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 .
Election/Restrictions
Claims 62-74 and 98-117 are pending and are examined.
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. This application is a Continuation of U.S. Patent Application No. 16/821,674 (now U.S. Patent No. 11,702,472), filed March 17, 2020, which is a Divisional of U.S. Patent Application No. 15/368,278 (now U.S. Patent No. 10,633,441), filed December 2, 2016, which is a Continuation of International Patent Application No. PCT/US2015/034552, filed June 5, 2015, which claims priority to U.S. Provisional Patent Application Serial No. 62/008,851, filed June 6, 2014.
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 62-74 and 98-117 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 increasing immune-activating cytokine production in response to a cancer cell that expresses mesothelin, does not reasonably provide enablement for a generic “cancer cell”. 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 claims are drawn to a method of increasing immune-activating cytokine production in response to a cancer cell, comprising administering an effective amount
of immunoresponsive cells comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain is characterized by a specific 6 CDR set.
Thus, from the onset, it is clear that, in order for the specific claimed effect to be produced (“increasing immune-activating cytokine production”) the immunoresponsive cell which carries the CAR necessarily needs to interact with the cognate ligand to the extracellular antigen-binding domain. Absent this interaction, the effect would not be noticed.
Not all cancer cells express mesothelin on their surface. For instance Frierson et al. (Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas. Hum. Pathol. 34, 605-609, 2003) shows that a limited number of cancer types are expressing mesothelin at various levels (table 1 and Discussion section). Thus, considering that more than ~200 cancer types are known, this does not constitute a representative number of species of the cancer genus claimed. Trying to obtain the effect claimed in absence of the cognate ligand (mesothelin) would be extremely improbable and skilled artisan would be forced to perform an enormous amount of experimentation with no expectation of success. Therefore, this amount of experimentation is considered undue and the Application is enabled only for cases in which the cancer cell express mesothelin on their surface.
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.
Claims 62-64 and 99-103 are rejected under 35 U.S.C. 103 as being unpatentable over Lanitis et al. (Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. Mol. Ther. 20, 633–643, 2012) in view of Dimitrov et al. (U.S. Pat. No. 8,357,783).
The claims are drawn to a method of increasing immune-activating cytokine production in response to a cancer cell in a subject, comprising administering an effective amount of immunoresponsive cells comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain specifically binds to human mesothelin comprises:
(a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEO ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEO ID NO: 12, and a CDR3 comprising the amino acid sequence set forth in SEO ID NO: 13; and
(b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEO ID NO: 14, a CDR2 comprising the amino acid sequence set forth in SEO ID NO: 15, and a CDR3 comprising the amino acid sequence set forth in SEO ID NO: 16. The heavy chain variable region comprises an amino acid sequence that is at least about 95% identical to amino acids 1-119 of SEQ ID NO: 1, wherein SEQ ID NOS: 11-13 are invariable; and/or (b) the light chain variable region comprises an amino acid sequence that is at least about 95% identical to amino acids 1-107 of SEQ ID NO: 3, wherein SEQ ID NOS: 14-16 are invariable. The extracellular antigen-binding domain comprises a human single-chain variable fragment (scFv). A linker is also positioned between the heavy chain variable region and the light chain variable region. The immune-activating cytokine is selected from the group consisting of (GM-CSF), IFN- α, IFN-β, IFN-γ, TNF-α, IL-2, IL-3, IL-6, IL-11, IL-7, IL-12, IL-15, IL-21, and interferon regulatory factor 7 (IRF7).
Lanitis et al. teach an anti-mesothelin (P4 scFv) chimeric receptor expressed in T cells. Lanitis teach that human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors.(Lanitis et al, abstract). The P4 CAR T cells control large, well-established tumors in immunodeficient mice. First generation CAR possessing only CD3z signaling had modest impact on tumor outgrowth in vivo, while second generation CAR comprising CD3z fused to a CD28 costimulatory domain mediated tumor regression in vivo. Primary human T-cells expressing a fully human CAR-targeting mesothelin are highly effective in response controlling large, well-established tumors (p. 640, discussion section).
While Lanitis et al. teach P4 scFv. They do not teach an anti-mesothelin antibody comprising SEQ ID NOs: 11-13 in the heavy variable region and SEQ ID NOs: 14-16 in the light variable region.
Dimitrov et al. teach human monoclonal antibodies that specifically bind human mesothelin with a binding affinity of about 25 nM or less. Methods of treating a subject with cancer are also disclosed. The human monoclonal antibodies bind mesothelin with a dissociation constant (Kd) of about 25 nM or less. In one embodiment, the Kd is about 20 nM or less. In another embodiment, the Kd is about 5 to about 10 nM. In some embodiments, the human monoclonal antibodies are Fab fragments and Fab m912 was converted to scFv and IgG formats, and tested for binding to cells by flow cytometry. It was found that m912 in both formats, scFv and IgG1, can bind specifically to cell surface-associated mesothelin (Figs. 2C and 3A; col. 2, lines 18-30).
The CDR sequences (and the variable heavy domain and variable light domain
sequences) claimed in the instant Application are identical with the sequences in the Patent for the monoclonal antibody m912 (Col. 38).
Since the properties of the antibody are conferred by the complete set of the CDRs and since the sequences are the same, inherently the antibody of the patent has the same properties as the antibody of the mesothelin binding protein of the instant Application.
It would have been obvious for a person of ordinary skill in the art at the time that
the invention was filed to have used the teachings of Lanitis et al. with the antibody of Dimitrov et al. to obtain a mesothelin targeting CAR with a reasonable expectation of success. This is because substituting antibodies that bind to targets in CAR construct is routine in the art. (See for example, Lanitis et al., Figure 1, which shows the structures of CAR constructs for mesothelin and CD19). One would have done so because Dimitrov et al. teaches that their antibody binds mesothelin with high affinity.
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Lanitis et al. in view of Dimitrov et al. (both cited supra) and in further view of Chen et al. (Fusion protein linkers: Property, design and functionality. Adv. Drug Del. Reviews).
The claim adds the limitation that a linker is positioned between the heavy chain
variable region and the light chain variable region of the extracellular antigen binding domain of the CAR, a linker comprising the amino acid sequence set forth in SEQ ID NO: 17 (GGGGS)3.
The teachings of Lanitis et al. and Dimitrov et al. were presented supra. While Lanitis mentions a generic linker (Fig. 1), Dimitrov indicated a GGGGS linker (SEQ ID NO: 8).
Chen et al., reviewing the state of the art, indicate that (GGGGS)3 is a routinely used linker for scFv because increases stability and folding (table 3).
It would have been obvious for a person of ordinary skill in the art at the time that
the invention was filed to have used the teachings of Chen et al., combined with the disclosures of Lanitis et al. and Dimitrov et al. to obtain a mesothelin targeting CAR comprising a (GGGGS)3 in the extracellular antigen-binding domain with a reasonable expectation of success. This is because Dimitrov already used the single module GGGGS and using 3 module would have offered stability and flexibility as indicated by Chen et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 62-74 and 98-117 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No.11,702,472. Although the claims at issue are not identical, they are not patentably distinct from each other because by performing the method of the U.S. Patent a skilled artisan would actually perform the methods of the instant Application.
Claims 61, 99, 100, 111 and 112 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-24 and 28 of the of U.S. Patent No. 10,538,588 (‘588 Patent) in view of Powell et al. (WO2013063419 – cited by Applicant).
The claims are drawn to a method of increasing immune-activating cytokine production in response to a cancer cell, comprising administering an effective amount of immunoresponsive cells comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain specifically binds to human mesothelin and comprises
(a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEO ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEO ID NO: 12, and a CDR3 comprising the amino acid sequence set forth in SEO ID NO: 13; and
(b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEO ID NO: 14, a CDR2 comprising the amino acid sequence set forth in SEO ID NO: 15, and a CDR3 comprising the amino acid sequence set forth in SEO ID NO: 16. The binding domain also may comprise (a) the heavy chain variable region comprises an amino acid sequence that is at least about 95% identical to amino acids 1-119 of SEQ ID NO: 1, wherein SEQ ID NOS: 11-13 are invariable; and/or (b) the light chain variable region comprises an amino acid sequence that is at least about 95% identical to amino acids 1-107 of SEQ ID NO: 3, wherein SEQ ID NOS: 14-16 are invariable. The cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a pluripotent stem cell from which a lymphoid cell may be differentiated.
The ’588 Patent claims an immunoresponsive cell comprising the a chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain, a transmembrane domain and an intracellular domain, wherein the extracellular antigen-binding domain comprises a single-chain variable fragment (scFv), wherein the scFv comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:11, (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:12, (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:13, (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:14, (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:15, and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:16. The immunoresponsive cell of claim 21, wherein the immunoresponsive cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a human embryonic stem cell, and a pluripotent stem cell from which lymphoid cells may be differentiated. Also claimed is a pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 21 and a pharmaceutically acceptable excipient.
The ‘588 patent is silent about using the immunoresponsive cell for increasing the immune-activating cytokine production in response to a cancer cell.
Powell et al. disclosed a genetically modified cell comprising an isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the isolated nucleic acid sequence comprises the sequence of a human mesothelin binding domain and the nucleic acid sequence of a CD3 zeta signaling domain; the genetically modified cell is a T cell that exhibits an antitumor immunity when the cell is cross-linked with a mesothelin protein (p. 3) . The reference also provides a method of providing an anti-tumor immunity in a mammal, the method comprising administering to the mammal an effective amount of a genetically modified cell comprising an isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the isolated nucleic acid sequence comprises the sequence of a human mesothelin binding domain and the nucleic acid sequence of a CD3 zeta signaling domain (p.4). The anti-tumor immunity response elicited by the CAR-modified T cells may be an active or a passive immune response. The fully-human CAR transduced T cells exhibit specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing the mesothelin (p.5; fig 2).
It would have been obvious for a person of ordinary skill in the art at the time that the invention was filed to increase immune-activating cytokine production in response to a mesothelin expressing cancer cell as taught by Powell et al. with a CAR comprising the antigen binding domain as described in the ‘588 Patent with a reasonable expectation of success. This is because a skilled artisan would have used known and tested constructs for solving an existent problem. A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Conclusion
No claims are allowed.
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ELLY-GERALD STOICA
Primary Examiner
Art Unit 1647
/Elly-Gerald Stoica/ Primary Examiner, Art Unit 1647