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 invention group 1 (original claims 1-25) with species Vβ12 in claim 3, VHCDRs comprising SEQ ID NOs: 58-60 and VLCDR 62-64 in claim 4 corresponding to VH and VL comprising SEQ ID NOs: 57 and 61 respectively in claim 5, a CAR comprising sequence of SEQ ID NO: 154 encoding by SEQ ID NO: 2, and costimulatory molecule 4-1BB in the reply filed on 10/16/2025 is acknowledged.
Claims 6, 20 and 26 have been cancelled.
Claims 1-5, 7-19, 21-25 and 27-58 are pending.
Claims 27-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim.
Claims 1-5, 7-19, and 21-25, drawn to a Chimeric Antigen Receptor (CAR), and a nucleic acid encoding the CAR comprising an extracellular domain that binds to Vβ region of a T cell receptor (TCR), transmembrane, intracellular signaling domain etc., are examined on merits.
Priority
It is acknowledged that application is 371 national stage application of PCT/US2021/015659 filed at 1/29/2021 that claims benefit of 62/967,371 filed at 1/29/2020.
Information Disclosure Statement
The information disclosure statement (s) (IDS) submitted on 11/23/2022 and 6/19/2024 are/is considered by the examiner and initialed copies/copy of the PTO-1449 are/is enclosed.
Interview Summary
Applicant’s representative Lukas Pfannenstiel was contacted on 11/4/2025 for potential typographic error and purpose of sequence search for elected LCDR1-3 recited in claim 4 etc. Applicant elects an antibody comprising VH domain of SEQ ID NO: 57 comprising HCDR1-3 (SEQ ID NOs 58-60) paired to VL domain of SEQ ID NO: 61 comprising LCDR1-3 having SEQ ID NOs: 62-63, in which the claimed LCDR1-3 contain only two CDR sequences (LCDR1-2) listed in the claims. Applicant confirms that is typographic error and corrects that LCDR1-3 for elected antibody should comprise SEQ ID NOs: 62, 63 and 64 respectively as described in the specification. For the compact persecution, the elected LCDR1-3 having SEQ ID NOs: 62-63, as written in the claim, are corrected, searched, and examined based on the sequences of SEQ ID NOs: 62-64 and the objection below is made in this application for the reason of record.
Claim Objections
Claims 3-4 and 17-18 are objected to for reciting…… LCDRs1-3 comprise the sequences of SEQ ID NOs: 62-63 (e.g. claim 3-(a), line 2-3 of claim 4…) as typographical error since LCDR1-3 are 3 peptides in a fusion in a VL domain. The specification describes an extracellular domain binding to Vβ12 comprising CDR sequences selected from SEQ ID NO: 58-60 and 62-64…… [0045, 0067….]. The specification at [0170] teaches VHCDR1-3 comprising the sequences of SEQ ID NO: 58, 59 and 60 and VLCDR1-3 comprising the sequences of SEQ ID NO: 62, 63 and 64 as following:
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no LCDR1-3 comprises merely the sequences of SEQ ID NOs 62-63 described in the application.
For the search purpose, applicant’s representative Lukas Pfannenstiel is contacted, who confirms that the corrected sequences for elected LCDR1-3 are SEQ ID NOs: 62, 63 and 64 respectively. Mr. Pfannenstiel also confirms that correction will be made in the response to this Office action (see attached interview summary above).
Claim Rejections - 35 USC § 112
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.
Written Description: extracellular domain binding to Vβ and nucleic acid encoding thereof
Claims 1, 8-11, 15, and 22-25 and 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Possession may be shown. For claimed product the specification must provide sufficient distinguishing identifying characteristics of the genus, including disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, level of skill and knowledge in the art, and predictability in the art or any combination thereof.
The two independent claims are broadly drawn to
Claim 1. A nucleic acid encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular domain that binds a Vp region of a T cell receptor, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises a costimulatory signaling region.
Claim 15. A CAR comprising an extracellular domain that binds a V3 region of a T cell receptor, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises a costimulatory signaling region.
Thus, the phrase “extracellular domain” would comprise a molecule with any structure (peptide, small molecule, peptidomimetic, nucleotide…..) as long as it binds to a Vβ domain of TCR.
The specification teaches that the invention related a T cell receptor (TCR) Chimeric Antigen Receptor (TCRVβ-CAR) comprising a domain (extracellular domain) binding to Vβ region of T cell receptor [0007]). Then the specification teaches the extracellular domain being antibody, Fab or, scFv (figures 7, 9, 11-12), which are all defined by full sets of CDRs with peptide sequences and nucleotides encoding thereof, including elected anti-Vβ12 antibody comprising LCDR1-3 sequences of SEQ ID NOs: 62-64 within the VL domain of SEQ ID NO: 61 and HCDR1-3 sequences of SEQ ID NOs: 58-60 with the VH domain of SEQ ID NO: 57 ([0009-0012 and [0170] and [0183]). The specification also teaches the amino acid sequences of TCRVβ-CAR including SEQ ID NO: 154 with 464 amino acids) which is encoded by the nucleotide sequence of SEQ ID NO: 2 as claimed. The specification also teaches and contemplates methods of TCRVβ-CAR-T therapy for targeting of T cell associated diseases including T cell lymphoma etc. (examples 1-9 and [0425]+).
In the entire application, there is no any extracellular domain binding to Vβ region of TCR other than the antibodies provided. There are no structures of any domain other than antibody’s CDRs or VH/VL defined in this application.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875.
The Court, in Abbvie v. Centocor (Fed. Cir. 2014), held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionallyclaimed genus.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d ,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information in the broadly claimed extracellular domains binding to any Vβ region of TCR that are in a form of TCRVβ-CAR. The specification does not provide data or result or description to correlating the extracellular domain with the function of binding to TCRVβ in a form of CAR. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed, merely providing the antibodies or antigen binding fragment thereof for Vβ-TCR, the skilled artisan cannot envision the structures of the claimed extracellular domain binding to Vβ-TCR. Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Therefore, only the antibody or antigen binding fragment with a full set of 6 CDRs or a VL paired to a VL domain binding to Vβ-TCR including elected anti-Vβ12-TCR antibody comprising LCDR1-3 within the VL domain of SEQ ID NO: 61 and HCDR1-3 within the VH domain of SEQ ID NO: 57, but not the broadly claimed extracellular domain binding to Vβ region of TCR in a CAR, meet the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Applicant is referred to written description guidance at http://www.uspto.gov/web/patents/guides.htm and recent memorandum (Feb 22, 2018): Clarification of written Description Guidance for Claims Drawn to Antibodies and Status of 2008 Training Materials.
Claim Rejections - 35 USC § 103
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 1-2, 8-11, 15-16, and 22-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over McLean-Tooke et al (Clin Experim Immun 151:190-198, 2007) in view of Ying et al (Mole Therapy: Oncolytics 15: 60-68, Dec 2019).
McLean-Tooke et al teach T cell receptor Vβ repertoire of T lymphocytes, wherein the Vβ region comprises Vβ2, Vβ5.1, Vβ 9, Vβ12…. etc. (p190-192 and table 1). McLean-Tooke et al teach monoclonal antibodies binding to Vβ regions and method of using the antibody staining the Vβ domain for analysis of the antigens.
McLean-Tooke et al do not teach the anti-Vβ antibodies in Chimeric Antigen Receptor (CAR).
Making and using a CAR for immunotherapy has been reported, developed and improved in recent years. For example, Ying et al teach different generations of CARs comprising an antibody or antigen binding fragment Fab, or scFv fused to transmembrane domain, intracellular signaling domain comprising costimulatory signaling region comprise CD28 and CD3ζ (28zCAR) or 4-BB and CD3ζ (BBz CAR) in late generation of CARs and vectors comprising nucleotides encoding the CARs. Ying et al also teach a CD19-CAR-T for CD19 expressed B-cell malignancy therapy, wherein the CAR-T formed by transduction of T cell with a CAR expressing polynucleotides encoding anti-CD19 antibody or scFv thereof, transmembrane domain, intracellular signaling domain… to express the CAR in T cells (figure 1 and page 61) and method of infusing the CAR-T cell to patient for treatment (figures 2-3 and tables 2-3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the methods to form a TCRVβ-CAR with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated to apply the antibody to Vβ of TCR of McLean-Tooke et al to the teachings on CAR formation taught by Ying et al in order to benefit the treatment for T-cell associated malignance including T-cell lymphoma because Ying et al have shown CD19-CAR comprising anti-CD19 antibody and intracellular signaling 4-1BB-CD3ζ or CD28-CD3ζ being successfully used for B-cell lymphoma treatment. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success for combining the teachings to form a TCRVβ CAR for treating T-cell associated disease including lymphoma because Ying et al have shown structure and method of making CD19-CAR for treating CD19 expressed B-cell lymphoma and anti-Vβ-TCR antibody is available at the time of filing the instant application as shown by McLean-Tooke et al. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Improper Markush grouping
Claims 3, 5, 7, 12-14, 17, 19, and 21 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush groupings of CDRs, VH, or VL etc. are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
each of the CDRs, VHs, or VLs of the antibodies listed in the claims has unique sequence and binding activity which are not shared by the other antibodies listed in the claims. The elected antibody comprising LCDRs of SEQ ID Nos: 62-64 and HCDRs of SEQ ID Nos: 58, 59, and 60 or VL domain having the sequence of SEQ ID NO: 61 and VH domain having the sequence of SEQ ID NO: 57 does not share and have common structure in sequences and binding function/activity with the other antibodies in the list.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
In the claimed CAR, an antibody comprising a VH domain having the sequence of SEQ ID NO: 57 that comprises HCDR1-3 having the sequences of SEQ ID NOs: 58-60 paired to a VL domain of SEQ ID NO: 61 that comprises the sequences of SEQ ID NOs: 62-64 are free of prior art.
Claims 1-3, 5, 7-17, 19 and 21-25 are rejected. Claims 4 and 18 are objected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEI YAO/Primary Examiner, Art Unit 1642