDB; BJA05212.
XX
CC PT Immunocytokine in medicinal composition for treating inflammatory disease
CC PT or cancer in subject in need, comprises interleukin-15, interleukin-15
CC PT receptor a subunit and antibodies targeting treatment of related cell
CC PT surface antigens.
XX
CC PS Claim 18; SEQ ID NO 86; 39pp; Chinese.
XX
CC The present invention relates to a novel immunocytokine comprising an
CC interleukin-15 (IL-15), interleukin-15 receptor alpha subunit (IL-15Ra)
CC and antibodies targeting treatment of related cell surface antigens. The
CC IL-15 is connected to the N-terminus of a heavy chain variable (VH)
CC region of the antibody directly or through a connecting peptide, and the
CC IL-15Ra is connected to the N-terminus of a light chain variable (VL)
CC region of the antibody directly or through a connecting peptide or the IL
CC -15 is connected to the N-terminus of the VL region of the antibody
CC directly or through a connecting peptide, and the IL-15Ra is connected to
CC the N-terminus of the VH region of the antibody directly or through a
CC connecting peptide, or the IL-15 is connected to C-terminus of a light
CC chain constant (CL) region of antibody directly or through a connecting
CC peptide and the IL-15Ra is connected to C-terminus of a heavy chain
CC constant (CH) region of the antibody directly or through a connecting
CC peptide. The invention further claims: (1) a nucleic acid encoding the
CC immunocytokine; (2) a vector comprising the nucleic acid; (3) a host cell
CC comprising the vector; (4) a medicinal composition comprising the
CC immunocytokine and a carrier; and (5) a method for treating inflammatory
CC disease or cancer in a subject. The immunocytokine of the present
CC invention is useful in a medicinal composition for treating inflammatory
CC disease and cancer. The present sequence represents a fusion protein
CC (comprising a human IL-15Ra sushi-anti-PD-L1 antibody light chain) which
CC is used for treating inflammatory disease and cancer.
XX
SQ Sequence 295 AA;
Query Match 100.0%; Score 1106; Length 295;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 82 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 141
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 142 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPP 201
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 202 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 261
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 262 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 295
Prosecution Insights