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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of TCR No. 27 CDR amino acid sequences, specific substitutions for disulfide bond formation, TCR a chain variable domain of SEQ ID NO: 85 and TCR b chain variable domain of SEQ ID NO: 117, TCR a chain variable domain of SEQ ID NO: 82 and TCR b chain variable domain of SEQ ID NO: 2, and TCR No. s-27 a chain variable domain of SEQ ID NO: 35 and TCR b chain variable domain of SEQ ID NO: 4 in the reply filed on October 6, 2025 is acknowledged.
Claim Status
Claims 4, 9, 16, and 21 have been amended.
Claim 8 has been canceled.
Claims 5-7, 13, 18-19, 23-24, 26-28, and 32-33 were previously canceled.
Claims 1-4, 9-12, 14-17, 20-22, 25, and 29-31 are pending and under consideration.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/CN2020/106291 filed on July 31, 2020 which claims the benefit of China Application 201910713184.9 filed on August 2, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
However, support for the claimed invention cannot be determined because the foreign priority documents provided for Application No. CN201910713184.9 are not in English. Applicant cannot rely upon the certified copy of the foreign priority application to overcome any prior art rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Failure to provide a certified translation may result in no benefit being accorded for the non-English application. Accordingly, the PCT/CN2020/106291 filing date of August 2, 2019 will be used for the purpose of applying prior art.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on January 31, 2022, February 2, 2022, and September 12, 2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. To note, the IDS submitted on February 2, 2022 is a watermarked copy of the IDS submitted January 31, 2022.
Specification
The disclosure is objected to because of the following informalities:
The table beginning on page 4: The top left column should be labeled as TCR No., not CDR No.. In addition, TCR NO. 44 CDR2a is missing the SEQ ID NO..
Appropriate correction is required.
Claim Objections
Claims 9 and 22 are objected to because of the following informalities:
Claim 9 recites a table of TCR CDR amino acid sequences, however, the top left column is labeled CDR No. instead of TCR No..
Claim 9 (pg. 7) – TCR No. 44 CDR2a (IRTGQAE) is missing the SEQ ID NO. In addition, the SEQ ID NO for this amino acid sequence was not found during a cursory search of the instant disclosure.
Claim 22 recites “at C- or N-terminal”, however, it should read “at the C- or N-terminus”.
Appropriate correction is required.
Claim Interpretation
The instant specification discloses Fig. 1a and Fig. 1b show the amino acid sequences of a and b chain variable domains of a wild type TCR capable of specifically binding to SLLMWITQC-HLA A0201 complex, respectively. Figures 1a and 1b depict amino acid sequences SEQ ID NO: 1 and SEQ ID NO: 2, respectively. Accordingly, the wild type TCR recited in claim 2 is being interpreted to mean a TCR comprising an a chain variable domain with the amino acid sequence of SEQ ID NO: 1 and a b chain variable domain with the amino acid sequence of SEQ ID NO: 2.
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.
Claims 11, 14, 17, 22, and 31 are rejected under 35 U.S.C. 112(b) 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.
Claims 11, 14, 17, 22, and 31 recite the term “preferably”, however, it is unclear if the portion of the claims that is recited as being preferable (or more preferable) is required. Therefore, a person skilled in the art could not determine what is and what is not encompassed by the claims.
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.
Claim 31 is rejected under 35 U.S.C. 112(a) because the specification, while being enabling for:
A method of treatment NY-ESO-1 positive cancer comprising administering to a subject in need thereof a TCR comprising a and b chain variable domains having at least 90% homology to SEQ ID NO: 1 and SEQ ID NO: 2, respectively, wherein the TCR is conjugated to a therapeutic agent, does not reasonable provide enablement for:
A method of treatment NY-ESO-1 positive cancer comprising administering to a subject in need thereof a TCR comprising a and b chain variable domains having at least 90% homology to SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, in re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable.
The instant claims are directed to a method of treatment of cancer comprising administering to a subject a recombinant TCR that specifically binds to a SLLMWITQC-HLA A0201 complex. The state of the art is such that recombinant, soluble TCRs specific for tumor peptide/HLA complexes can be used to deliver an associated therapeutic agent to tumor cells for treating cancer [see WO 03/020763, pg. 16]. However, the instant claims broadly encompass treating a disease (i.e., cancer) with a recombinant TCR alone, and do not require that it be associated with a therapeutic agent. The state of the art is such that treating cancer with a recombinant TCR alone would be highly unpredictable. For example, as taught by Boulter and Jakobsen (2005), a soluble TCR would function to block or mask peptide MHC expressed by cancer cells, thereby preventing T cell recognition, which would be expected to further worsen the cancer.
Thus, given the unpredictability of the art and the breadth of the claims, the instant specification must provide a sufficient an enabling disclosure commensurate in scope with the instant claims. The specification provides guidance for using a recombinant TCR to target an associated therapeutic agent to tumor cells for treating NY-ESO positive cancers. The specification does not provide any guidance or examples for using a recombinant TCR alone, in the absence of an associated therapeutic agent, for treating cancer, as broadly encompassed by the instant claims. Thus, given the unpredictability of the art and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the method as broadly claimed.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claims 1-4, 10-12, 14, 17, 22, 25, and 29-31 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Li et al. (WO 2017/076308; Espacenet Translation 10/28/2025) (“Li”). This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
The instant claims are drawn to a TCR that binds SLLMWITQC-HLA A0201 complex comprising a and b chain variable domains that are at least 90% homologous to the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, wherein the TCR can be administered as a method for treating a disease to a subject in need thereof.
Li discloses a T cell receptor (TCR), characterized in that the TCR can bind to the SLLMWITQC-HLAA0201 complex [claim 1], wherein the TCR comprises a TCRa chain variable domain and a TCRb chain variable domain wherein the amino acid sequence of bCDR3 is ASSLGSNEQY (SEQ ID NO: 15) [claim 2], the amino acid sequence of bCDR1 is SGHDY (SEQ ID NO:13), and the amino acid sequence of aCDR2 is IRSNERE (SEQ ID NO:11) [claim 3]. The TCR is characterized in that it comprises a TCRa chain variable domain and a TCRb chain variable domain, wherein the TCRa chain variable domain is an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and/or the TCRb chain variable domain is an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5 [claim 4], wherein the TCR comprises the a chain variable domain amino acid sequence SEQ ID NO: 1 [claim 5], wherein the TCR comprises the b chain variable domain amino acid sequence SEQ ID NO: 5 [claim 6].
Li further discloses the TCR is a soluble [claim 9] ab heterodimer comprising a TCR a chain constant region TRAC*01 and a TCR b chain constant regionTRBC1*01 or TRBC2*01 [claim 7]. The TCR comprises (a) all or part of the TCR a chain excluding the transmembrane domain; and (b) all or part of the TCR b chain excluding the transmembrane domain; and (a) and (b) each comprise a functional variable domain, or a functional variable domain and at least a portion of the TCR chain constant domain [claim 15], wherein the cysteine residues form an artificial disulfide bond between the constant domains of the a and b chains of the TCR [claim 16], wherein the cysteine residues are substituted at Thr48 of exon 1 of TRAC*01 and Ser57 of exon 1 of TRBC1*01 or TRBC2*01 [claim 17]. The TCR is a single chain TCR [claim 10] composed of an a chain variable domain and a b chain variable domain connected by a peptide linker sequence [claim 11], wherein the TCR has one or more mutations in the a or β chain variable regions at amino acid positions 11, 13, 19, 21, 53, 76, 89, 91, or 94 [claim 12].
Additionally, Li discloses a conjugate is bound to the C- or N terminus of the a and/or β chain of the TCR [claim 22], wherein the conjugate bound to the T cell receptor is a detectable marker, a therapeutic agent, a PK modifying moiety, or a combination thereof, preferably, the therapeutic agent is an anti-CD3 antibody [claim 23]. A multivalent TCR complex, characterized in that it comprises at least two TCR molecules, and at least one of the TCR molecules is the disclosed TCR [claim 24].
Also disclosed is a nucleic acid sequence encoding the TCR [claim 25] a vector containing the nucleic acid molecule [claim 29], and an isolated host cell, characterized in that the host cell contains the vector or the chromosome of which is integrated with the exogenous nucleic acid molecule [claim 30]. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the TCR [claim 32]. A method for treating a disease, comprising administering an appropriate amount of the TCR to a subject in need of treatment, preferably the disease is a tumor including neuroblastoma, sarcoma, melanoma, prostate cancer, bladder cancer, breast cancer, multiple myeloma, hepatocellular carcinoma, oral squamous cell carcinoma, esophageal cancer, gastric cancer, lung cancer, head and neck squamous cell carcinoma, colon cancer, and ovarian cancer [claim 34].
The a chain variable domain amino acid sequence (SEQ ID NO: 1) and b chain variable domain amino acid sequence (SEQ ID NO: 2) recited in the instant claims are 100% identical to SEQ ID NO: 1 and SEQ ID NO: 5 disclosed by Li.
Therefore, absent a showing of any difference, the TCR product disclosed by the prior art is deemed to anticipate the claimed TCR.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 17, and 31 are rejected under 35 U.S.C. 103 as being obvious over Li et al. (WO 2017/076308; Espacenet Translation 10/28/2025) (“Li”).
The instant claims are drawn to a TCR that binds SLLMWITQC-HLA A0201 complex comprising a and b chain variable domains that are at least 90% homologous to the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, wherein the TCR is a single chain TCR; preferably, the TCR is a single chain TCR consisting of an a chain variable domain and a b chain variable domain linked by a flexible short peptide sequence (linker); more preferably, a hydrophobic core of the a and/or b chain variable domain of the TCR is mutated. A method for treating a disease, comprising administering the TCR to a subject in need thereof; preferably, the disease is NY-ESO-1 positive tumor.
The teachings of Li are set forth above.
Specifically, Li teaches the TCR comprising SEQ ID NO: 1 and SEQ ID NO: 2 wherein the TCR is a single chain TCR [claim 10] composed of an a chain variable domain and a b chain variable domain connected by a peptide linker sequence [claim 11]. Mutations are made in the a and/or β chain variable regions at amino acid positions 11, 13, 19, 21, 53, 76, 89, 91, or 94 [claim 12] which occur in the hydrophobic core region of the TCR and improves the stability of the TCR [pg. 19, par. 2].
Li further teaches that the TCR specifically binds the SLLMWITQC-HLAA0201 complex [claim 1] which is a short peptide derived from NY-ESO-1 antigen that is expressed in various types of tumor tissues and the target for the treatment of NY-ESO-1-related diseases [pg. 1-2]. The TCR can be administered as a method for treating a disease, comprising administering an appropriate amount of the TCR to a subject in need of treatment, preferably the disease is a tumor including neuroblastoma, sarcoma, melanoma, prostate cancer, bladder cancer, breast cancer, multiple myeloma, hepatocellular carcinoma, oral squamous cell carcinoma, esophageal cancer, gastric cancer, lung cancer, head and neck squamous cell carcinoma, colon cancer, and ovarian cancer [claim 34]. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Allowable Subject Matter
Claims 9, 15-16, and 20-21 are objected to as being dependent upon a rejected independent claim, but would be allowable if rewritten in independent form including all of the limitations of the independent claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Claim 9 – Elected TCR No. 27 comprising CDR1a (SEQ ID NO: 130), CDR2a (SEQ ID NO: 129), CDR3a (SEQ ID NO: 140), CDR1b (SEQ ID NO: 128), CDR2b (SEQ ID NO: 134), and CDR3b (SEQ ID NO: 139).
Claim 15 – Elected a chain variable domain comprising SEQ ID NO: 85 and b chain variable domain comprising SEQ ID NO: 117.
Claim 16 – Elected TCR No. 27 a chain variable domain comprising SEQ ID NO: 82 and b chain variable domain comprising SEQ ID NO: 2.
Claim 20 - Elected a chain variable domain comprising SEQ ID NO: 35 and b chain variable domain comprising SEQ ID NO: 43.
Claim 21 – Elected TCR No. s-27 a chain variable domain comprising SEQ ID NO: 35 and b chain variable domain comprising SEQ ID NO: 4.
There is no prior art that teaches a TCR with the specific CDR amino acid sequences or a and b chain variable domain amino acid sequences as recited in the instant claims. The closest prior art to the claimed amino acid sequences, WO 2017/076308 referenced above, is directed to TCRs that bind to SLLMWITQC-HLA A0201 complex, however, does not teach or suggest the presently claimed TCR with the specific sequences.
Additional Search and Consideration
Elected TCR No. 27 is free of prior art. Therefore, the amino acid sequences of the a chain and b chain CDR regions for the following TCR Nos. were selected from the table recited in claim 15 for additional search:
TCR Nos. 22-26, 28-30, 35-37, 46, 48-51, and 53-97
The amino acid sequences for the a chain and b chain CDR regions for TCR Nos. 22-26, 28-30, 35-37, 46, 48-51, and 53-65, 67, and 70-97 recited in claim 15 are free of prior art.
However, the amino acid sequences for the a chain and b chain CDR regions of TCR Nos. 66 and 68-69 are disclosed in prior art documents WO 2017/076308, WO 2018/099402 (cited in IDS 9/12/2022), CN 106632660 (cited in IDS 2/2/2022), and US Patent No. 12,344,652.
TCR Nos. 1-21, 31-34, 38-45, 47, and 52 were not searched due to timing constraints, however, will be considered upon reply to this Office Action
Additional References
The following pertinent prior art references were found during examination but were not relied upon as grounds of rejection:
US Patent No. 12,344,652
WO 2018/099402 (cited in IDS 9/12/2022).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
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, Daniel Kolker can be reached on (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at (866) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000.
/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644
Prosecution Insights