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
Applicant’s election without traverse of Group I, claimed in claims 6,9,11,16,33,37,40,43,46,50, 54, 64, 74, 75 and 77 in the reply filed on 7/5/22 was previously acknowledged. Election was made of CAR (second protein domain), ER domain and SEQ ID NO: 58 (degradation domain), Bazedoxifene (stabilization compound), Furin cleavage site, 4-IBB (CD137)(costimulatory signaling domain), CD3-zeta stimulatory domain (primary signaling domain), scFV (antigen binding domain) and antigen binding domain that binds CLEC12A.
In the reply filed 1/12/24, Applicants amended claims 6, 9, 11, 16, 33, 43, 46, 50, 54,64,65, 75, 77, 87, 90, 93, 99, 104 and 112. Claims 19, 22, 40, 96, 100, 107, 109, 118, 120, 158 and 160 were canceled. Claims 167-182 were added.
In the reply filed 10/1/24, Applicants amended claims 6,16, 54, 77 and canceled claim 9.
In the reply filed 10/22/25, Applicants amended claims 6, 16, 37, 43, 50, 167-169 and 174. Claim 11 was canceled.
Claims 6, 16, 33, 37, 43, 46, 50, 54, 64, 65, 69-70, 73, 74, 75, 77, 87, 90, 93, 99, 104, 111-112 and 167-169, 171-182 are pending.
Claims 87, 90, 93, 99, 104, 111, 112, 171-172, 178 and 179 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Please note that claims 170 and 172 are withdrawn because furin (elected species) is not a mammalian extracellular protease. The species of CD19 was found so the species was extended to claim 175.
Applicants argue in the response filed 10/22/25 that the claim 170 should not withdrawn because the elected species of “furin” can localize and function extracellularly. Applicants argue that Zhang et al. (submitted in ids filed 10/22/25) discloses that furin extracellularly cleaves secreted PTEN and states furin also exists in the extracellular space.
The Examiner disagrees that furin is classified as both an intra and extracellular protease and the instant specification does not define it as such. Nevertheless, in view of compact prosecution, claim 170 will be rejoined. Please note that claims 69-70 and 73 are also rejoined because the nucleic acid, vector and viral particle are taught by the cited prior art.
Claims 6, 16, 33, 37, 43, 46, 50, 54, 64-65, 69-70, 73-75, 77, 167-169, 170, 173-175, 176-177 and 180-182 are under consideration.
Claim Rejections - 35 USC § 112(a)-Maintained and Revised
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.
The rejection of claims 6, 16, 33, 37, 43, 46, 50, 54, 64-65, 69-70, 73-75, 77, 167-170, 173-177 and 180-182 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 is maintained. 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. This rejection is maintained but revised in view of the amendment to the claims.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person would know what proteins meet the limitation of degradation domains, heterologous protease cleavage site and CARs comprises an antigen binding domain, a transmembrane domain and one or more intracellular signaling domains.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Claim 6 is drawn to a fusion protein, comprising a degradation domain and a chimeric antigen receptor (CAR), wherein the degradation domain and the CAR are separated by a heterologous protease cleavage site, wherein the degradation domain has a state associated with the first level of surface or extracellular expression and a second state associated with a second level of surface expression and/or extracellular expression of the fusion protein, wherein the second level is increased over the first level in the presence of a stabilization compound, wherein the CAR comprised an antigen binding domain, transmembrane domain and one or more intracellular signaling domains, wherein the degradation domain is an ER domain and comprises an amino acid at least 90% identical to SEQ ID NO: 58,121 or 970; the degradation domain is FKBP and comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 56 or the degradation domain is DHFR domain and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 57.
The specific sequences of the heterologous protease cleavage site, antigen binding domain, transmembrane domain and one or more intracellular domains are not defined in the claim. With respect to “degradation domain”, the claim was amended to claim a degradation domain at least 90% identical to SEQ ID NO: 58,121,970, 56 or 57. Therefore, fragments and variants of SEQ ID NO: SEQ ID NO: 58,121,970, 56 or 57 are contemplated. The instant specification defines the “CAR” components [PGPUB 0236-0237]:
The term “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a recombinant polypeptide construct comprising at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as “an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule as defined below. In some embodiments, the domains in the CAR polypeptide construct are in the same polypeptide chain, e.g., comprise a chimeric fusion protein. In some embodiments, the domains in the CAR polypeptide construct are not contiguous with each other, e.g., are in different polypeptide chains, e.g., in regulatable chimeric antigen receptor (ROAR).
In one aspect, the stimulatory molecule is the zeta chain associated with the T cell receptor complex. In one aspect, the cytoplasmic signaling domain comprises a primary signaling domain (e.g., a primary signaling domain of CD3-zeta). In one aspect, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In one aspect, the costimulatory molecule is chosen from 4-1BB (i.e., CD137), CD27, ICOS, and/or CD28. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a co-stimulatory molecule and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising two functional signaling domains derived from one or more co-stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more co-stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In one aspect the CAR comprises an optional leader sequence at the amino-terminus (N-ter) of the CAR fusion protein. In one aspect, the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen binding domain, wherein the leader sequence is optionally cleaved from the antigen recognition domain (e.g., a scFv) during cellular processing and localization of the CAR to the cellular membrane.
Therefore, the broadest reasonable interpretation of the claims includes degradation domains of SEQ ID NO: 58,121,970, 56 or 57 and fragments and variants thereof at least 90% identical, a CAR comprising any antigen binding domain, any transmembrane domain and any intracellular signaling domain and any heterologous protease cleave site.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: The structure of the CAR is not defined in the claim. With respect the CAR, Applicants reduce to practice CD19scFvCAR. The amino acid of other CAR sequence are provided in Table 15 and 16 (CAR-19 and CAR-BMCA). A person of skill in the art would not know what features are required for the claimed function. For example, An et al. (“Engineering FKBP based destabilizing domains to build sophisticated protein regulation systems” PLOS One 12/30/2015) teach that engineering of FKBP to function as destabilization domain through mutations of FKBP. However, the claim does not recite a specific mutation or mutations that result in FKBP functioning as a degradation domain. The instant specification states that the term chimeric antigen receptor refers to a recombinant polypeptide construct comprising at least an extracellular antigen binding domain, a TM domain and a cytoplasmic signaling domain. That is not sufficient to meet the written description requirement because the claims are so broad one of ordinary skill in the art would not be apprised that Applicants had possession of the claimed genus of CARs.
(d) representative number of samples: Applicants have described the degradation domains of FKBPFD, ER-alphaFD and DHFRFD and anti-CD19scFvCAR and BCMA CAR. Guedan et al. (“Engineering and Design of Chimeric Antigen Receptors” Molecular Therapy Methods & Clinical Development; Vol. 12 March 2019) teaches that despite intensive research efforts to define optimal CAR design, a universally improved CAR structure has not yet been discovered. As of now, each CAR construct needs empirical testing for evaluation and several studies indicate that small modifications can have major consequences on the therapeutic outcomes (p. 146, 1st col.). Therefore, CARs exemplified in the instant specification is not sufficient since the state of the art teaches that there is great diversity and small changes or modifications can greatly affect the function of the CARs. With respect to the degradation domain, there is no disclosure of critical residues, motifs or tolerable/intolerable substitutions or deletions. In other words, the specification does not define which variations are permissible (i.e. results in a degradation domain that has the claimed function). Therefore, each part of the fusion protein is broadly defined and the combination of results in an enormous genus of fusion proteins.
The genus of degradation domains and CARs is enormous and the examples provided in the specification are small. One of ordinary skill in the art could not extrapolate all CARs (comprising any antigen binding domain, transmembrane domain and one or more intracellular signaling domain) and degradation domains. Thus, the claims lack written description because the specification does not demonstrate possession of the full scope of the claims.
Response to Arguments
Applicant's arguments filed 10/24/25 have been fully considered but they are not persuasive. Applicants argue that claim 6 has been amended to recite the degradation domain are at least 90% identical to SEQ ID NO: 58, 121, 970, 56 or 58 and the CARs comprise an antigen binding domain, a transmembrane domain and one or more intracellular signaling domains. Applicants argue that claim 6 is not extremely broad because the specification describes and tested multiple fusion proteins encompassed by the claims. Applicants argue that Ex. 3 describes transduction of Jurkat cells with ER, FKBP or DHFR degron fused to a CAR construct. Applicants argue that multiple CAR constructs can be sued to the degradation domain (Ex. 15-16 and 24-26).
This argument is not persuasive because there is substantial variation in CARs and degradation domains and the applicants did not describe a sufficient variety of the species in the specification. The examples in the specification do not reflect the great variety of degradation domains and CARs. If one considers the great variability in structure of the CARs, degradation domains at least 90% identical to SEQ ID NO: 58,121, 970, 56 or 57 and heterologous protease cleavage sites, the number of fusion proteins is enormous and the examples provided are not representative because the genus is sufficiently large. The claim recites a fusion protein comprising multiple independently broad parts, resulting in a large genus of fusion proteins. The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples. In the instant case, the claims and specification were analyzed and were found to lack adequate written description. The specification does not show that the applicants were in possession of the claimed invention.
For the reasons presented, the rejection is maintained.
Claim Rejections - 35 USC § 103-Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 6, 16, 33, 37, 64, 69-70, 73-75, 77, 167-170, 180 and 182 are rejected under 35 U.S.C. 103 as being unpatentable over Wandless et al. (USPN 8,173,792) in view of Heuser et al. (Gene Therapy 2003, 10. 1408-1419) and Chen et al. (Adv Drug Deliv Rev. PMC 2014).
Wandless et al. teach a conditional protein stability system comprising a protein of interest and a variant of FKBP having a mutation (claim 1). Wandless et al. teach the stability affected proteins are derived from FKBP (Abstract). Wandless et al. teach in some embodiments, the stability-affecting protein is a variant FKBP and the fusion protein is destabilized in the presence of a FKBP ligand. In particular embodiments, the variant FKBP includes a C-terminal extension of amino acids substantially identical to that of sequence of SEQ ID NO: 18. In particular embodiments, the variant FKBP includes the substitution F36V (col. 4, lines 34-41). Wandless et al. teach fusion proteins of interest can be made with FKBP (col. 2, lines 39-41, col. 4, lines 1-21). Wandless et al. also teach variants of DHFR fused to the N or C terminus of a protein of interest (col. 4, lines 45-48). Wandless et al. teach that a fusion protein of a destabilizing domain to a protein of interest results in degradation of the entire protein. Addition of a ligand for the destabilizing domain protects the fusion from degradation (fig. 1A and B). Fig. 5 disclosed that the destabilizing domain confers Shield-1 dependent stability to a transmembrane protein (col. 5, lines 33-38). Therefore, Wandless et al. teach the degradation domains regulate on demand regulation of protein stability. With respect to “the degradation domain is an FKBP domain comprising an amino acid at least 90% identical to SEQ ID NO: 56”, Wandless et al. teach the degradation domain of SEQ ID NO: 6, which is 99.1% identical to instantly claimed SEQ ID NO: 56.
Wandless et al. does not teach the protein of interest is a CAR. However, the teachings of Heuser et al. cure this deficiency.
Heuser et al. investigates how the intracellular domains affects cell surface expression stability (p. 1409, left col). Heuser et al. teach the results imply that the intracellular signaling domain affects substantially the stability and function of receptor expression and the efficiency of the receptor mediated cellular activation (p, 1415, bottom of 2nd col.). Heuser et al. teach that a rational design of T cell immunoreceptors must address the receptors cell surface expression and activation properties (last para, p. 1416). Therefore, Heuser et al. recognizes that CAR stability is an engineering target.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to fuse a degradation domain, such as a modified FKBP or DHFR domain to a CAR in order to regulate stability of the CAR protein because Wandless et al. teach that FKBP and DHFR domains can be use as degradation or destabilization domains when genetically fused to a protein of interest, thereby conferring ligand dependent degradation control. A person would look to the teachings of Heuser et al. that teaches stability of the CAR is a an engineering target and have a motivation to fuse a degradation domain to a CAR in order to regulate the stability on demand. There is a reasonable expectation of success because Wandless et al. teach the system is compatible with transmembrane proteins, supporting its applicability to membrane bound receptors such as CARs.
The references above do not teach a heterologous protease site, however the teachings of Chen et al. cure this deficiency.
Chen et al. teach fusion proteins have been developed as a class of novel biomolecules with multi-functional properties. Chen et al. teach the successful construction of fusion proteins requires two indispensable elements the component proteins and the linker (p. 2, 2nd para.). Chen et al. teach that direct fusion of proteins without a linker can lead to many undesirable outcomes including misfolding of the fusion proteins, low yield in protein production or impaired bioactivity (p. 2 2nd para.). Chen et al. teach suitable linkers include cleavable linkers that release free functional domains in vivo (p. 6, para 3.3). In particular, Chen et al. teach a furin cleavable linker with a recognition sequence -Arg-X-Arg/Lys-Arg (p. 13, 1st para). Chen et al. teach that Furin has been applied in various fusion proteins.
It would have been obvious to a person of ordinary skill in the art to include a furin protease cleavage site in the fusion protein comprising a CAR and degradation domain in order to reduce undesirable outcomes such as misfolding, low yield, low production and impaired bioactivity. There is a reasonable expectation of success given that it is routine in the art to include protease cleave sites in fusion proteins.
With respect to the limitation “wherein the degradation domain has a first state associated with a first level…..” the fusion protein made obvious by Wandless et al., Heuser et al. and Chen et al. would necessarily have all of the activities and properties of the composition of claim 6. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, the combined references make obvious the fusion protein of claim 6, therefore the same protein would have the same properties.
With respect to claim 16, as indicated above, Wandless et al. teach the degradation domain is FKBP and the stabilization compound is Shield-1 (fig. 5).
With respect to claims 33, 37, 167, 168, 169, 170, furin is a mammalian intracellular and extracellular protease. Chen et al. teach a furin cleavable linker with a recognition sequence -Arg-X-Arg/Lys-Arg (p. 13, 1st para), wherein X is any amino acid. It would have been obvious to a person of ordinary skill in the art to optimize the furin cleavage site to arrive at SEQ ID NO: 123, since the consensus cleavage motif is well known in the art. There is a reasonable expectation of success given that Chen et al. teach the consensus sequence and cleavage with furin is routine in the art.
With respect to claims 64 and 180, Wandless et al. teach FKBP domain was N-terminal to the protein of interest (Fig. 6, 1K). Wandless et al. also teach the DHFR is located at the N- or C-terminus of the protein of interest (col 4, lines 45-48). It would have been obvious to optimize the order of the components in the fusion protein. There is a reasonable expectation of success given that each component are know in the art.
With respect to claims 69-70 and 73, Wandless et al. teach nucleic acids encoding the fusion proteins (top of col. 4). Wandless et al. teach the cells maybe transfected using an expression vector of transduced (i.e. infected) using a viral vector (col. 19, lines 45-58).
With respect to claims 74-75, Wandless et al. teach the fusion protein and stability ligand are introduced into a cell (col. 4, lines 1-14; col. 5, lines 7-23).
With respect to claim 77, and the limitation of (i) and (ii), the fusion protein made obvious by Wandless et al., Heuser et al. and Chen et al. would necessarily have all of the activities and properties of the composition of claims 6 and 74. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, the combined references make obvious the fusion protein of claim 6 and the cell of claim 74. Wandless et al. teach that a fusion protein of a destabilizing domain to a protein of interest results in degradation of the entire protein. Addition of a ligand for the destabilizing domain protects the fusion from degradation (fig. 1A and B). Fig. 5 disclosed that the destabilizing domain confers Shield-1 dependent stability to a transmembrane protein (col. 5, lines 33-38). Therefore, Wandless et al. teach the degradation domains regulate on demand regulation of protein stability. Therefore the same fusion protein in the presence of the stabilization compound would necessarily have the same properties.
With respect to claim 182, It would have been obvious to a person of ordinary skill in the art to include the protease furin in the cell that cleaves the protease cleavage site in order to reduce undesirable outcomes such as misfolding, low yield, low production and impaired bioactivity. There is a reasonable expectation of success given that the proteases and cleavage sites are routine in fusion proteins.
Response to Arguments
Applicant's arguments filed 10/22/25 have been fully considered but they are not persuasive. Applicants argue that the instant invention is based on the discovery that the degradation domain can be separated from the protein of interest by a protease cleavage site. Applicants argue that the instant specification demonstrated that fusion proteins comprising degradation domains and a CAR separated by a heterologous protease cleavage site can be used to effectively control CAR expression and lead to compound dependent tumor killing both in vitro and in vivo. Applicants argue the claimed fusion protein is not taught of suggested by the prior art. Applicants argue that the system of Wandless works on opposing principles as fusion proteins recited in the instant claims. Applicants argue that Heuser et al. does not provide a teaching or suggestion that regulating CAR expression using an endogenously added compound and degradation domain. Applicants argue that a skilled artisan looking to improve CAR expression stability or inactivation would not be motivated to combine the immunoreceptors of Heuser with the destabilizing compound domains of Wandless. Applicants argue that Chen et al. does not teach or suggest to use furin cleavage site for expression of a transmembrane polypeptide, let alone a fusion protein comprising a CAR and a degradation domain. Applicants argue that the inclusion of the protease cleavage site is not merely to reduce undesirable outcomes, rather inclusion of the protease cleavage site is involved in control of CAR expression and activity based on the presence of the stabilization compound and cognate protease. Applicants argue that there is nothing in Chen to suggest placement of a protease cleavage site between a CAR and a degradation domain for regulation of expression of a CAR. Applicants further argue that there is no reasonable expectation of success given that there are certain disadvantages associated with disrupting the desired function of the protein of interest due to size and or conformation of the fusion protein. Applicants further argue surprising and unexpected results of the invention. Applicants argue that fusion proteins comprising a CAR, a heterologous protease cleavage site and a degradation domain can specifically kill tumor cells in a manner that is compound dependent and is noninferior to the parental CAR construct. Applicants argue that Ex. 27 (primary human T-cells transduced with a fusion protein (FurON CART19). Applicants argue that as shown in Fig. 46, the tumor progressed in the negative control and mice treating with FurON CART19 alone but tumor growth was inhibited when the mice were infused with CART19 or FurON CART19 infused with bazedoxifene. The results demonstrate that not only can CAR expression be controlled in vivo but that the CAR following treatment with a stabilization compound has comparable tumor inhibitory activity as the positive control.
These arguments were considered but are not persuasive because the independent claim does not require any particular protease, any specific cleavage kinetics, any tumor killing efficacy and any particular mechanism by which cleavage or stabilization controls CAR expression. With respect to the argument that Wandless operates on “opposing principles” is unsupported. Wandless explicitly teaches two states of protein expression, low vs stabilized in the presence of the stabilizing compound, which directly corresponds to the language reciting a first and second surface expression. Moreover, as indicated above, the combined references make obvious the limitations of claim 6, therefore the same fusion protein would have the same properties. Applicants argument that there is no reasonable expectation of success is not persuasive because Wandless teaches degradation domains fused to proteins of interest (including membrane associated proteins), Heuser teaches CARs are routinely engineered and modified and Chen teaches protease cleavage sites as routine fusion protein design tools. Therefore, a skilled artisan would expect a fused degradation domain-CAR to be expressible with conditional stabilization to modulate expression and a cleavable linker to reduce undesirable outcomes such as misfolding, low yield, low production and impaired bioactivity. The unexpected results are not commensurate in scope with the claims as the experiments were with a specific CAR, a specific degradation domain (comprising a specific seq id) and a specific protease cleavage site. Therefore, the data is limited to specific constructs and proteases. There is no evidence provided that the same results would occur across the full scope of the claims. The cited references teach all of the elements claimed and provide a motivation to combine and a reasonable expectation of success. For the reasons presented above, the rejection is maintained.
Claims 6, 16, 33, 37,43, 46,50, 54, 64, 69-70, 73-75, 77, 167-170, 173-176 and 180-182 are rejected under 35 U.S.C. 103 as being unpatentable over Wandless et al. (USPN 8,173,792), Heuser et al. (Gene Therapy 2003, 10. 1408-1419) and Chen et al. (Adv Drug Deliv Rev. PMC 2014) in view of Bedoya et al. (USPN 10,273,300).
The teachings of Wandless et al., Heuser et al. and Bedoya et al. are presented in detail above. The references do not teach the sequence of the CAR, however the teachings of Bedoya et al. cure this deficiency.
Bedoya et al. teach methods of making immune effector cells (e.g. T-cells, NK cells) that can be engineered to express CARs (Abstract).
With respect to claims 43, 46 and 50, Bedoya et al. teach the CARs of the invention comprise at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule and/or a costimulatory molecule(col. 18, lines 37-45). Bedoya et al. teach the intracellular signaling domain of the CAR is CD3-zeta (col. 18, lines 59-60). Bedoya et al. teach the antigen binding domain is an scFv (col. 19, lines 26-27 and col.20 1st para.).
It would have been obvious to a person of ordinary skill in the art to use the CARs of Bedoya et al. in the fusion protein of Wandless et al. Heuser et al. and Chen et al. in the fusion protein because Bedoya et al. teach methods of making and used CARs in effector cells. There is a reasonable expectation of success given Bedoya et al. teach the method of making and expressing the CARs in immune effector cells.
With respect to claim 54, Bedoya teaches the CAR is SEQ ID NO: 77 which is identical to instantly claimed SEQ ID NO: 897 (Table 3, cols 69-70).
PNG
media_image1.png
775
793
media_image1.png
Greyscale
With respect to claim 173, Bedoya et al. teach the costimulatory domain is 4-1BB and/or CD28 (col. 18, lines 66-67).
With respect to claims 174 and 175, SEQ ID NO: 77 of Bedoya is a CD19 CAR (Table 3). Bedoya et al. also teach the antigen binding domain of CLEC12A (col. 58, line 8).
With respect to claim 176, SEQ ID NO: 77 of Bedoya et al. comprises instantly claimed SEQ ID NO: 357.
With respect to claim 181, Bedoya et al. teach human effector cells (Abstract, claim 1).
Response to Arguments
Applicant's arguments filed 10/22/25 have been fully considered but they are not persuasive. Applicants argue that Bedoya does not remedy the deficiency of Wandless, Heuser and Chen. Applicants argue that a skilled artisan would not have a motivation and reasonable expectation of success to combine the teachings of Wandless, Heuser, Chen and Bedoya to arrive at the claimed fusion proteins.
This argument is not persuasive for the reasons presented above. Furthermore, It would have been obvious to a person of ordinary skill in the art to use the CARs of Bedoya et al. in the fusion protein of Wandless et al. Heuser et al. and Chen et al. in the fusion protein because Bedoya et al. teach methods of making and used CARs in effector cells. There is a reasonable expectation of success given Bedoya et al. teach the method of making and expressing the CARs in immune effector cells.
Claims 6, 16, 33, 37,43, 46,50, 54, 64, 65, 69-70, 73-75, 77, 167-170, 173-177 and 180-182 are rejected under 35 U.S.C. 103 as being unpatentable over Wandless et al. (USPN 8,173,792), Heuser et al. (Gene Therapy 2003, 10. 1408-1419), Chen et al. (Adv Drug Deliv Rev. PMC 2014) and Bedoya et al. (USPN 10,273,300) in view of Schonfeld et al. (EP3115373).
The references do not teach the fusion protein comprises a signal peptide. However, the teachings of Schonfeld et al. cure this deficiency.
Schonfeld et al. teach chimeric antigen receptors that comprises a signal peptide and linker region (Abstract [0001]). Schonfeld et al. teach the signal peptide directs the transport and localization of the protein within a cell [0025]. Schonfeld et al. teach that the signal peptide allows the transport of the multi-functional protein of the invention to the cel membrane and surface and allows the correct localization of the multi-functional protein [0026]. Schonfeld et al. teach the linker region serves as a flexible spacer and is essential for the functionality of the multi-functional proteins of the invention.
With respect to claims 65 and 177, it would have been obvious to a person or ordinary skill in the art to include a signal peptide and linker in the CAR to allow for the proper transport and localization of the CAR. A person would be motivated to also include the linker because Schonfeld et al. teach its essential for the functionality of the proteins. It would have been obvious to optimize the placement of the signal peptide and linker in the fusion protein. There is a reasonable expectation of success given that signal peptides and linkers are routinely used in fusion proteins to ensure proper localization.
Response to Arguments
Applicant's arguments filed 10/22/25 have been fully considered but they are not persuasive. Applicants argue that Schonfeld does not cure the deficiencies of Wandless, Heuser, Chen and Bedoya. Applicants argue that a skilled artisan would not have a motivation and reasonable expectation of success to combine the teachings of Wandless, Heuser, Chen, Bedoya and Schonfeld to arrive at the claimed fusion proteins.
This argument is not persuasive for the reasons presented above. Furthermore, it would have been obvious to a person or ordinary skill in the art to include a signal peptide and linker in the CAR to allow for the proper transport and localization of the CAR. A person would be motivated to also include the linker because Schonfeld et al. teach its essential for the functionality of the proteins. It would have been obvious to optimize the placement of the signal peptide and linker in the fusion protein. There is a reasonable expectation of success given that signal peptides and linkers are routinely used in fusion proteins to ensure proper localization.
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 6, 16, 33, 37, 43, 46, 50, 54, 64-65, 69-70, 73-75, 77, 167-169, 170, 173-175, 176-177 and 180-182 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,999,802. Although the claims at issue are not identical, they are not patentably distinct from each other because the USPN claims a fusion protein comprising a CRBN binding polypeptide and a CAR (claim 1), wherein the fusion protein further comprises a degradation domain (claim 5), wherein the fusion protein comprises a degradation domain, a heterologous protease cleavage site, the CAR and a CRBN binding peptide (claim 6), wherein the degradation domain is an ER domain (claims 16-17), wherein the heterologous cleavage site is a furin site (claims 24-26), wherein the degradation domain is an FKBP domain of DHFR domain (claims 28-32). Therefore, the USPN claims a fusion protein comprising a CAR, the same degradation domains as instantly claimed and a heterologous protease site. Please note the claim language of claim 6 is open and therefore does not preclude other components to the fusion protein. Therefore, the USPN anticipates the instant claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TARA L MARTINEZ whose telephone number is (571)270-1470. The examiner can normally be reached Mon-Fri 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TARA L MARTINEZ/Examiner, Art Unit 1654