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 .
Claim Status
Claims 4-25, 29-50, 52-53, 56-63, 65, 73-95, and 97-101 are cancelled. Claims 1-3, 26-28, 51, 54-55, 64, 66-72, 96, and 102-103 as filed on are pending and under examination.
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 1-3, 26-28, 51, 54-55, 64, 66-72, 96, and 102-103 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 1 is to a CAR comprising an anti-CCR4 antigen binding domain, a transmembrane domain, and an intracellular domain. The claim does not define any of the antigen binding domain sequence.
Claim 26 is to a nucleic acid that encodes a CAR comprising an anti-CCR4 antigen binding domain, a transmembrane domain, and an intracellular domain. The claim does not define any of the antigen binding domain sequence.
Claim 54 is to a modified immune cell or precursor thereof that comprises the a CAR comprising an anti-CCR4 antigen binding domain, a transmembrane domain, and an intracellular domain. The claim does not define any of the antigen binding domain sequence.
Claim 64 is to a method of generating a CAR by introducing a nucleic acid that encodes a CAR comprising an anti-CCR4 antigen binding domain, a transmembrane domain, and an intracellular domain. The claim does not define any of the antigen binding domain sequence.
Claim 66 is to a method of treating cancer in a subject by administering a modified immune cell or precursor thereof that comprises the a CAR comprising an anti-CCR4 antigen binding domain, a transmembrane domain, and an intracellular domain. The claim does not define any of the antigen binding domain sequence.
Claims 2, 27, and 71 requires one of the HCDRs of the claims is SEQ ID NO: 2, 4, or 6.
Claims 3, 28, and 72 requires one of the LCDRs of the claims is SEQ ID NO: 8, 10, or 12.
The dependent claims 26, 51, 55, 67-70, 96, and 102-103 do not have any limitations for the sequence of the antigen binding domain of the CAR.
None of the claims require all three CDRs of the heavy or light chain and none of the claims require a full set of six CDRs.
Summary of Species Disclosed in the original specification
Applicant discloses one CCR4 antigen binding domain comprising the HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 4, and HCDR3 of SEQ ID NO: 6, with LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 12 (Table 1).
State of the Relevant Art
Cc-chemokine Receptor 4 (CCR4) is a G protein-coupled seven transmembrane domain chemokine receptor that binds multiple chemokines. It is highly expressed by many T cell malignancies including lymphoma and leukemia and its activity is associated in phagocytosis and inflammation (Gunnarsson (US 20100310464 A1) (PTO-892) ([0005]-[0008]). CCR4 plays a crucial role in normal and tumor immunity with a known role in inhibiting tumor specific immunity in cancer patients ([0008]).
Chimeric Antigen Receptors (CARs) comprise an antigen binding domain which binds a target based on the CDRs of the variable heavy and variable light chain of the scFv of the CAR Marasco (US 20170362297 A1) (IDS) (Figure 2a, [0042], [0049]).
It is well known in the art that antigen binding of the scFv of the CAR have their binding activity from the same structure as traditional antibodies. A traditional antibody comprises a variable heavy and variable light chain which each comprise 3 CDRs which are the HCDR1, HCDR2, and HCDR3 in the variable heavy chain and LCDR1, LCDR2, and LCDR3 in the variable light chain. It is the CDRs that form an intact antigen-binding site in an antibody which contain the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1).
The skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al., Proc. Nat’l Acad. Sci. USA, 79:1979-83 (1982) (PTO-892). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. E.g., Abstract. Similarly, Brown et al., J. Immunol., 156(9):3285-91 (1996) (PTO-892), teach that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. These older citations are supported my more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Marvin” PTO-892) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
The earlier work of Rudikoff and Brown is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (“Chiu” PTO-892). Chiu teaches that the complementarity- determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary
structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last
paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3,
HCDR1 and HCDR2 could not predict HCDR3 In the decades since Rudikoff the field
has increased understanding of antibody engineering. Structure-Based antibody
engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in
Section 2 in particular second paragraph of page 11). Chiu notes the advancement in
antibody engineering but notes it is still not possible to predict the point mutations that
would improve affinity in antibodies (Page 51 in lines 6-12).
In general, absent at least the conserved structure of the CDRs of the heavy chain and light chain of an antibody, the skilled artisan would not be able to visualize or otherwise predict an antibody with a particular set of functional properties would look like structurally.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses one combination of six CDRs that binds CCR4.
As shown in the art changes to a single amino acid in one CDR of an antibody or antigen binding domain would result in unpredictable changes to the binding activity. The disclosure of a single antigen binding CDR set is only representative of that species of the genus. The disclosure by the applicant cannot be considered representative of the genus of all scFv that bind CCR4.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
The function of an antigen binding domain is binding its target antigen. This function comes from its unique combination of CDRs. The structure function correlation of a set of CDRs exists only for the combination disclosed it does not provide a structure/function correlation for any other set of CDRs even ones with only a single amino acid changed. The applicant has provided one structure with the known function of binding CCR4.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the countless antigen binding domains encompassed by the claims that meet the highly general structural requirements of the claims would also possess the required functional activity. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of compositions as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
None of the claims are limited to the scFv disclosed by applicant. Limiting the claims to a CAR comprising the heavy and light CDRs of HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 4, and HCDR3 of SEQ ID NO: 6, with LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 12 would overcome this rejection.
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, 26, 51, 54, 64, 66-67, 70, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Marasco (US 20170362297 A1) (IDS).
Regarding claim 1, Marasco teaches a CAR comprising an antigen-binding domain, a transmembrane domain, and an intracellular domain (claim 1) where the antigen binding domain binds CCR4 (claim 9 and Figure 1).
Regarding claims 26, 51, 54, Marasco teaches a vector comprising a nucleic acid encoding an anti-CCR4 CAR and the expression of that vector in a genetically engineered cell ([0008] and claims 11-20). Marasco further teaches a modified immune cell comprising the CAR ([0041]-[0042]).
Regarding claim 64, Marasco teaches the generation of a modified immune cell by introducing a vector encoding the CAR ([0108]).
Regarding claims 66 and 70, Marasco teaches the administration of the modified T cells for the treatment of cancer (0141]-[0147]).
Regarding claims 67 and 96, the method of administering the CAR T cells of Marasco would inherently have this biological activity.
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 1-3, 26-28, and 70-72 are rejected under 35 U.S.C. 103 as being unpatentable over Marasco (US 20170362297 A1) (IDS) and Gunnarsson (US 20100310464 A1) (PTO-892).
Regarding claim 1, Marasco teaches a CAR comprising an antigen-binding domain, a transmembrane domain, and an intracellular domain (claim 1) where the antigen binding domain binds CCR4 (claim 9 and Figure 1).
Regarding claim 26, Marasco teaches a vector comprising a nucleic acid encoding an anti-CCR4 CAR and the expression of that vector in a genetically engineered cell ([0008] and claims 11-20). Marasco further teaches a modified immune cell comprising the CAR ([0041]-[0042]).
Regarding claim 70, Marasco teaches the administration of the modified T cells for the treatment of cancer (0141]-[0147]).
Marasco teaches the substitution of the scFv of their CAR with known in the art scFv antibodies specific for the targets of interest including CCR4 ([0048]-[0058]).
Marasco does not teach the specific anti-CCR4 scFv of the claims.
Gunnarsson teaches the antibody of HCDR1, 2, and 3 of instant SEQ ID NO: 2, 4, and 6, with LCDR1 of instant SEQ ID NO: 8, 10, and 12 is KM3060 (Table 11). Gunnarsson teaches this antibody selectively binds to lymphoma cells that express CCR4 (figures 5-7). Gunnarsson teaches the use of CCR4 targeting with scFv for use in the treatment of cancer (abstract).
It would have been obvious at the time the application was filed to substitute the generic anti-CCR4 scFv of the CAR T cell of Marasco with the anti-CCR4 antigen binding domain of KM3060 taught by Gunnarsson. One of skill in the art would have been motivated to substitute the generic CCR4 binding domain of the CAR of Marasco with the one taught by Gunnarsson as Marasco teaches the ability to substitute the binding domains in the generic CAR of their teachings and specifically teaches using art taught CCR4 binding domains. There would have been a reasonable expectation of success as Marasco teaches success with substitution and Gunnarsson teaches the antibody of KM3060 for use in methods of treating cancer and further Marasco teaches the use of CAR T cells that bind CCR4 for use in a method of treating cancer.
Claims 1 and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Marasco (US 20170362297 A1) (IDS) and Kamiya et. al. Blood Advances. 2(5):517-528 (2018) (PTO-892).
Regarding claim 1, Marasco teaches a CAR comprising an antigen-binding domain, a transmembrane domain, and an intracellular domain (claim 1) where the antigen binding domain binds CCR4 (claim 9 and Figure 1).
Regarding claim 54, Marasco teaches a vector comprising a nucleic acid encoding an anti-CCR4 CAR and the expression of that vector in a genetically engineered cell ([0008] and claims 11-20). Marasco further teaches a modified immune cell comprising the CAR ([0041]-[0042]).
Marasco does not teach the use of a fusion with a KDEL sequence.
This deficiency is filled by Kamiya.
Kamiya teaches the risk of graft-versus-host disease (GVHD) and the risk of host tissue recognition when using allogenic T cells in CAR T therapy for the treatment of cancer (abstract and page 517 in “Introduction” in par 2 and page 518 in col 1 in lines 1-4). Kamiya teaches the use of constructs that prevent transport of targeted proteins to the cell membrane (page 518 in col 1 in par 2). Kamiya teaches a single vector encoding the CAR and PEBL (Figure 5). Kamiya teaches a decrease in GVHD when using the PEBL system and further teaches the CAR maintains use in the treatment of leukemia (Figure 5 and page 523 in col 2 in “Discussion”). Kamiya teaches the best PEBLs use in their method was either the KDEL or KKXX sequence (page 524 in col 2 in lines 4-6). Kamiya teaches the ability to produce a single viral vector that expresses the PEBL and CAR for use with CARs currently in clinical trials (page 525 in col 1 in par 1). Kamiya teaches the use of this system would be expected to result in CAR T cells resistant to rejection and having higher potentcy and further teaches the application to block expression of T-cell antigens shared by normal and malignant T cells to avoid CAR-mediated fratricide while targeting T-cell leukemias and lymphomas (page 525 in col 2 in lines 3-9).
It would have been obvious at the time the application was filed to combine the anti-CCR4 CAR T cell of Marasco with the PEBL of KDEL system of Kamiya to produce a CAR T cell with protection from fratricide for increased persistence and potentncy of the CAR T cells of Marasco. One of skill in the art would have been motivated to combine the T cell targeting CAR T of Marasco with the protective invention of KDEL use taught by Kamiya that improved persistence and potency of their T cell targeting CAR T cell. There would have been a reasonable expectation of success as Kamiya is teaching towards the application of their PEBL system with other CAR T cells.
Claims 1, 54, 64, 68-70 and 101-102 are rejected under 35 U.S.C. 103 as being unpatentable over Marasco (US 20170362297 A1) (IDS), Gunnarsson (US 20100310464 A1) (PTO-892), Ishitsuka et. al. Int J Hematol. 106:522-532 (2017) (PTO-892), and Vercellino et. al. Lymphoid Neoplasia. 4(22):5607-5615 (2020) (PTO-892).
Regarding claim 1, Marasco teaches a CAR comprising an antigen-binding domain, a transmembrane domain, and an intracellular domain (claim 1) where the antigen binding domain binds CCR4 (claim 9 and Figure 1).
Regarding claims 54, Marasco teaches a vector comprising a nucleic acid encoding an anti-CCR4 CAR and the expression of that vector in a genetically engineered cell ([0008] and claims 11-20). Marasco further teaches a modified immune cell comprising the CAR ([0041]-[0042]).
Regarding claim 64, Marasco teaches the generation of a modified immune cell by introducing a vector encoding the CAR ([0108]).
Regarding claims 70, Marasco teaches the administration of the modified T cells for the treatment of cancer (0141]-[0147]).
Marasco teaches the treatment lymphoma and leukemia ([0137]).
Marasco does not teach the treatment of refractory cancer after treatment with mogamulizumab.
These deficiencies are filed by Gunnarsson, Ishitsuka, and Vercellino.
Gunnarsson teaches the use of CCR4 binding domains in the treatment of lymphoma and leukemia including Diffuse B-cell lymphoma (DBCL) (abstract and [0019]).
Ishitsuka teaches the use of mogamulizumab as a first line treatment in patients with lymphoma and leukemia (Abstract, Figure 1, and Table 1).
Vercellino teaches the use of CAR-T cells in the treatment of lymphoma patients that have failed 2 previous lines of therapy (abstract). Vercellino teaches first line treatment with immunotherapy, second line treatment with chemotherapeutics, and then using CAR-T cell therapy for patients with refractory lymphoma that still require treatment (page 5607 (“Introduction” and page 5608 in col 1 in lines 1-4).
It would have been obvious at the time the application was filed to modify the method of treating lymphoma using the anti-CCR4 CAR T cell therapy taught by Marasco for use in refractory lymphomas after first line immunotherapy of mogamulizumab as taught by Gunnarsson, Ishitsuka, and Vercellino. One of skill in the art would have been motivated by the teachings of Vercellino to apply the method of treatment comprising the administration a CAR T cell in refractory lymphoma patients as Vercellino teaches their successful use in patients previously treated with immunotherapy. It was known in the art as shown by Vercellino that first line treatment for lymphomas was immunotherapies, Ishitsuka teaches mogamulizumab as a first-line immunotherapy for lymphomas. Vercellino teaches CAR T cell therapies as successful in refractory patients and Marasco teaches the use of its anti-CCR4 CAR T cell therapies in a method of treating cancer broadly while Gunnarsson teaches the use of anti-CCR4 binding domains in treatment of lymphomas. There would have been a reasonable expectation of success as Vercellino teaches CAR T cell therapies as a successful therapeutic for refractory lymphomas.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643