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 .
Applicant’s response filed on 07/01/2026 is acknowledged.
Claims 1-3, 9, 12-13, 19, 22-23, 29, 32-33, 35, 37, 39, 42-48 and 55-56 are pending.
Applicant's election with traverse of Group I and the species of “GC33BBZ-Bel-2CAR-T of HCDR3: SEQ ID NO: 20, HCDR2: SEQ ID NO: 21, HCDR1: SEQ ID NO: 22, LCDR3: SEQ ID NO: 23, LCDR2: SEQ ID NO: 24, and LCDR1: SEQ ID NO: 25 of VH: SEQ ID NO: 26 and VL: SEQ ID NO: 27 and the antibody or the antigen binding fragment thereof: SEQ ID NO: 28; transmembrane domain: SEQ ID NO: 47; co-stimulatory domain: SEQ ID NO: 48; intracellular signaling domain: SEQ ID NO: 49; hinge region: SEQ ID NO: SEQ ID NO: 50; CAR: SEQ ID NO: 58; and Bcl protein: SEQ ID NO: 52” in the reply filed on 07/01/2026 is acknowledged. The traversal is on the ground(s) that “M.P.E.P. §803 requires a showing of burden on the search and it is believed that the claims of the present application would be part of an overlapping search area. Furthermore, electronic searching allows for a search of many, or theoretically all, relevant subclasses without substantial additional effort. Accordingly, Applicant respectfully traverses the Restriction Requirement on the grounds that a search and examination of the entire application would not place a serious burden on the Examiner, whereas it would be a serious burden on Applicant to prosecute and maintain separate applications.
In addition, the citation of art to deny lack of unity without a full analysis of how the art cited is or is not applicable to the claims as presented does not meet the required burden of establishing that a special technical feature does not contribute over the known art. To the contrary, Applicant respectfully disagrees that anticipation over the cited WO 2020/219504 has been shown”. This is not found persuasive because Applicant has not provided any reasoning for the argument that WO 2020/219504 does not anticipate. In addition, the argument that the enormous number of species encompassed by the instant claims are not a burden to search is unpersuasive.
The requirement is still deemed proper and is therefore made FINAL.
Claims 46-48 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and claims 2-3, 9, 12-13, 19 and 32 are withdrawn as being drawn to a non-elected species there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07/01/2026.
Claims 1, 22-23, 29, 33, 35, 37, 39, 43-45 and 55 are under consideration as they read on GC33BBZ-Bel-2CAR-T of HCDR3: SEQ ID NO: 20, HCDR2: SEQ ID NO: 21, HCDR1: SEQ ID NO: 22, LCDR3: SEQ ID NO: 23, LCDR2: SEQ ID NO: 24, and LCDR1: SEQ ID NO: 25 of VH: SEQ ID NO: 26 and VL: SEQ ID NO: 27 and the antibody or the antigen binding fragment thereof: SEQ ID NO: 28; transmembrane domain: SEQ ID NO: 47; co-stimulatory domain: SEQ ID NO: 48; intracellular signaling domain: SEQ ID NO: 49; hinge region: SEQ ID NO: SEQ ID NO: 50; CAR: SEQ ID NO: 58; and Bcl protein: SEQ ID NO: 52.
Applicant’s IDS document filed on 07/06/2023 has been considered.
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 23 and 44 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 23 recites that the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the antibody may comprise more than one of the recited sequences at each category. It is unclear how the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 can comprise more than one of the sequences since these CDRs comprising more than one sequence does not meet the structural requirements for the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the antibody.
Claim 44 recites that “the immune effector cell comprises T cells” and that is indefinite because it is unclear how a single cell may comprise more than one T cell.
Correction is required.
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, 22-23, 29, 33, 35, 37, 39, 43-45 and 55 are rejected under 35 U.S.C. 112, first first paragraph, because the specification, while being enabling for : an immunedoes not reasonably provide enablement for: an immune, comprising and/or expressing a chimeric antigen receptor (CAR), and a Bcl-2 protein or a functionally active fragment thereof of claim 1; wherein the CAR comprises an antigen binding domain, and the antigen binding domain comprises an antibody or an antigen binding fragment thereof specifically binding to GPC-3 of claim 22; wherein the antibody or the antigen binding fragment thereof comprises a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 22, SEQ IDNO: 31, and SEQ ID NO: 40, wherein the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 21, SEQ ID NO: 30, and SEQ ID NO: 39, wherein the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 20 SEQ ID NO: 29, and SEQ ID NO: 38, wherein the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 25, SEQ ID NO: 34, and SEQ ID NO:43, wherein the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 24, SEQ ID NO: 33, and SEQ ID NO: 42, and wherein the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 23, SEQ ID NO: 32 and SEQ ID NO: 41 of claim 23; wherein the antibody or the antigen binding fragment thereof comprises a VH and a VL, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 26, SEQ ID NO: 35, and SEQ ID NO: 44, and wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 27, SEQ ID NO: 36, and SEQ ID NO: 45 of claim 29; wherein the CAR comprises a transmembrane domain, and the transmembrane domain comprises a transmembrane domain derived from a protein selected from the group consisting of: CD28, CD3e, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154 of claim 33; wherein the CAR comprises a co-stimulatory domain, and the co-stimulatory domain comprises one or more co-stimulatory domains of a protein selected from the group consisting of: co-stimulatory signaling regions in CD28, 4-1BB, CD40L, TIM1, CD226, DR3, SLAM, ICOS, OX40, NKG2D, 2B4, CD244, FccRIy, BTLA, CD27, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, and DAP12 of claim 35; wherein the CAR comprises an intracellular signaling domain, and the intracellular signaling domain comprises an intracellular signaling domain derived from CD3ζ of claim 37; wherein the CAR comprises a hinge region, and the hinge region is located between the antigen binding domain and the transmembrane domain of claim 39; wherein the Bcl-2 protein or the functionally active fragment thereof is an exogenous Bcl-2 protein or a functionally active fragment thereof of claim 43; wherein the immune effector cell comprises T cells of claim 44; wherein the Bcl-2 protein or the functionally active fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 52 of claim 45; and a composition comprising the immune effector cell according to claim 1 of claim 55. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
The claims are not commensurate in scope with the enablement provided in the specification. The specification does not support the broad scope of the method claims because the specification does not disclose the following:
an immune
any functionally active fragment of any Bcl-2 protein and compositions thereof.
any CAR comprising any antigen binding domain wherein the antigen binding domain comprises any antibody specifically binding to GPC-3 or an antigen binding fragment thereof.
The specification does not disclose the genus of anti-GPC-3 antibodies wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, are mixed and matched from any of the following recitations: wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 22, SEQ IDNO: 31, and SEQ ID NO: 40, wherein the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 21, SEQ ID NO: 30, and SEQ ID NO: 39, wherein the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 20 SEQ ID NO: 29, and SEQ ID NO: 38, wherein the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 25, SEQ ID NO: 34, and SEQ ID NO:43, wherein the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 24, SEQ ID NO: 33, and SEQ ID NO: 42, and wherein the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 23, SEQ ID NO: 32 and SEQ ID NO: 41.
The specification does not disclose any antibody or the antigen binding fragment thereof comprises a VH and a VL which are mixed and matched from wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 26, SEQ ID NO: 35, and SEQ ID NO: 44, and wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 27, SEQ ID NO: 36, and SEQ ID NO: 45.
The specification does not adequately disclose any transmembrane domain derived from a protein selected from the group consisting of: CD28, CD3e, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
The specification does not adequately disclose any co-stimulatory domain comprising one or more co-stimulatory domains of a protein selected from the group consisting of: co-stimulatory signaling regions in CD28, 4-1BB, CD40L, TIM1, CD226, DR3, SLAM, ICOS, OX40, NKG2D, 2B4, CD244, FccRIy, BTLA, CD27, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, and DAP12
The specification does not adequately disclose any intracellular signaling domain derived from CD3ζ
The specification does not adequately disclose any immune effector cell which comprises more than one T cell.
The general co-transfection of any CAR and any Blc-2 protein into any cell would not result in immune effector cells, much less immune effector cells that can be made and used to treat tumors as recited in the claims.
The specification provides insufficient guidance as to which of the essentially infinite possible choices of CAR and any Blc-2 protein into any cell is likely to be successful in treating tumors in vivo.
The specification essentially discloses a laundry list of different antigen combinations, antibody combinations, transmembrane domain combinations, costimulatory domain combinations and intracellular signaling domain combinations but provides no guidance regarding the actual structure of immune effector cells comprising the CAR and the BCl-2 protein that can perform the claimed function. The examples disclose functional embodiments which are not commensurate in scope with the present claims. Furthermore, as noted above, the art is highly unpredictable. Thus, given the unpredictability of the art, the breadth of the claims, and the lack of guidance provided by the instant specification, it would require undue experimentation to make and use the genus of immune effector cells in the claimed method.
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
The state of the art is such that providing CAR T cells that can function as recited in the present claims, requires careful titration of strength of signaling through the CARS, and not every tumor antigen or antibody thereto will work to provide said function (See Hanada et al.(PTO-892; Reference U). Hanada et al teaches that one critical factor in providing said function is to utilize an scFV with a low affinity for the tumor antigen. (In particular, whole document).
The state of the art is such that signaling modules in CAR constructs have complex and unpredictable consequences and canonical signaling events do not predict functional outcomes in CARS (See Lindner et al. (PTO-892; Reference V); page 4, whole document in particular). Furthermore, the spatial configuration of the CAR itself has significant functional consequences, and effects are highly context dependent and are influenced by a myriad of factors including affinity of the CAR, inherent signaling capacity, whether it signals tonically, and where the antigen epitope is physically located (In particular, page 4, whole document). Therefore, using a genus of costimulatory signaling in combination with a genus of antibody targeting domains to provide the claimed function would be highly unpredictable.
Thus, based on the unpredictability of the art and the breath of the claims, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims. The enablement set forth in the specification is not commensurate in scope with the genus of cells and CARs encompassed by the instant claims. Furthermore, no guidance is provided regarding antibody or antibody fragment selection in combination with particular costimulatory signaling domains that provides the functionally recited in the instant claims. Thus, given the unpredictability of the art, the breadth of the claims, and the lack of guidance provided by the instant specification, it would require undue experimentation to make and use the genus of claimed cells in the claimed methods.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed method invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement. Without such guidance, the intended outcome for the method invention is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986).
See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
12. Claims 1, 22-23, 29, 33, 35, 37, 39, 43-45 and 55 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: an immune
Applicant is not in possession of: an immunea chimeric antigen receptor (CAR), and a Bcl-2 protein or a functionally active fragment thereof of claim 1; wherein the CAR comprises an antigen binding domain, and the antigen binding domain comprises an antibody or an antigen binding fragment thereof specifically binding to GPC-3 of claim 22; wherein the antibody or the antigen binding fragment thereof comprises a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 22, SEQ IDNO: 31, and SEQ ID NO: 40, wherein the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 21, SEQ ID NO: 30, and SEQ ID NO: 39, wherein the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 20 SEQ ID NO: 29, and SEQ ID NO: 38, wherein the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 25, SEQ ID NO: 34, and SEQ ID NO:43, wherein the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 24, SEQ ID NO: 33, and SEQ ID NO: 42, and wherein the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 23, SEQ ID NO: 32 and SEQ ID NO: 41 of claim 23; wherein the antibody or the antigen binding fragment thereof comprises a VH and a VL, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 26, SEQ ID NO: 35, and SEQ ID NO: 44, and wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 27, SEQ ID NO: 36, and SEQ ID NO: 45 of claim 29; wherein the CAR comprises a transmembrane domain, and the transmembrane domain comprises a transmembrane domain derived from a protein selected from the group consisting of: CD28, CD3e, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154 of claim 33; wherein the CAR comprises a co-stimulatory domain, and the co-stimulatory domain comprises one or more co-stimulatory domains of a protein selected from the group consisting of: co-stimulatory signaling regions in CD28, 4-1BB, CD40L, TIM1, CD226, DR3, SLAM, ICOS, OX40, NKG2D, 2B4, CD244, FccRIy, BTLA, CD27, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, and DAP12 of claim 35; wherein the CAR comprises an intracellular signaling domain, and the intracellular signaling domain comprises an intracellular signaling domain derived from CD3ζ of claim 37; wherein the CAR comprises a hinge region, and the hinge region is located between the antigen binding domain and the transmembrane domain of claim 39; wherein the Bcl-2 protein or the functionally active fragment thereof is an exogenous Bcl-2 protein or a functionally active fragment thereof of claim 43; wherein the immune effector cell comprises T cells of claim 44; wherein the Bcl-2 protein or the functionally active fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 52 of claim 45; and a composition comprising the immune effector cell according to claim 1 of claim 55.
Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of immune effector cells comprising a CAR and a Bcl 2 protein or functionally active fragment thereof.
The specification has not adequately described an immune
any functionally active fragment of any Bcl-2 protein and compositions thereof.
The specification has not adequately described any CAR comprising any antigen binding domain wherein the antigen binding domain comprises any antibody specifically binding to GPC-3 or an antigen binding fragment thereof.
The specification has not adequately described the genus of anti-GPC-3 antibodies wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, are mixed and matched from any of the following recitations: wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 22, SEQ IDNO: 31, and SEQ ID NO: 40, wherein the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 21, SEQ ID NO: 30, and SEQ ID NO: 39, wherein the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 20 SEQ ID NO: 29, and SEQ ID NO: 38, wherein the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 25, SEQ ID NO: 34, and SEQ ID NO:43, wherein the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 24, SEQ ID NO: 33, and SEQ ID NO: 42, and wherein the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 23, SEQ ID NO: 32 and SEQ ID NO: 41. The genus of antibodies encompassed would have combinations that are not present in the antibodies that were actually produced in the specification which are shown to bind to GPC-3.
The specification has not adequately described any antibody or the antigen binding fragment thereof comprises a VH and a VL which are mixed and matched from wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 26, SEQ ID NO: 35, and SEQ ID NO: 44, and wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 27, SEQ ID NO: 36, and SEQ ID NO: 45. The genus of antibodies encompassed would have combinations that are not present in the antibodies that were actually produced in the specification which are shown to bind to GPC-3.
The specification has not adequately described any transmembrane domain “derived” from a protein selected from the group consisting of: CD28, CD3e, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
The specification has not adequately described any co-stimulatory domain comprising one or more co-stimulatory domains of a protein selected from the group consisting of: co-stimulatory signaling regions in CD28, 4-1BB, CD40L, TIM1, CD226, DR3, SLAM, ICOS, OX40, NKG2D, 2B4, CD244, FccRIy, BTLA, CD27, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, and DAP12
The specification has not adequately described any intracellular signaling domain “derived” from CD3ζ
The specification has not adequately described any immune effector cell which comprises more than one T cell.
The instant claims are drawn to T cell comprising a first and second CAR.
The specification describes the following on pages 7-11:
“In the present application, the term "chimeric antigen receptor" or "CAR", also referred to as "chimeric receptor", "T receptor", or chimeric immune receptor, generally refers to a recombinant polypeptide construct including at least a extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to as "intracellular signaling domain"). For example, the chimeric antigen receptor may include a targeting moiety (e.g., the moiety binding to a tumor-related antigen), a hinge region, a transmembrane domain, a co-stimulatory domain, and an intracellular signaling domain.
The terms "Bcl-2" and "Bcl-2 protein" may be used interchangeably and generally refer to the encoded products of bcl-2 proto-oncogenes. In some embodiments, the amino acid sequence of Bcl-2 protein may be as set forth in SEQ ID NO: 52. In the present application, the term covers full-length Bcl-2 proteins and homologues, analogues, truncations, mutants, and functionally active fragments thereof. In the present application, the term covers exogenous Bcl-2 proteins or functionally active fragments thereof.
In the present application, the term "antigen binding domain" generally refers to a domain capable of binding to a target antigen. The antigen binding domain may include a chimeric antigen receptor, a fragment thereof, an antibody or an antigen binding fragment thereof, which is capable of (specifically) binding to an antigen. The antigen binding domain may be of natural, synthetic, semi-synthetic or recombinant origin. In some embodiments, the antigen binding domain may include an antibody or an antigen binding fragment thereof. For example, the antigen binding domain may include a single-chain antibody.
In the present application, the term "transmembrane domain" generally refers to a domain capable of spanning the cytoplasmic membrane. The transmembrane domain may usually contain three structural regions: an N-terminal extracellular region, an intermediate transmembrane extension region, and a C-terminal cytoplasmic region. The transmembrane domain may also contain an intracellular region or a cytoplasmic region.
In the present application, the term "co-stimulatory domain" generally refers to an intracellular domain that can provide immune co-stimulatory molecules. Where, the co-stimulatory molecules may be cell surface molecule required for an effective response of the lymphocyte to the antigen. In some embodiments, the co-stimulatory domain may be the intracellular part of the co-stimulatory molecules or the truncated forms thereof.
In the present application, the term "intracellular signaling domain" generally refers to a domain located inside a cell capable of conducting signals. In the present application, the intracellular signaling domain can conduct signals into the cells. The term covers intracellular signaling domains capable of inducing effector function signals and any truncated portions thereof.”
The claims broadly encompass a wide genus of structurally different antigen binding domains which include any “domain capable of binding to a target antigen”, Bcl-2 which includes homologues, analogues, truncations, mutants, and functionally active fragments thereof, and intracellular signaling domain, costimulatory domain and transmembrane domains without any limited structures. The specification has not adequately describe what is encompassed by the term “derived” such that intracellular signaling domain, costimulatory domain and transmembrane domains derived from molecules would have a limited structure. The specification does not describe a correlation between said structure and function, and there is no art recognized correlation between said structure and function. The only species of antigen binding domain disclosed by the instant specification are antibodies or fragments thereof. This is not sufficiently representative of the broad genus of binding domains encompassed by the instant claims. Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Elf Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
The CAR of SEQ ID NOs 53-62 are not sufficiently representative of the broad genus of CAR encompassed by the present claims. Furthermore, the state of the art is such that providing the claimed function of treating tumors in a subject is highly unpredictable and depending on numerous factors. The specification provides no guidance regarding which combination of elements would function as claimed. See Novozymes A/S v. DuPont Nutrition Biosciences. 107 USPQ2d 1457 (Fed. Cir. 2013). In Novozymes the court held that the problem is that “the specification failed to inform the reader which member of that group was the right one.” Accordingly, because “[t]he actual inventive work of producing a [working variant] was left for subsequent inventors to complete,” the application provided insufficient written description for the claims. Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed immune effector cells. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Furthermore, the claims encompass CARs comprising one or more costimulatory domains. The state of the art is such that signaling modules in CAR constructs have complex and unpredictable consequences and canonical signaling events do not predict functional outcomes in CARS (see Lindner (PTO-892; Reference V) page 4, in particular). Furthermore, the spatial configuration of the CAR itself has significant functional consequences, and effects are highly context dependent and are influenced by a myriad of factors including affinity of the CAR, inherent signaling capacity, whether it signals tonically, and where the antigen epitope is physically located (In particular, page 4). The specification has reduced to practice species that are not sufficiently representative of the broad genus of immune effector cells encompassed by the instant claims, and the specification does not disclose a correlation between CAR structure and functions claimed.
The instant application has not provided a sufficient description showing possession of the necessary 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 genus of T cells comprising CARs with co-stimulatory domains, transmembrane domains and intracellular signaling domaina encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species; then the Requirement may be alternatively met by reduction to drawings, or 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 genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Given the claimed broadly class of CARs and cells, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making the CARS and cells with the recited functions and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
13. 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.
14. 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.
15. 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.
16. Claims 1, 22-23, 29, 44 and 55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over WO 2017/002934 (PTO-892; Reference N) as evidenced by the translation in U.S. Patent Application Publication 2018/0169237 (PTO-892; Reference A). (citations refer to paragraphs in U.S. Patent Application Publication 2018/0169237) as evidenced by Gratiot Deans et al. (PTO-892; Reference W) and the attached sequence alignment.
WO 2017/002934 teaches GPC3 chimeric antigen receptor (CAR) gene-transfected T cells (W02014/180306) as immunocytes that may be used as the GPC3-targeting therapeutic agent. Combined use of GPC3-targeting therapeutic agent with additional anticancer agent (In particular, paragraph [0149], whole document).
The reference teaches the GPC3 targeting agent of reference SEQ ID NO:47 (100% sequence identical to instant SEQ ID NO:26) and reference SEQ ID NO:52 (100% sequence identical to instant SEQ ID NO:27) (In particular, claim 9 and 25,
Gratiot Deans et al. is being used as an evidentiary reference to show that T cells comprise Bcl2 protein (In particular, whole document).
The reference teachings anticipate the claimed invention.
17. Claims 1, 22-23, 29, 33, 35, 37, 39, 44 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/019772 (PTO-892; Reference O) in view of each of WO 2006/046751 (PTO-892; Reference P) and WO 2006/006693 (PTO-892; Reference Q) by Gratiot Deans et al. (PTO-892; Reference W) and the attached sequence alignment.
WO 2018/019772 teaches CAR T cells which comprise Anti-GPC3 antibodies include the human monoclonal anti-GPC3 antibodies MDX-1414 (Medarex), HN3 (disclosed e.g. in WO 2012/145469 Al), the humanized mouse monoclonal anti-GPC3 antibodies GC33 (also known as RO5137382, RG7686; described e.g. in WO 2006/046751 Al) and YP7 (described e.g. in WO 2013/181543 Al), and anti-GPC3 antibodies disclosed in WO 2009/012394 Al, WO 2006/046751 Al, WO 2013/181543 Al, WO 2012/145469 Al, WO 2016/036973 Al, WO 2006/006693 Al, WO 2013/070468 WO 2007/047291, each hereby incorporated by reference in their entirety. (In particular, page 12, whole document).
WO 2018/019772 teaches the CAR T cells which comprise anti-GPC3 antibodies and 1.) costimulatory domains from CD226, CD28 and 4-1BB; 2.) transmembrane regions from CD28 and CD8; and 3.) hinge regions from IgG1. (In particular, page 2).
WO 2018/019772 teaches the hinge locate between the antigen binding domain and the transmembrane domain (In particular page 8, line 4)
WO 2018/019772 teaches the intracellular signaling domain is from CD3ζ (In particular, page 8, line 25-26).
The claimed invention differs from the prior art in the recitation of the VH and VL of SEQ ID NOs 26 and 27 of claim 29; and the CDRs of SEQ ID NOs 20-22 and 23-25 of claim 23.
The antibodies of WO 2006/046751 and WO 2006/006693 are incorporated by reference into WO 2018/019772. Each of these references teach the antibody of instant SEQ ID NOs 26 and 27.
WO 2006/046751 teaches the antibody of reference SEQ ID NO:191 (instant SEQ ID NO:27) and SEQ ID NO:87 (instant SEQ ID NO:26).
WO 2006/046751 teaches the antibody of reference SEQ ID NO:107 (instant SEQ ID NO:27) and SEQ ID NO:84 (instant SEQ ID NO:26).
Gratiot Deans et al. is being used as an evidentiary reference to show that T cells comprise Bcl2 protein (In particular, whole document).
It would have been obvious to have arranged the cells comprising the recited CARs as claimed based on the specific teachings within WO 2018/019772 to do so. As evidenced by Gratiot Deans et al. the T-cells naturally comprise Bcl-2 protein.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
18. No claim is allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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September 5, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641
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