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
This application was filed on 7/13/23 with claims 1-101. On 1/19/24, applicant submitted a preliminary amendment canceling claims 24-75, 77-93, and 96-101 and amending claims 15, 17, 21, and 76. Claims 1-23, 76, 94, and 95 are under examination.
Claim Objections
The examiner objects to claims 1, 94, and 95 for reciting periods other than within abbreviations or at the end of the claim. See MPEP 608.01(n).
For consistency, the examiner objects to claim 76 for referring to the nucleic acid of claim 15 as a “nucleic acid molecule.”
The examiner requests that future claim listings be formatted with double spacing between lines within each claim.
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.
Claim 4 is 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.
Claim 4 refers to a humanized mouse CD64 signal peptide. The term “humanized” in this art is generally used to refer to antibodies and those antibodies with, for example, human framework regions and complementarity-determining regions (CDRs) from another mammalian source. (See, e.g., Prendergast, 1999, USP 5958753, at column 7, lines 27-31 (reference A on PTO-892); Yu et al., US 20020006403, at paragraph 117 (reference B on PTO-892); Salmans et al., US 20200331992, at paragraph 244 (reference C on PTO-892).) The art also recognized that humanized antibody chains can contain signal sequences (Toda et al., US 20200261594, at paragraphs 681-682 (reference D on PTO-892). Skilled artisans also understood that chimeric receptors can contain humanized antigen-binding domains. (See, e.g., Trager et al., US 20210060073, at paragraphs 56-59 (reference E on PTO-892).) The art does not appear, however, to have recognized the concept of a “humanized” signal sequence within a chimeric receptor.
There is no apparent relationship between the sequence of CD64’s signal peptide in mice and in humans. The FCGR1_HUMAN sequence listing (reference U on PTO-892) identifies the sequence of human CD64’s signal sequence as MWFLTTLLLWV PVDG (residues 1-15). The FCGR1_MOUSE sequence listing (reference V on PTO-892) identifies the sequence of mouse CD64’s signal sequence as MILTSFGDDM WLLTTLLLWV PVGG (residues 1-24). A diligent search of the contemporaneous and prior art revealed no teachings as to which residues of the mouse signal sequence must be mutated, or in what way, to generate a “humanized” sequence. These sequences being disparate, and the specification providing no guidance, the skilled artisan would not have concluded that applicant possessed a chimeric receptor comprising a humanized mouse CD64 signal peptide.
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 4 and 95 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 4 refers to a “humanized” mouse CD64 signal peptide. The person of ordinary skill in the art would not have understood the scope of this limitation because there is no apparent relationship between the sequence of CD64’s signal peptide in mouse and in human. The FCGR1_HUMAN sequence listing (https://www.ncbi.nlm.nih.gov/protein/P12314.2) identifies the sequence of human CD64’s signal sequence as MWFLTTLLLWV PVDG (residues 1-15). The FCGR1_MOUSE sequence listing (https://www.ncbi.nlm.nih.gov/protein/119873) identifies the sequence of mouse CD64’s signal sequence as MILTSFGDDM WLLTTLLLWV PVGG (residues 1-24). These sequences being disparate, the skilled artisan would not have understood which mutations of mouse CD64’s signal sequence result in “humanization” and which do not. See MPEP 2173.05(a) (meaning of new terminology must be reasonably clear when read in light of specification).
Claim 95 refers to an extracellular ligand binding domain of CD64 (i.e., from any source) that comprises various domains identified by amino-acid positions. These domains lack clear antecedent basis in “an extracellular ligand binding domain of CD64” because many such domains were known as of the effective filing date. For example, skilled artisans were aware of full-length human CD64, which contains a C-strand at residues 133-139, a C’-strand at residues 142-148, and a C’E loop at residues 148-149. (See FCGR1_HUMAN sequence listing; reference U on PTO-892.) Within applicants’ SEQ ID NO:3, however (which the specification indicates is an extracellular ligand binding domain of CD64 (page 1, lines 31-33)), these human sequences correspond to residues 118-121 and 127-134. (See appendix to Office action.) In mouse CD64, the C-strand is at residues 64-69, the C’-strand is at residues 71-73, and there is no C’E loop. (See FCGR1_MOUSE sequence listing; reference V on PTO-892.) The skilled artisan would not have understood the scope of the claimed invention because there are multiple comparator sequences available for the amino-acid positions. Clarification is required. See MPEP 2173.05(b) (reference to an object that is variable renders claim indefinite when relationship between limitation and object not sufficiently defined).
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.
Claims 1, 8, 11, 15-21, 94, and 95 are rejected under 35 U.S.C. 102(a) as being anticipated by Nanjing (2019, CN 110201158; 1/19/24 IDS, foreign patent document A). Regarding claim 95, this rejection addresses the embodiment in which the extracellular binding domain of CD64 is that of human CD64 after the signal peptide has been cleaved.
Nanjing teaches a chimeric receptor comprising (A) the Fc[Symbol font/0x67]R1 extracellular region of CD64, (B) the CD8[Symbol font/0x61] hinge region, (C) the CD28 transmembrane domain, and (D) the intracellular signaling regions of 4-1BB and CD3z. (Figure 1; claims 1 and 4; see also appendix to Office action showing that Nanjing’s SEQ ID NO:1 is 100% identical to claimed SEQ ID NO:3, the extracellular ligand binding domain of CD64 (examined specification at page 1, lines 31-33).)
Regarding claims 15-20, Nanjing teaches a pCAR lentiviral vector comprising the Fc[Symbol font/0x67]R1 chimeric gene of Figure 1 (which contains the components of examined claim 1). (Paragraphs 114-117.) Regarding claim 21, Nanjing transfects this pCAR lentiviral vector into HEK293T cells. (Paragraphs 118-121.)
Claims 5 and 12-14 are rejected under 35 U.S.C. 102(a) as being anticipated by Nanjing (2019, CN 110201158; 1/19/24 IDS, foreign patent document A) as evidenced by Akinrinmade et al. (2017, Biomedicines 5: 56; 1/19/24 IDS nonpatent literature document A).
Nanjing teaches a chimeric receptor comprising (A) the Fc[Symbol font/0x67]R1 extracellular region of CD64, (B) the CD8[Symbol font/0x61] hinge region, (C) the CD28 transmembrane domain, and (D) the intracellular signaling regions of 4-1BB and CD3z. (Figure 1; claims 1 and 4; see also appendix to Office action showing that Nanjing’s SEQ ID NO:1 is 100% identical to claimed SEQ ID NO:3, the extracellular ligand binding domain of CD64 (examined specification, page 1, lines 31-33).)
Regarding claim 5, Akinrinmade is cited solely as evidence that the extracellular domain of CD64 contains D1, D2, and D3 domains. (Figure 2.) As demonstrated in the appendix to this Office action, Nanjing’s SEQ ID NO:1 is the full extracellular domain of CD64 (examined SEQ ID NO:3), so it inherently contains the D1, D2, and D3 domains.
Regarding claims 12-14, Akinrinmade is cited solely as evidence that the extracellular domain of CD64 binds IgG1 and IgG3. (Section 3 at page 4 of 18.) Nanjing’s chimeric receptor contains the extracellular domain of CD64 and therefore inherently binds IgG1 and IgG3.
Claims 1, 2, 8, 9-11, 15-22, and 94 are rejected under 35 U.S.C. 102(a) as being anticipated by Chen et al. (2017, Oncotarget 8; 37128-39; reference W on PTO-892).
Chen teaches a chimeric receptor containing a signal peptide, the extracellular domain of CD64 (i.e., examined SEQ ID NO:3), the transmembrane domain of CD28, and tandem CD28 and 4-1BB activation domains linked to a CD3z intracellular signaling domain. (Pages 37129-30.) Regarding claims 15-22, Chen teaches expressing the chimeric receptor in natural killer cells via a lentiviral vector. (Page 37130.)
Claims 5 and 12-14 are as evidenced by rejected under 35 U.S.C. 102(a) as being anticipated by Chen et al. (2017, Oncotarget 8; 37128-39) as evidenced by Akinrinmade et al. (2017, Biomedicines 5: 56; 1/19/24 IDS nonpatent literature document A).
Chen teaches a chimeric receptor containing a signal peptide, the extracellular domain of CD64, the transmembrane domain of CD28, and tandem CD28 and 4-1BB activation domains linked to a CD3z intracellular signaling domain. (Pages 37129-30.)
Regarding claim 5, Akinrinmade is cited solely as evidence that the extracellular domain of CD64 contains D1, D2, and D3 domains. (Figure 2.) Chen’s chimeric receptor contains the full extracellular domain of CD64 (examined SEQ ID NO:3), so it inherently contains the D1, D2, and D3 domains.
Regarding claims 12-14, Akinrinmade is cited solely as evidence that the extracellular domain of CD64 binds IgG1 and IgG3. (Section 3 at page 4 of 18.) Chen’s chimeric receptor contains the extracellular domain of CD64 and therefore inherently binds IgG1 and IgG3.
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.
Claims 2, 9, 10, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Nanjing (2019, CN 110201158; 1/19/24 IDS, foreign patent document A) taken in view of Chen et al. (2017, Oncotarget 8; 37128-37139; reference W on PTO-892).
Nanjing teaches a chimeric receptor comprising (A) the Fc[Symbol font/0x67]R1 extracellular region of CD64, (B) the CD8[Symbol font/0x61] hinge region, (C) the CD28 transmembrane domain, and (D) the intracellular signaling regions of 4-1BB and CD3z. (Figure 1; claims 1 and 4; see also appendix to Office action showing that Nanjing’s SEQ ID NO:1 is 100% identical to claimed SEQ ID NO:3, the extracellular ligand binding domain of CD64 (examined specification, page 1, lines 31-33).)
Nanjing does not teach that the chimeric receptor contains a signal peptide or a CD28-CD3z intracellular domain. Nanjing does not teach expressing the chimeric receptor in an immune cell.
Chen teaches a chimeric receptor containing a signal peptide, the extracellular domain of CD64, the transmembrane domain of CD28, and tandem CD28 and 4-1BB activation domains linked to a CD3z intracellular signaling domain. (Pages 37129-30.) Chen teaches expressing the chimeric receptor in natural killer cells via a lentiviral vector. (Page 37130.)
It would have been obvious to add Chen’s signal peptide to Nanjing’s chimeric receptor in order to target the receptor to the cell surface, as suggested by Chen. It would have been further obvious to include a CD28-CD3z intracellular domain in Nanjing’s chimeric receptor and to express the resulting receptor in an immune cell (e.g., a natural killer cell) because Chen teaches that chimeric receptors containing this domain are biologically active within immune cells.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (2017, Oncotarget 8; 37128-37139; reference W on PTO-892) taken in view of Osman (1992, Journal of Immunology 148: 1470-75; reference X on PTO-892 and abstract provided) and Finney (US 20090123944; reference G on PTO-892).
Chen teaches a chimeric receptor containing a signal peptide, the extracellular domain of CD64, the transmembrane domain of CD28, and tandem CD28 and 4-1BB activation domains linked to a CD3z intracellular signaling domain. (Pages 37129-30.)
Chen does not specify that the signal peptide is a mouse CD64 signal peptide.
Osman teaches that mouse Fc[Symbol font/0x67]R1 (i.e., CD64) contains a signal sequence. (Abstract (“The first and second exons encode the signal peptide”).)
Finney teaches that signal sequences function to target the extracellular region to the cell surface of a host cell. (Paragraph 9.)
It would have been obvious to select Osman’s mouse Fc[Symbol font/0x67]R1 signal sequence as the signal sequence in Chen’s chimeric receptor because Finney teaches that signal sequences target proteins to the surface of a host cell and Chen’s chimeric receptor functions at the cell surface.
Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Nanjing (2019, CN 110201158; 1/19/24 IDS, foreign patent document A) taken in view of Valamehr et al. (WO 2019/126748; reference N on PTO-892).
Nanjing teaches a chimeric receptor comprising (A) the Fc[Symbol font/0x67]R1 extracellular region of CD64, (B) the CD8[Symbol font/0x61] hinge region, (C) the CD28 transmembrane domain, and (D) the intracellular signaling regions of 4-1BB and CD3z. (Figure 1; claims 1 and 4; see also appendix to Office action showing that Nanjing’s SEQ ID NO:1 is 100% identical to claimed SEQ ID NO:3, the extracellular ligand binding domain of CD64 (examined specification, page 1, lines 31-33).)
Regarding claim 7, Nanjing does not teach a chimeric receptor with a hinge domain. Regarding claim 9, Nanjing does not teach a chimeric receptor comprising a CD28 intracellular domain.
Valamehr teaches chimeric receptors including those containing CD28 or 4-1BB intracellular domains and CD64 extracellular domains. (Paragraphs 128-129.) Valamehr teaches that chimeric receptors with CD28-costimulatory domains may contain hinge domains. (Paragraph 138.)
It would have been obvious before the effective filing date to substitute Valamehr’s CD28 intracellular domain for Nanjing’s 4-1BB intracellular domain because Valamehr teaches that both are available for use in chimeric receptors. It would have been further obvious to include a hinge domain along with the CD28 intracellular domain according to the teachings of Valamehr. One of ordinary skill would have expected success in generating such a chimeric receptor based on Valamehr’s teachings that such receptors can be constructed. Claims 7 and 9 do not require that the chimeric receptor have any particular function.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (2017, Oncotarget 8; 37128-37139; reference W on PTO-892) taken in view of Wu et al. (US 20200283501; reference F on PTO-892).
Chen teaches a chimeric receptor containing a signal peptide, the extracellular domain of CD64, the transmembrane domain of CD28, and tandem CD28 and 4-1BB activation domains linked to a CD3z intracellular signaling domain. (Pages 37129-30.) Chen teaches expressing the chimeric receptor in natural killer cells via a lentiviral vector. (Page 37130.)
Chen does not teach expressing the chimeric receptor in a T cell. Wu teaches expressing a CD64-containing chimeric receptor in NK cells or T cells. (Paragraph 53.) Wu teaches that the expression of the chimeric receptor can increase the recombinant cell's effector function in killing target cells—e.g., tumor cells and virus-infected cells—in the presence of natural and therapeutic antibodies compared to the unmodified host cell.
It would have been obvious to substitute Wu’s T cells for Chen’s NK cells as the transfection target because Wu establishes that both are suitable for expression of CD64-containing chimeric receptors. Substituting equivalents known for the same purpose would have been prima facie obvious; see MPEP 2144.06(II).
Claim 76 is rejected under 35 U.S.C. 103 as being unpatentable over Nanjing (2019, CN 110201158; 1/19/24 IDS, foreign patent document A).
The teachings of Nanjing are relied upon as above. Furthermore, Nanjing teaches that the chimeric receptor improves the therapeutic effect of antibody drugs through antibody-dependent cytotoxicity (ADCC). (Paragraph 11.) Specifically, Nanjing demonstrates ADCC with the chimeric receptor and nixtuzumab on sgc7901, HCT116 and MKN-45 cancer-cell lines. (Paragraphs 37-40 and Figure 12.)
It would have been obvious to provide Nanjing’s chimeric-receptor-expressing lentiviral vector to a subject to treat cancer because Nanjing demonstrates that the vector can produce chimeric receptor that enhances the toxicity of nixtuzumab against cancer-cell lines.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LORA E BARNHART DRISCOLL, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
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/Lora E Barnhart Driscoll/Primary Examiner, Art Unit 3991