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 .
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022,That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application-process/filing-online/legal-framework-efs-web), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Under ST.26, it is impermissible for a SEQ ID number to be used to refer to sequences having fewer than 4 amino acid residues. 37 CFR 831 is reproduced below for Applicant’s convenience (emphasis added by the Examiner).
1.831 Requirements for patent applications filed on or after July 1, 2022, having nucleotide and/or amino acid sequence disclosures.
(a) Patent applications disclosing nucleotide and/or amino acid sequences by enumeration of their residues, as defined in paragraph (b) of this section, must contain, as a separate part of the disclosure, a computer readable Sequence Listing in XML format (a "Sequence Listing XML"). Disclosed nucleotide or amino acid sequences that do not meet the definition in paragraph (b) of this section must not be included in the "Sequence Listing XML." The "Sequence Listing XML" contains the information of the nucleotide and/or amino acid sequences disclosed in the patent application using the symbols and format in accordance with the requirements of §§ 1.832 through 1.834.
(b) Nucleotide and/or amino acid sequences, as used in this section and §§ 1.832 through 1.835, encompass:
(1) An unbranched sequence or linear region of a branched sequence containing 4 or more specifically defined amino acids, wherein the amino acids form a single peptide backbone; or
(2) An unbranched sequence or linear region of a branched sequence of 10 or more specifically defined nucleotides, wherein adjacent nucleotides are joined by:
(i) A 3' to 5' (or 5' to 3') phosphodiester linkage; or
(ii) Any chemical bond that results in an arrangement of adjacent nucleobases that mimics the arrangement of nucleobases in naturally occurring nucleic acids (i.e., nucleotide analogs).
(c) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing XML" in accordance with paragraph (a) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a) ), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a) ) in the Brief Description is clear.
(d) "Enumeration of its residues" means disclosure of a nucleotide or amino acid sequence in a patent application by listing, in order, each residue of the sequence, where the residues are represented in the manner as defined in paragraph 3(c)(i) or (ii) of WIPO Standard ST.26 (incorporated by reference, see § 1.839 ).
(e) "Specifically defined" means any amino acid or nucleotide as defined in paragraph 3(k) of WIPO Standard ST.26.
(f) "Amino acid" includes any D- or L-amino acid or modified amino acid as defined in paragraph 3(a) of WIPO Standard ST.26.
(g) "Modified amino acid" includes any amino acid as described in paragraph 3(e) of WIPO Standard ST.26.
(h) "Nucleotide" includes any nucleotide, nucleotide analog, or modified nucleotide as defined in paragraphs 3(f) and 3(g) of WIPO Standard ST.26.
(i) "Modified nucleotide" includes any nucleotide as described in paragraph 3(f) of WIPO Standard ST.26.
(j) A "Sequence listing XML" must not include any sequences having fewer than 10 specifically defined nucleotides, or fewer than 4 specifically defined amino acids.
[Added 87 FR 30806, May, 20, 2022, effective July 1, 2022]
The XML sequence listing contains no data or is blank (i.e. “000”) for the LCDR2 tripeptide sequence “KVS” identified by SEQ ID NO: 14 in the claims, Table 2, and elsewhere in the Specification. While it is appropriate for the tripeptide to not appear in the sequence listing, per 37 CFR 1.831, it is impermissible for any sequence having fewer than 4 specifically defined amino acids to be defined by SEQ ID NO. As such, Applicant must remove all reference made by way of SEQ ID number for any sequence having fewer than 4 amino acids, including the tripeptide “KVS". For example, instant claim 1 must not recite “SEQ ID NO:14” but must instead just spell out the tripeptide “KVS”. Similarly, Table 2 also cannot assign SEQ ID numbers for any tripeptide sequences. Note that such changes must be made at all occurrences everywhere in the specification, including figures, drawings, and text for any amino acid sequence having less than 4 residues.
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.
Claims 33-34 and 43-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating am F77-overexpressing prostate cancer comprising administering an anti-F77 scFv antibody as part of a targeted therapy (e.g. as an antibody-drug conjugate, bispecific T cell engager, or CAR-engineered immune cell) or in combination with an anti-cancer agent, does not reasonably provide enablement for treating any prostate cancer not expressing F77 using an anti-F77 scFv antibody as a standalone or unconjugated therapy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The nature of the invention relates immunotherapies, including prostate cancer-specific antibodies, prostate cancer-specific humanized antibodies and fragments thereof (see Technical Field, Para. 0004 of the Specification).
Claim 33 is broadly drawn to a method of treating a subject with prostate cancer comprising administering an effective amount of the scFv of claim 1.
Claim 43 is broadly drawn to a method of treating a subject with prostate cancer comprising administering to the subject an effective amount of the mammalian T cell of claim 39.
The specification teaches the generation of mouse monoclonal antibody (mAb) F77 and its humanized variants (Examples 1 and 2). The humanized variant F77N76S was shown to retain the binding activity of the F77 antibody for prostate cancer cells (PC-3) (Example 3). Further, F77-specific CAR T cells effectively targeted F77 antigen expressed on prostate tumor cells and inhibited tumor growth while having little to no effect on cells having low or no F77 expression (RWPE-1, PC3 FUT1 KO, and U87 EGFRvIII) (Example 5, in particular, Para. 0172 -0191). However, the specification does not appear to provide any evidence that
1) the claimed anti-F77 scFv fragments as a standalone or unconjugated therapy can effectively treat F77-overexpressing prostate cancer in a subject or
2) the claimed anti-F77 scFv fragment either alone or as part of a targeted therapy (e.g. CAR T cell) can effectively treat prostate tumor cells that do not express F77.
Moreover, there is no guidance provided in the specification of any specific dosage regimen or amount effective to achieve a therapeutic effect using an anti-F77-scFv fragment as a standalone therapy, or any required functional characteristics of the antibody (e.g. Fc-mediated effector function such as antibody-dependent cellular cytotoxicity (ADCC), including isotype to elicit such activity).
The art teaches that unconjugated antibodies directed to tumor-associated antigens are not always effective as standalone therapies even when capable of engaging immune effector mechanisms. For example, it is reported that such antibodies produce insufficient levels of cytotoxicity in vivo and are not curative. As such, unconjugated antibodies specific for tumor associated antigens are more effective in combination therapies and/or repurposed as a targeted therapy such as conjugated/engineered formats (e.g. immunoconjugates which facilitate delivery of potent cytotoxic agents) (Wagoner et al, Abstract and Section 6: Strategies to Overcome ADCP Limitations; and Smaglo et al, Abstract). Thus, at the time of filing, it had not been established that merely targeting tumor-associated antigens with unconjugated antibodies predictably results in therapeutic benefit.
Additionally, the art does not teach that anti-F77 scFv antibodies either alone or as a part of a targeted therapy (e.g. the CAR T cell of claim 43) can effectively target other antigens on prostate tumor cells. Indeed, as discussed above, the specification demonstrates that the claimed anti-F77 CAR T cells did not effectively target or kill cells having low or no expression of F77. Thus, the claimed anti-F77 scFv antibodies/CAR T cells do not predictably target other antigens on prostate tumor cells absent of evidence provided in the specification or taught by the art.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering and oncology. Even at this high level of skill, in the absence of further guidance, artisans would have to engage in undue trial-and-error experimentation (e.g. in vitro functional assays and animal tumor models) to determine whether 1) the unconjugated antibodies encompassed by the claims can effectively treat an F77-overexpressing prostate cancer in a subject and 2) the F77-specific scFv CAR T cells can target other antigens besides F77.
Claims 34 and 44-47 depend either directly on either claim 33 or 43 but do not cure the deficiencies of either claim and thus are also rejected.
Therefore, the specification is not enabling over the full scope of the claims.
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 1, 5, 7-14, 18, 20, 21, 23-27, 29-30, 33-41, and 43-47 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.
Regarding claims 1 and 14, the XML sequence listing contains no data or is blank (i.e. “000”) for the light chain CDR2 tripeptide sequence “KVS” identified by SEQ ID NO: 14 . Thus, it is unclear to artisans which meaning --- “000” or “KVS”--- should be assigned to SEQ ID NO: 14 as it cannot have both. Thus, the metes and bounds of patent protection desired cannot be readily determined. Claims 5, 7-13, 18, 20, 21, 23-27, 29-30, 33-41, and 43-47 incorporate limitations of either claim 1 or claim 14 but do not cure the 112(b) deficiencies of these claims and are thus also rejected.
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.
(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, 5, 23, 24, and 33 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Greene et al (US20140348831A1), hereinafter Greene.
Greene discloses antibodies that target prostate cancer lipid-like antigen (PCLA) on prostate cancer cells, wherein the anti-PCLA antibody is, for example, the mouse monoclonal antibody clone F77 comprising a VL chain of SEQ ID NO: 1 and a VH chain of SEQ ID NO: 4 (Abstract, Summary: Para. 0007, and Para. 0071). The VL chain of SEQ ID NO: 1 fully comprises the light chain CDRs of SEQ ID NOs: 12, 14, and 15 recited in the instant claims; and the VH chain of SEQ ID NO: 4 fully comprises the heavy chain CDRs of SEQ ID NOs: 8, 9, and 11 recited in the instant claims. In some embodiments, the anti-PCLA antibodies are “functional fragments” such as Fab and scFv (Para. 0009, Para. 0029, and Para. 0067). The anti-PCLA antibodies or functional fragments thereof can also be humanized (Para. 0009 and Para. 0029). In other embodiments, the antibody functional fragment includes chimeric fusions between antibody chains and other molecules (Para. 0067). Methods for treating PCLA-associated prostate cancer comprising administering to the subject a pharmaceutical composition comprising an effective amount of the anti-PCLA antibody or antigen-binding fragment thereof are also disclosed (Abstract, Para. 0009, Para. 0024, and Para. 0027).
Thus, Greene meets the limitations of instant claims 1, 5, 23, 24, and 33.
VH chain of F77 anti-PCLA antibody (SEQ ID NO: 4) fully comprises the heavy chain CDRs of SEQ ID NOs: 8, 9, and 11 recited in the instant claims.
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VL chain of F77 anti-PCLA antibody (SEQ ID NO: 1) fully comprises the light chain CDRs of SEQ ID NOs: 12, 14, and 15 recited in the instant claims.
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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.
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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Greene, as applied to claims 1, 5, 23, 24, and 33 above, and further in view of Chen et al (US20120082666A1), hereinafter Chen.
The teachings of Greene have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the scFv comprises the heavy chain framework regions at least 95% identical to the framework regions of SEQ ID NOs: 23 or 24.
However, Chen teaches therapeutic antibodies comprising a human VH3 framework region of SEQ ID NO: 53 which fully comprises the framework regions of SEQ ID NO: 24 (Abstract and Para. 0045). Humanization of said antibodies is achieved by incorporating this human framework region (Para. 0304).
It would have been obvious to one of ordinary skill in the art to modify the anti-F77 scFv antibody disclosed by Greene such that it comprises the human VH3 framework (FW) of SEQ ID NO: 53 disclosed by Chen. One of ordinary skill in the art would have been motivated to do so since Chen discloses this framework region as suitable for use in humanizing therapeutic antibodies. Further, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would have reasonably expected that the anti-F77 scFv disclosed by Greene having the human VH3 framework of SEQ ID NO: 53 disclosed by Chen can effectively treat prostate cancer in a human subject.
VH3 human framework (FW) of SEQ ID NO: 53 disclosed in the prior art fully comprises the framework regions of SEQ ID NO: 24 recited in the instant claims.
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Claims 8-11, 25-27, 29-30, 35-41, 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Greene, as applied to claims 1, 5, 23, 24, and 33 above, and further in view of Wiltzius et al (US20170283500A1), hereinafter Wiltzius.
The teachings of Greene have been discussed above and differ from the instantly claimed invention in that chimeric antigen receptors comprising the anti-PCLA antibody or antigen-binding fragment thereof are not specifically taught, wherein the CAR comprises an scFv antigen binding domain, transmembrane domain, signal transduction domain, and a costimulatory domain.
However, Wiltzius teaches that chimeric antigen receptors (CARs) endow engineered cells with antigen specificity while enhancing their ability to recognize and kill a target cell (Para. 0010). The CAR generally comprises a fusion of an antigen-binding domain, extracellular domain, a transmembrane domain, one or more costimulatory domains, and one or more activating domains (Para. 0010). The antigen binding molecule is an scFv fragment or a Fab fragment (Para. 0076, Para. 0132, Para. 0151, and Para. 0162). The linker present between the VH and VL domains of the antigen binding molecule can be the Gly-Ser linker GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 145, corresponding to SEQ ID NO: 25 of the instant claims) (Para. 0036). The antigen binding molecule can target a tumor associated antigen (Para. 0148). The transmembrane domain can be a CD8 transmembrane domain of SEQ ID NO: 14 having 100% sequence identity to SEQ ID NO: 48 of the instant claims; or a CD28 transmembrane domain of SEQ ID NO: 6 having 100% sequence identity to SEQ ID NO: 50 of the instant claims (Para. 0116-0120). The costimulatory domain can be a 4-1BB costimulatory domain of SEQ ID NO: 142 having 100% sequence identity to SEQ ID NO: 49 of the instant claims (Para. 0022-0023 and Para. 0098); or a CD28 costimulatory domain of SEQ ID NO: 8 having 100% sequence identity to SEQ ID NO: 51 of the instant claims (Para. 0022, Para. 0024, Para. 0077-0078, Para. 0090-0091, and Para. 0098). The intracellular signaling domain can be a CD3 zeta signaling domain of SEQ ID NO: 10 or SEQ ID NO: 146 having 100% identity to SEQ ID NOs: 53 and 52, respectively, as recited in the instant claims (Para. 0099-0102 and Para. 0293). Further disclosed are polynucleotides encoding the chimeric antigen receptors, and vectors comprising the polynucleotides. In some embodiments, the vector is a lentiviral vector (such as pGAR) (Para. 0027). Suitable host cells comprising the vector for expression and cloning of the polynucleotide include, without limitation, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells such as mammalian cells (Para. 0225). In some embodiments, an expression vector carrying the coding sequence of a chimeric receptor as disclosed herein can be introduced into a population of human donor T cells, NK cells or NKT cells (Para. 0223). Lastly disclosed are methods for treating cancer in a subject comprising administering an engineered cell expressing a chimeric antigen receptor that targets a tumor associated antigen (Para.0201-0205). Target doses for CAR T cells can range from 1×106—2×10 cells/kg or, more preferably, 2×106 cells/kg. Doses above and below this range may be appropriate for certain subjects, and appropriate dose levels can be determined by the healthcare provider as needed (Para. 0204).
It would have been obvious to one of ordinary skill in the art to modify the anti-F77 scFv chimeric proteins disclosed by Greene such that the chimeric proteins are chimeric antigen receptors having an anti-F77 specific antigen-binding domain. One of ordinary skill in the art would have been motivated to do so because chimeric antigen receptors (CARs) can effectively target a tumor-associated antigen and kill tumor cells as taught by Wiltzius. Further, Wiltzius discloses several transmembrane, costimulatory, and signaling/activating domains having the amino acid sequences recited in the instant claims and identifies these domains as suitable for use in CARs. Additionally, artisans would have been motivated to provide lentiviral vectors comprising a nucleic acid sequence encoding the F77-specific CAR and human T cells in order to generate CAR T cells as taught by Wiltzius. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation optimal dosages of mammalian T cells to administer to a subject in order to arrive at the embodiments recited in the instant claims. Therefore, one of ordinary skill in the art would have reasonably expected that CAR T cells comprising an anti-F77 specific scFv to effectively treat prostate cancer in a subject.
CD8 TM domain: SEQ ID NO: 48 (instant claims) vs SEQ ID NO: 14 (prior art).
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4-1BB costimulatory domain: SEQ ID NO: 49 (instant claims) vs SEQ ID NO: 142 (prior art)
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CD3zeta signaling domain: SEQ ID NO: 52 (instant claims) vs SEQ ID NO: 146 (prior art)
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CD28 TM domain: SEQ ID NO: 50 (instant claims) vs SEQ ID NO: 6 (prior art).
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CD28 costimulatory domain: SEQ ID NO: 51 (instant claims) vs SEQ ID NO: 8 (prior art)
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CD3zeta signaling domain: SEQ ID NO: 53 (instant claims) vs SEQ ID NO: 10 (prior art)
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Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Greene in view of Wiltzius, as applied to claims 1, 5, 8-11, 23-27, 29-30, 33, 35-41, 43-46 above, and further in view of Orentas et al (US20160053017A1), hereinafter Orentas.
The teachings of Greene in view of Wiltzius have been discussed above and differ from the instantly claimed invention in that it is not taught that the costimulatory domain comprises the amino acid sequence of either SEQ ID NO: 42 or SEQ ID NO: 43.
However, Orentas discloses chimeric antigen receptors having an intracellular domain of SEQ ID NO: 73 or 74 (Para. 0048 and 0050). The intracellular domain of SEQ ID NO: 73 fully comprises the CD28zeta (CD28 + CD3 zeta) costimulatory domain of SEQ ID NO: 43 recited in the instant claims. The intracellular domain of SEQ ID NO: 74 fully comprises the 4-1BBzeta (4-1BB + CD3 zeta) costimulatory domain of SEQ ID NO: 42 recited in the instant claims.
It would have been obvious to one of ordinary skill in the art to modify the F77-specific CAR T cell disclosed by Greene in view of Wiltzius such that costimulatory and activating/signaling domains are substituted with a 4-1BBzeta or CD28zeta disclosed by Orentas. One of ordinary skill in the art would have been motivated to do so since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would reasonably expect that the F77-specific CAR T cells disclosed by Greene in view of Wiltzius comprising a 4-1BBzeta or CD28zeta costimulatory/signaling domain disclosed by Orentas to effectively treat a subject having prostate cancer.
The intracellular domain of SEQ ID NO: 74 fully comprises the 4-1BBzeta (4-1BB + CD3 zeta) costimulatory domain of SEQ ID NO: 42 recited in the instant claims.
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The intracellular domain of SEQ ID NO: 73 fully comprises the CD28zeta (CD28 + CD3 zeta) costimulatory domain of SEQ ID NO: 43 recited in the instant claims.
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Claims 34 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Greene in view of Wiltzius, as applied to claims 1, 5, 8-11, 23-27, 29-30, 33, 35-41, 43-46 above, and further in view of Markman (Markman, Mauri. "Prostate Cancer Stages." Cancer Center, City of Hope, 23 June 2022, webpage).
The teachings of Greene in view of Witzius have been discussed above and differ from the instantly claimed invention in that it is not taught that the subject treated with the anti-F77 scFv antibody or F77-specific chimeric antigen receptor has stage I-IV prostate cancer.
However, Markman teaches that to determine the appropriate treatment for cancer, practitioners need to know how far the cancer has progressed, or its stage. Identifying the stage of cancer not only helps the care team determine a treatment plan, it also helps predict a potential prognosis. Stage 1 is assigned to early-stage prostate cancer when the cancer cells are still localized to the prostate, meaning they have not spread outside of the prostate gland. Stage 2 prostate cancer means the cancer has not spread outside the prostate gland, but it's more at risk of growing than cancers in stage 1. Stage 3 prostate cancer refers to a locally advanced cancer, which means the cancer cells have spread outside their site of origin. The tumor has progressed and is more likely to grow and spread, with results showing a high Gleason score and elevated PSA levels. Stage 4 prostate cancer is an advanced-stage prostate cancer that has spread (metastasized) to distant sites or to the lymph nodes (see entire document).
It would have been obvious to one of ordinary skill in the art to modify the method of treating prostate cancer in a subject with the F77-specific CAR T cell disclosed by Greene and Wiltzius such that the subject has stage I-IV prostate cancer as taught by Markmann. One of ordinary skill in the art would have been motivated to do so since subjects having stage I-IV prostate cancer represent a patient population that would benefit from therapeutic intervention with the F77-specific CAR T cells taught by Greene in view of Wiltzius. Further, determining the prostate cancer stage helps guide treatment decisions and predict overall prognosis as taught by Markman. Therefore one of ordinary skill in the art would reasonably expect that the F77-specific CAR T cells disclosed by Greene in view of Wiltzius can effectively treat a subject having stage I-IV prostate cancer.
Claims 14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Greene et al (US20140348831A1), hereinafter Greene, in view of Sivelle et al (Sivelle, Coline et al. “Fab is the most efficient format to express functional antibodies by yeast surface display.” mAbs vol. 10,5 (2018): 720-729. doi:10.1080/19420862.2018.1468952), hereinafter Sivelle.
Greene discloses antibodies that target prostate cancer lipid-like antigen (PCLA) on prostate cancer cells, wherein the anti-PCLA antibody is, for example, the mouse monoclonal antibody clone F77 comprising a VL chain of SEQ ID NO: 1 and a VH chain of SEQ ID NO: 4 (Abstract, Summary: Para. 0007, and Para. 0071). The VL chain of SEQ ID NO: 1 fully comprises the light chain CDRs of SEQ ID NOs: 12, 14, and 15 recited in the instant claims; and the VH chain of SEQ ID NO: 4 fully comprises the heavy chain CDRs of SEQ ID NOs: 8, 9, and 11 recited in the instant claims. In some embodiments, the anti-PCLA antibodies are “functional fragments” such as Fab (Para. 0009, Para. 0029, and Para. 0067). The anti-PCLA antibodies or functional fragments thereof can also be humanized (Para. 0009 and Para. 0029).
Greene does not specifically disclose that the humanized anti-F77 Fab is an single-chain Fab (scFab).
However, Sivelle teaches that single chain Fab (scFab) derived from Fab is obtained through introduction of a polypeptide linker connecting the light chain and the heavy chain. Thus, it combines some advantages of the scFv (single chain and one expression plasmid, level of expression) with the stability and lower tendency to aggregate of the Fab. The linker prevents the display of unpaired heavy chain antibodies (devoid of light chain), which can sometimes interfere with the selection steps. (see 5th paragraph of Introduction).
It would have been obvious to modify the anti-F77 Fab fragment disclosed by Greene such that that Fab is a single-chain Fab (scFab) molecule. One of ordinary skill in the art would have been motivated to do so since scFabs combine advantages of scFv fragments (single chain and one expression plasmid, level of expression) with the stability and lower tendency to aggregate of the Fab as taught by Sivelle. Therefore, one of ordinary skill in the art would reasonably expect an anti-F77 scFab to be able to effectively treat prostate cancer in a subject.
VH chain of F77 anti-PCLA antibody (SEQ ID NO: 4) fully comprises the heavy chain CDRs of SEQ ID NOs: 8, 9, and 11 recited in the instant claims.
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VL chain of F77 anti-PCLA antibody (SEQ ID NO: 1) fully comprises the light chain CDRs of SEQ ID NOs: 12, 14, and 15 recited in the instant claims.
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Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Greene in view of Sivelle, as applied to claims 14 and 18 above, and further in view of Chen et al (US20120082666A1), hereinafter Chen.
The teachings of Greene in view of Sivelle have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the humanized scFab comprises the heavy chain framework regions at least 95% identical to the framework regions of SEQ ID NOs: 23 or 24.
However, Chen teaches therapeutic antibodies comprising a human VH3 framework region of SEQ ID NO: 53 which fully comprises the framework regions of SEQ ID NO: 24 recited in the instant claims (Abstract and Para. 0045). Humanization of murine antibodies can be achieved by incorporating this human framework region (Para. 0304).
It would have been obvious to one of ordinary skill in the art to modify the humanized anti-F77 scFab antibody taught by Greene in view of Sivelle such that it comprises the human VH3 framework (FW) of SEQ ID NO: 53 disclosed by Chen. One of ordinary skill in the art would have been motivated to do so since Chen discloses this framework region as suitable for use in the humanization of murine antibodies. Further, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Therefore, one of ordinary skill in the art would have reasonably expected that the humanized anti-F77 scFab taught by Greene in view of Sivelle having the human VH3 framework of SEQ ID NO: 53 disclosed by Chen can effectively treat prostate cancer in a human subject.
VH3 human framework (FW) of SEQ ID NO: 53 disclosed in the prior art fully comprises the framework regions of SEQ ID NO: 24 recited in the instant claims.
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Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Greene in view of Sivelle, as applied to claims 14 and 18 above, and further in view of Zhang et al (US20210040197A1), hereinafter Zhang.
The teachings of Greene in view of Sivelle have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the linker present in the anti-F77 scFab has the amino acid sequence of SEQ ID NO: 25 or 26.
However, Zhang teaches that single chain Fabs (scFabs) comprise a linker that is preferably at least 30 amino acids in length, and in certain aspects between 32 and 50 amino acids (Para. 0262). Exemplary linkers that can be used in scFabs include flexible glycine-serine linkers, including 4, 5, 6, or more repeats of G4S (SEQ ID NO: 3) (see Section 6.2.3, particularly Para. 0273-0274). The linkers of SEQ ID NOs: 25 and 26 recited in the instant claims are 4 and 6 repeats of G4S, respectively.
It would have been obvious to one of ordinary skill in the art to modify the anti-F77 scFab taught by Greene in view of Sivelle such that the flexible linker present between the VH and VL domains is 4 or 6 repeats of the glycine-serine linker G4S disclosed by Zhang. One of ordinary skill in the art would have been motivated to do so since Zhang teaches that scFabs comprise a linker that is preferably at least 30 amino acids in length and points to exemplary linkers suitable for use in scFabs, including, for example, 4 or 6 repeats of the glycine-serine linker G4S. Therefore, one of ordinary skill in the art would reasonably expect that anti-F77 scFabs comprising 4 or 6 repeats of G4S to be suitable for use in treating prostate cancer in a subject.
Conclusion
Claim 22 is allowable. Claims 2-4,6,15-17,19,28,31-32 and 42 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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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