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 .
Claims 89-107 are pending and under consideration.
Specification
The disclosure is objected to because of the following informalities: There are several references to different colors. For example, Page 86, line 15 states: Furin refers to a Furin recognition site that was introduced to shorten the tails of the protein after the 2A cleavage. Mutation or insertion is highlighted in green. The sequence highlighted in blue is P2A, in red is mCherry (marker protein). References to colors in the specification are not permitted. In contrast, references to colors in the drawings were previously approved by the Office (see petition decision mailed 10/16/2024).
The disclosure is further objected to because of the following informalities: The specification is objected on page 9, line 27 for recitation of a nucleic acid sequence in the absence of a sequence identifier. See 37 CFR 1.821(c). 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.
Appropriate corrections are 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 89-108 are rejected as vague and indefinite for reciting the term “interface” in claim 89. It’s not clear what comprises an “interface” between the constant and variable regions. The specification teaches [0066] that the interface is composed of the surfaces of the variable region (e.g., VH or VL) that interacts with the constant region (e.g., Cα or Cβ) on each miTCR chain that forms the pair. Thus, this appears to be a general term. However, the specification also teaches [0218] that although the specific residue located at the interface for the VH and VL from different antibodies will be different, the key is to modify whatever interface residues from VH and VL in order to have sufficient contact with the interface residues from TCR constant region. Thus, the “interface” can have specifically defined residues. Hence, the term appears indefinite in conjunction with a specific structure and one of ordinary skill in the art would not know if they were infringing upon at least claim 89. Dependent claims were also included in this rejection because it’s not clear if/how the interface is structurally limited.
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 89-108 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 89-108 are broadly drawn to engineered chimeric MHC-independent TCR (miTCR) constructs wherein the constructs comprise a first peptide chain that comprises an alpha constant chain that is at least 80% identical to SEQ ID NO:49 (along with a first antigen binding domain comprising a VH or VL chain) and a second beta constant chain at least 80% identical to SEQ ID NO:50 (also comprising a second antigen binding domain with either VH or VL chain domains) wherein the first and second chains of the construct are capable of self-assembling into a miTCR pair when expressed on a cell and wherein the pair is also capable of specifically binding to a target antigen. Thus, as written, the alpha and beta chains can have a wide variety of insertions, substitutions, and deletions AND can further comprise any antibody heavy chain and any antibody light chain (Claim 92; and specification pages 22-23).
The specification teaches [0048] that miTCRs as described herein comprise completely human TCR alpha and beta constant region sequences, except slightly modified to make the TCR alpha and beta constant regions form disulfide bonds to stabilize the pairing. Further, the specification teaches [0049] that each chain has one single C mutation. The T and S are believed to likely be the only two residues in the WT constant chain that would be useful to be mutated into C, and other C modifications can be made. SEQ ID NO:49 is the wildtype alpha chain sequence without the T47C modification, and SEQ ID NO:50 is the wildtype beta chain sequence without the S56C modification. The specification theorizes [0054] that by replacing the antigen-recognition domains of the TCR (alpha and beta variable chains) with the antigen-recognition domains of the immunoglobulin molecule (variable heavy (VH) and light chains (VL)), the miTCRs are able to preserve the highly-regulated TCR complex-driven cellular activation and integrate MHC-independent antigen recognition. Regarding the antigen recognition domains, the specification broadly teaches [0058] that the miTCR pair can comprise any antigen binding domain or tumor binding domain. The antigen binding domain can comprise any domain that binds to an antigen expressed by the targeted cell type (e.g., an antigen, such as CD19). However, the specification also teaches [0065] that the interface between the engineered VH and VL AND the native TCR are critical to mimicking or restoring the native TCR variable and TCR constant region interface interactions or “reduce stress in the protein”. The length, area, region, or portion of peptides that is closer in proximity to the constant region is relatively stable, while the distal part of the variable chains, which are responsible for antigen binding, are different for each variable chain corresponding to different antigen binding fragments or domains. Thus, this peptide region closer to the constant chain is most likely to need modifications to reduce conflicts and enhance protein stability and expression [0067]. Notably, the specification teaches [0068] that “except for the PD insertion at the beginning of the TCR alpha constant chain (it is an insertion, not a mutation), all the mutations were made at the variable region (VL and/or VH of the antigen binding domain) to alleviate the conflict.” In contrast to the huge genus of possible target antigens and possible alpha and beta chains, applicants have only provided a written description of miTCRs directed against the CD19 surface molecule. [0185] Four plasmid sequences were developed and are directed against the CD19 surface molecule. They employ the FMC63 anti-CD19 antigen-recognition domains. They are paired variable heavy or variable light chains with TCR alpha or beta constant regions to create a single chain antigen receptor. However, the specification teaches [0188, 0205] that even these constructs had issues being expressed on T cells so mutations and optimizations had to be developed. Further, the written description is lacking regarding the predictably of treating a subject having a genus of cancers. For example, the specification teaches [0215] that a few mutated miTCRs were selected to evaluate cytotoxic function against cancer cells in vitro. However, correlation of one particular species/model does not reasonably extrapolate to possession of treating a genus of cancers.
Thus, the written description is not commensurate in scope with the genus of hundreds of thousands of potential miTCRS constructs that can differ by as much as 20% in the alpha and beta chains and that also comprise amino acids in the VH and VL chains that could potentially bind any target antigen or be reliably expressed on the cell surface. Further, as noted above, except for the PD insertion at the beginning of the TCR alpha constant chain, mutations were limited to the binding areas located within the variable region of the antigen binding domain. And, except for CD19, the specification does not demonstrate possession that any other possible miTCR constructs would predictably have antigenic specificity for the genus of targeted antigens. Moreover, it’s evident that the bulk of miTCR conception was based on a multitude of trial and error (Example 3, optimization and demonstration of miTCR function). The specification also teaches [0071] that since each antibody is different, it was discovered that there is a need to tailor each new chimera receptor to optimize the interface interaction. Tailoring these structural details can change a lot of aspects of the receptor, including protein expression and function.
The state of the art of MHC independent TCR constructs for targeted therapy appears undeveloped. Lu et al. (J Immunol. 2020 June 15; 204(12): 3351–3359) teach that peripheral T cells normally recognize only linear peptides presented by major histocompatibility antigens (MHCs), a feature referred to as “MHC-restriction”. However, in CD4/CD8 coreceptor-deficient mice that are also MHC-deficient QuadKO mice (B2m−/−H-2Ab1−/−CD4−/−CD8a−/− ), the thymus generates mature T cells expressing MHC-independent TCRs that bind to conformational epitopes on native ligands independently of MHC. But, to date, “there is no structural information available on MHC-independent TCR and how they recognize non-MHC ligands remains unknown.”.
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 above, the skilled artisan cannot envision the genus of miTCR constructs as claimed that would predictably bind to any targeted antigen or be predictably expressed upon the cell surface, and 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.
Claim Rejections - 35 USC § 102
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.
Claim(s) 89-95, and 100-108 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chaudhary, P. (WO2018102795, published July 2018).
Regarding claim 89, Chaudhary teaches a construct comprising an engineered TCR comprising a first subunit comprising a constant region alpha chain at least 80% identical to SEQ ID NO:49 and a second TCR subunit comprising a constant beta chain region that is at least 80% identical to SEQ ID NO:50. Below is a sequence comparison between applicant’s SEQ ID NO:25 with Chaudhary’s SEQ ID NO:3137. The overall match was 63.5%. Chaudhary’s sequence is a modified TCR comprising CD8 signal peptide, FMC63, VL, V5, human TCR beta-KACIAH, P2A, Myc tag, TCR alpha, F2A. Also, see claim 49 of Chaudhary. Further, the modified TCR of the prior art is inherently capable of self-assembling into a miTCR pair when expressed on a cell. Also, due to the vagueness of the term “interface” (See para 6, above), the TCR below also contains an interface between the constant and variable regions. Further, the TCR of the prior art comprises an antigen recognition domain comprising a VH and VL that specifically bind to CD19. (See claim 47 of Chaudhary).
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[AltContent: textbox (Boxed sequence is at least 80% identical to SEQ ID NO:49)]
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Regarding Claim 90, the sequence of Chaudhary appears to comprise one of VLCα and VHCβ or VHCα or VLCβ because of the high homology.
Regarding Claim 91, the sequence of Chaudhary at least one of the first peptide chain and second peptide chain comprises human TCR constant regions because of the high homology.
Regarding Claim 92, the sequence of Chaudhary contains heavy and light chains from an antibody (See claim 1 of Chaudhary).
Regarding claims 93-95, the target antigen of Chaudhary can be CD19. Chaudhary further teaches (Claim 184) that the antigen to be targeted can be associated with infection by a virus including HIV1, HIV2, HTLVl, Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus, adeno-associated virus, BK virus, Human Herpesvirus 6, Human Herpesvirus 8, influenza virus, parainfluenza virus, avian flu virus, MERS and SARS coronaviruses, Crimean Congo Hemorrhagic fever virus, rhino virus, enterovirus, Dengue virus, West Nile virus, Ebola virus, Marburg virus, Lassa fever virus, zika virus, RSV, measles virus, mumps virus, rhino virus, varicella virus, herpes simplex virus 1 and 2, varicella zoster virus, HIV-1, HTLVl, Hepatitis virus, enterovirus, hepatitis B virus, Hepatitis C virus, Nipah and Rift valley fever viruses, Japanese encephalitis virus, Merkel cell polyomavirus. The disease can also be associated with cancers of the colon, esophagus, and skin etc. (See claim 183 of Chaudhary).
Regarding claim 100, Chaudhary teaches [00137] that both VH and VL regions of FMC63 may be present. Also, the reference teaches that Chaudhary’s SEQ ID NO:3137 (sequence homology above) contains the FMC63 vL chain:
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Regarding claim 101, Chaudhary teaches [00119] that the intracellular signaling domain can comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals, or antigen independent stimulation. For example, a primary intracellular signaling domain can comprise a cytoplasmic sequence of CD3z, and a costimulatory intracellular signaling domain can comprise cytoplasmic sequence from co-receptor or costimulatory molecule, such as CD28 or 41BB.
Regarding claims 102-108, Chaudhary teaches pharmaceutical compositions [00419] and methods of treating a variety of cancers (see claims 181-183 of Chaudhary).
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643