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 .
Status of Claims
Claims 1, 2, 4, 6, 11-13, 15, 16, 19, 21, 23, 24, 29-32, 35, 36, 38 and 39 are pending.
Claims 2, 4, 6, 11-13, 15, 16, 19, 21, 23, 24, 29-32, 35, 36, 38 and 39 are amended.
Claims 1, 2, 4, 6, 11-13, 15, 16, 19, 21, 23, 24, 29-32, 35, 36, 38 and 39 are currently 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. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The U.S. effective filing date of all claims under examination is set at 04/15/2021 based on the App PCT/CN2021/087475 application (filed on 04/15/2021).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/26/2024 is being considered by the examiner.
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, 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.
Claims 1, 2, 4, 6, 11-13, 21, 23, 24, 29-32, 35, 36, 38 and 39 are rejected under 35 U.S.C. 103(a) as being unpatentable over Boyerinas (US20190350974A1 Date Published 2019-11-21) in view of Floss et al. (Mol Biol Cell. 2016 Jul 15;27(14):2301–2316) and Cao et al. (US20200339683A1 Date Published 2020-10-29).
Boyerinas teaches improved compositions for adoptive T cell therapies for treating, at least one symptom of a cancer and other types of diseases (Abstract). They teach improved TGFβ signal convertors, also referred to as chimeric TFGβ receptors or CTBRs, genetically modified cells, compositions, and methods of using the same (paragraph [0012]). They also teach a fusion polypeptide comprising: a first polypeptide comprising: an extracellular TFGβ1-binding domain of TGFβR2, a transmembrane domain, and an immune receptor intracellular signaling domain; a polypeptide cleavage signal; and a second polypeptide comprising: an extracellular TGFβ1-binding domain of TGFβR1, a transmembrane domain, and an immune receptor intracellular signaling domain (paragraph [0013]). They further teach in FIG 1 a polypeptide construct named CAR.CTBR12 which comprises at the N-terminal end a chimeric antigen receptor (CAR) linked to a T2A peptide, followed by the fusion protein or fusion polypeptide referred to as a CTBR12 or CTBR12 signal convertor (FIG 1, paragraphs [0045] and [0070]). They also further teach that the CTBR12 signal convertor comprises from the N-terminus to C-terminus: (i) a first signal peptide; (ii) a first polypeptide consisting of an extracellular TGFβR2, an IL-12Rβ2 transmembrane domain, and an IL-12Rβ2 signaling domain; (iii) a P2A polypeptide cleavage signal; (iv) a second signal peptide; and (v) a second polypeptide consisting of an extracellular TGFβR1, an IL-12Rβ1 transmembrane domain, and an IL-12Rβ1 signaling domain (FIG. 1 and paragraphs [0016], [0045] and [0258]). Further, Boyerinas teaches that the CTBR12 signal convertor converts an immunosuppressive TGFβ signal to an IL-12-mediated immunostimulatory signal (paragraph [0258]).
Boyerinas also teaches a polynucleotide encoding the fusion polypeptide (paragraph [0074]. They teach that T cells are engineered by introducing a polynucleotide or vector encoding a CAR and a CTBR signal convertor separated by one or more polypeptide cleavage signals (paragraph [0325]). They also teach that the expressed CARs comprise an extracellular binding domain that specifically binds to a target antigen expressed on tumor cells (paragraphs [0332] and [0327]). They further teach cells comprising the fusion polypeptide, the polynucleotide, or the vector can be hematopoietic cells, T cells, CD3+, CD4+, and/or CD8+ cells, immune effector cells, cytotoxic T lymphocytes (CTLs), tumor infiltrating lymphocytes (TILs), helper T cells, natural killer (NK) cells or natural killer T (NKT) cells (paragraphs [0076] to [0082]).
Boyerinas also teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the said fusion polypeptide, the said polynucleotide, the said vector, or the said engineered cell (paragraph [0087]). They teach a method of treating cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or an associated condition in a subject in need thereof comprising administering to the subject an effective amount of the said pharmaceutical composition (paragraphs [0088] and [0089])
Boyerinas does not specifically teach a fusion protein wherein the first intracellular domain comprises an intracellular domain of IL-23R, and a second intracellular domain comprises an intracellular domain of IL-12Rβ1. They also do not specifically teach a fusion protein wherein the intracellular domain of IL-23R comprises the amino acid sequence of instant SEQ ID NO: 15, or a functional variant having at least about 90% sequence identity; or the intracellular domain of IL-12Rβ1 comprises the amino acid sequence of instant SEQ ID NO: 16, or a functional variant having at least about 90% sequence identity.
However, these deficiencies are made up in the teachings of Floss et al. and Coe et al.
Floss et al. teaches that the receptors IL-12Rβ1 and IL-23R together form a receptor signaling complex with the cytokine IL-23 (Abstract). Upon binding of IL-23 to form an IL-12Rβ1/IL-23R receptor complex, activation of target cells such as T cells is mediated through the intracellular domains (ICDs) of the 12Rβ1/IL-23R receptor complex that comprise Box1 and Box2 motifs which associate with Janus kinases (Jak) and results in phosphorylation of STAT proteins in target cells (Abstract and FIGURE 8). They also teach that the 12Rβ1 ICD is crucial for IL-23-induced cellular proliferation and STAT3 phosphorylation, while the IL-23R ICD is important for activation of Jak2 (Pg. 2302 column right lines 20-22 and Pg. 2307 column right lines 18-20). Therefore, Floss et al. teaches that the intracellular domains of 12Rβ1 and IL-23R are important for activation of signaling cascades that lead to cell proliferation.
Cao et al. teaches a nucleic acid sequence encoding a fusion protein comprising a scFv binding SIGLEC-15, a linker, an extracellular domain, a transmembrane domain, and a cytoplasmic domain, wherein the scFv binds to a specific sequence, the linker is a GS linker, the extracellular domain is or comprises a SEQ ID NO: 36-42, the transmembrane domain is or comprises one of the SEQ ID NOs: 43-49, and/or the cytoplasmic domain is or comprises one of the SEQ ID NO: 50-56 (paragraphs [0111], [0112] and [0128]). Of note, the SEQ ID NO: 53 and the SEQ ID NO: 56 taught by Cao et al. are complete matches to instant SEQ ID NO: 16 and instant SEQ ID NO: 15, respectively (see alignments below). Cao et al. also teaches that SEQ ID NO: 53 corresponds to the sequence of an IL12 receptor while SEQ ID NO: 56 corresponds to the sequence of an IL23 receptor (Table 2 and paragraph [0119]).
Alignment 1: Alignment of instant SEQ ID NO: 15 (top Qy sequence) with SEQ ID NO: 56 of Boyerinas (bottom Db sequence)
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603
959
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Alignment 2: Alignment of instant SEQ ID NO: 16 (top sequence, Qy) with SEQ ID NO: 53 of Boyerinas (bottom sequence, Db)
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316
944
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a fusion protein comprising a first polypeptide comprising: a first extracellular TFGβ1-binding domain of TGFβR2, a first transmembrane domain, and a first immune receptor intracellular signaling domain; and a second polypeptide comprising: a second extracellular TGFβ1-binding domain of TGFβR1, a second transmembrane domain, and a second immune receptor intracellular signaling domain as taught by Boyerinas, and (1) substituting the first transmembrane domain of IL-12Rβ2 as taught by Boyerinas for the transmembrane domain of IL-12Rβ1 also as taught by Boyerinas; (2) substituting the first immune receptor intracellular signaling domain of IL-12Rβ2 as taught by Boyerinas for the IL-23R intracellular domain as taught by Floss et al. and Cao et al.; (3) including the second transmembrane domain of IL-12Rβ1 as taught by Boyerinas; and (4) including the second immune receptor intracellular signaling domain of IL-12Rβ1 as taught by Boyerinas also as taught by Floss et al. and Cao et al., to arrive at a fusion protein comprising:
a) a first polypeptide comprising:
i) a first extracellular domain comprising an extracellular domain of TGFβR2,
ii) a first transmembrane domain of IL-12Rβ1, and
iii) a first intracellular domain comprising an intracellular domain of one of IL-23R; and
b) a second polypeptide comprising:
i) a second extracellular domain comprising an extracellular domain of TGFβR1,
ii) a second transmembrane domain of IL-12Rβ1, and
iii) a second intracellular domain comprising an intracellular domain of IL-12Rβ1.
This is because Boyerinas teaches that the CTBR12 signal convertor of their invention is capable of converting an immunosuppressive TGFβ signal to an immunostimulatory signal in a T cell upon exposure to TGFβ from the tumor microenvironment thereby stimulating immune effector cell activity and function, and increasing production and/or secretion of proinflammatory cytokines (paragraphs [0243] and [0258]); Floss et al. teaches that the intracellular domains of IL-12Rβ1 and IL-23 are responsible for mediating the signaling cascades that activate and induce T cell proliferation, and therefore can be used to substitute the IL-12Rβ2/IL-12Rβ1 intracellular receptor domains of the TGFβ signal convertor construct of CTBR12 as taught by Boyerinas; and Cao et al. specifically teaches the amino acid sequences of the intracellular domains of IL-12Rβ1 and IL-23 that can substitute the IL-12Rβ2/IL-12Rβ1 intracellular receptor domains of the TGFβ signal convertor construct of CTBR12 as taught by Boyerinas.
In fact, the generation of the fusion proteins, wherein any of the domains in the fusion protein are swapped between those of the first polypeptide and the second polypeptide, is within the skill of one of ordinary skill in the art using common molecular biology techniques such that all of the formats recited in instant claim 4 a) to d) for the fusion protein can be achieved because Boyerinas, Floss et al. and Cao et al. teach all these domains as described above. As such, nucleic acids encoding the said fusion proteins, vectors that comprise said nucleic acids and engineered cells comprising said nucleic acids and fusion proteins, can also be generated through the combined methods described above.
This is an example of (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 29, wherein the nucleic acid sequence encoding the functional exogenous receptor is upstream or downstream to the nucleic acid sequences encoding the fusion protein, Boyerinas in FIG 1 teaches the polypeptide construct wherein the CAR is at the N-terminus of the CTBR12 fusion polypeptide. As such, this reflects that the nucleic acid sequence encoding the functional exogenous receptor that is a CAR is upstream to the nucleic acid sequences encoding the CTBR12 fusion protein. Therefore, using the combined methods of Boyerinas, Floss et al. and Cao et al., one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a nucleic acid wherein the nucleic acid sequence encoding the functional exogenous receptor that is a CAR is upstream to the nucleic acid sequences encoding the instant fusion protein generated by the combined method as described above to arrive at the nucleic acid of instant claim 29.
Allowable Subject Matter
Claims 15, 16, and 19 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642