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 .
Application Status
The Response to the Restriction/Election of Species Requirement filed on May 5, 2026 has been entered. Applicant’s election without traverse of the invention of Group I, drawn to method of treatment that comprises administering an engineered cell or nucleic acid comprising an inducible cell death system, is acknowledged. Applicant's further election without traverse of the corresponding species of inducible cell death system in which (a) the ligand-binding domains are the same and correspond to the hormone binding domain of the estrogen receptor (ER), having the amino acid sequence of SEQ ID NO: 42, with a cognate ligand of tamoxifen, and (b) the cell death-inducing domain derived from caspase 9, having the amino acid sequence of SEQ ID NO: 39, is further acknowledged. Applicant submits that claims 21-23 and 41-46 read on the elected invention and species.
The amended claims filed May 5, 2026 are acknowledged. Claims 21-25, 32-34, and 39-46 are pending. Claims 26-31 and 35-38 have been canceled. Claims 21 and 23 are amended. Claims 41-46 are newly added. Claims 221, 24-25, 32-34, and 39-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 21, 23, and 41-46 are examined herein on the merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See ¶ 00238. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Applicant may remedy this objection by removing the leading “www.” from the URL.
Claim Rejections - 35 USC § 112(b)
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 21, 23, 41-42, and 45-46 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 21 recites the limitation that “the polypeptide monomers are configured to oligomerize upon contacting the polypeptide monomers with a cognate ligand of the one or more ligand binding domains” (lines 7-9). This limitation renders the intended claim scope unclear because each of the “two or more” polypeptide monomers comprises one or more ligand-binding domains, which may either comprise (i) the same ligand-binding domain, thereby binding to the same cognate ligand (lines 11-24), or (ii) a first polypeptide monomer comprising a first ligand-binding domain and a second polypeptide monomer comprising a second ligand-binding domain, which differ from one another and thus bind to different cognate ligands (lines 25-29). Is the corresponding cognate ligand for each of the two or more polypeptide monomers administered (i.e., at least one per ligand-binding domain for each monomer)? When the ligand-binding domains differ, are the two (or more) corresponding cognate ligands administered? When the cognate ligand for one ligand-binding domain but not the other is administered, is this sufficient to promote oligomerization of both polypeptide monomers? The ambiguity regarding the intended claim scope thus renders the claim indefinite.
Claims 23 and 43-46 do not remedy this ambiguity and are similarly rejected. It is noted that while claims 43-44 each recite a specific cognate ligand, it is not clear whether the cognate ligand is intended to the one or more ligand-binding domains of the first monomer, the one or more ligand-binding domains of the second monomer, an additional monomer(s), or a combination thereof.
In addition, claims 21 and 41 recite that the ligand-binding domain of (i) comprises a “functional fragment” of one of a grouping of ligand-binding domains, while claim 45 recites that the cell death-inducing domain comprises “a functional truncation” of caspase 9. The terms “functional fragment” or “functional truncation” in the claims are relative terms which render the claim indefinite. The terms “functional fragment” or “functional truncation” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. What is the minimum and/or specific structure required, for example, for a hormone-binding domain of the estrogen receptor or for a progesterone receptor domain, to perform the required function of binding to a cognate ligand? Or the minimum and/or specific structure required for a truncation of caspase 9 to induce cell death?
Claim Rejections - 35 USC § 112(a)
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 21, 23, 41, and 43-46 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 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
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).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is a method of treatment wherein an engineered cell comprising an inducible cell death system or an engineered nucleic acid comprising the inducible cell death system is delivered to a subject in need thereof, which comprises two or more polypeptide monomers configured to oligomerize upon contacting the polypeptide monomers with a cognate ligand of the one or more ligand-binding domains of said polypeptide monomer(s), wherein the two or more polypeptide monomers comprise the same ligand-binding domain comprising a heavy chain variable region (VH) of an anti-nicotine antibody (e.g., claim 21 and dependent claims 23 and 45-46) or a “functional fragment” of a hormone-binding domain of estrogen receptor (ER) domain, a PYL domain, or a cannabidiol binding domain (e.g., claims 21, 23, 41, and 43-46). These limitations fail to satisfy the written description requirement because an insufficient level of structure is recited for carrying out the claimed functions of binding to a cognate ligand and oligomerizing with another polypeptide monomer. With respect to the anti-nicotine antibody VH, it is understood in the art that a VH and light chain variable region (VL) chain in a traditional immunoglobulin-based antibody, not two VH regions or two VL regions, would be expected to pair to form a functional binding domain for a ligand. With respect to the “functional fragments” of a hormone-binding domain of ER, etc., as also noted in the 35 U.S.C. § 112(b), it is not clear from the disclosure what minimum or specific portion of each respective structure is required to carry out the claimed function of ligand-binding and oligomerization.
Further at issue is the method of treatment above, wherein the cell death-inducing domain comprises “a functional truncation” of caspase 9 as set forth in claim 45. As also noted in the 35 U.S.C. § 112(b), it is not clear from the disclosure what minimum or specific portion of each respective structure is required to carry out the claimed function of inducing cell death.
State of the prior art. With respect to traditional immunoglobulins, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3).
With respect to ERs, Yasar (Reproductive Medicine and Biology (2016) 16: 4-20) teaches that ERs comprise a multifunctional carboxyl-terminal (E) domain, also called a ligand-binding domain, which comprises a hormone-binding site, a dimerization interface (homo- and heterodimerization), and a ligand-dependent co-regulator interaction function (activation function, AF-2) (e.g., pages 5-6), illustrated in Figure 1. Yasar states, “The binding of E2 is the pivotal step in the cellular action of the ERs that are present as dimers at the peri‐membrane, mitochondria, and nucleus. Estradiol binding induces a major structural re‐organization of the LBD that converts the inactive ER to the functionally active form by generating surfaces for enhanced stability of the ER dimer and of the interacting co‐regulatory proteins” (page 5). Yasar further states, “Although the structural features of the LBDs of ERα and ERβ largely overlap, the ligand‐binding pocket of ERβ differs from that of ERα, with only two amino‐acid positions. This, together with distinct residues outside of the LBD, generates differences in the size of the pockets that allow the binding of a ligand to receptors in a subtype‐specific manner” (page 7). Yasar further teaches that ERs also bind to various molecules with agonist, antagonist, or mixed agonist-antagonist properties, including tamoxifen and raloxifene (e.g., page 7). Yasar illustrates differences observed in the binding conformation of ERα to E2 versus 4-hydroxytamoxifen in Figure 3.
With respect to PYL domains, Zhang (Frontiers in Plant Science (2015) 6: 88) teaches that a family of PYLs has been identified as bona fide abscisic acid (ABA) receptors (e.g., Abstract; Figure 1). Regarding the mechanism of ABA binding to PYLs, Zhang discloses: “Based on ABA-bound structures, such as PYR1, PYL1, PYL2, PYL3, PYL9, and PYL10, These structural architectures share a common ligand-binding pocket. The L2 loop between the α3 helix and β2 strand, the L4 loop (also referred to as CL2 or “gate” loop) between the β3 and β4 strands, the L5 loop (also referred to as CL3 or “latch” loop) between the β5 and β6 strands, and the C-terminal helix α4 encompass the entrance of the ligand-binding pocket (Figure 2B, Figure S2), which is very important for ABA binding. PYLs possess a large internal cavity in which the ABA molecule sits by a combination of ionic bonds, hydrophobic interactions and water-mediated hydrogen bonds (Figure 2B, Figures S1, S2). The carboxyl of ABA forms a salt bridge with the amine group of lysine (PYR1 K59, PYL1 K86, PYL2 K64, PYL3 K79, PYL9 K63, and PYL10 K56) as well as a water-mediated hydrogen bond network with several side chains of polar residues. (…) Moreover, the hydroxyl group and the ketone group of ABA also interact with the polar side chains of PYLs through water-mediated hydrogen bonds. In addition, the pentadienoic acid moieties and the cyclohexene contact hydrophobically with many inward-facing apolar side chains in the PYLs' cavity. These residues that are involved in binding ABA are strictly conserved in PYLs” (pages 2-3).
With respect to caspase-9, Li (Oncotarget (2017) 8(14): 23996-24008) teaches that caspase-9 is comprise of three major domains: (1) a pro-domain, which comprises the Apaf-1 binding CARD domain; (2) a large subunit catalytic domain (LSCD); and (3) a small subunit catalytic domain (SSCD), illustrated in Figure 1. Li teaches that the activity of caspase-9 is stimulated by dimerization instead of cleavage (e.g., pages 23996-23997). Li discloses that one proposed hypothesis for how activation of caspase-9 takes place is the “induced conformation model”, which states that Apaf-1 binding to the caspase-9 CARD domain creates a conformational change in caspase-9 and is essential for activation (e.g., page 23997). An alternative hypothesis proposes that induced proximity promotes the formation of dimers that subsequently become activated and promote cell death (e.g., page 23997). Li further describes the inducible caspase-9 (iCasp9) construct, which is used in adoptive therapy as a suicide gene (e.g., page 24002). Li states that the optimized iCasp9 is based on a drug-binding domain, FK506-F36V linked via a short linker to Δcaspase9, a caspase-9 without its physiological CARD domain (e.g., page 24002). A chemical inducer of dimerization (CID), e.g., AP1903 or AP20187, is administered in order to activate the dimerization of Δcaspase9 and lead to apoptosis (e.g., page 24002).
Scope of species disclosed in original specification. Example 1 (page 148) describes possible inducible cell death systems and methods of the disclosure. System 1 (pertinent to the examined claims herein) comprises small molecule-regulated dimer- or oligomerization domains, illustrated in Figure 1A. Chemical induction of dimerization/oligomerization/proximity activates a pro-cell death-inducing gene producing by binding to specific ligand-binding domains (e.g., page 148). Table A describes exemplary systems which can be made, including selected systems in which iCasp9 is linked with ERT2 or ER and activated by tamoxifen or derivatives thereof (pages 149-150). Two constructs further comprise either FKBP or FRB in the ligand-binding domain. Proposed sequences of the component parts are shown in Table D. Example 3 (pages 168-169) describes a construct “SB03080”, comprising a progesterone receptor domain, a Gly/Ser linker, and iCasp9, which upon addition of mifepristone causes oligomerization through binding of the progesterone receptor domain to mifepristone (e.g., Figure 3A) and increases cell death as measured by %apoptotic and %dead cells (e.g., Figure 3B).
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. 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.
Although a number of species of estrogen receptor/caspase-9 inducible cell death systems and others have been set forth, they cannot be considered representative. For the ER/caspase-9 constructs in particular (as elected by Applicant), only one exemplary structure for the ER hormone-binding domains appears to be fully described (i.e., the ERT2 mutant domain set forth in SEQ ID NO: 42; see Table D at page 155), and two exemplary structures for caspase-9 are described: the caspase-9 domain having the amino acid sequence of SEQ ID NO: 39, and the iCasp9 domain comprising the amino acid sequence of SEQ ID NO: 48 (which comprises 100% sequence identity to residues 137-415 of SEQ ID NO: 33). The specification does not appear to provide support for the many possible functional fragments or truncations of these elements (aside from iCasp9 as a “truncation” of caspase-9) that are within the scope of the claims. The specification also does not provide guidance on which residues can be omitted or truncated from any given ligand-binding domain or cell death-inducing domain without affecting the function of the claimed system.
In addition, it is noted that while some of the claimed ligand-binding domains are drawn to structurally alike proteins that dimerize upon ligand binding (e.g., ER, progesterone receptor), it is noted that those comprising a VH or a VL from a conventional immunoglobulin antibody would not be expected to perform similarly based on the state of the art unless a functional pairing of a VH and VL, which together demonstrate the ability to bind to the cognate ligand, is present between two polypeptide monomers. A single-domain antibody (e.g., VHH) having three defined CDRs is a self-contained unit that would be expected to bind to its cognate antigen and does not need to dimerize with a second molecule to carry out this function.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless inducible cell death systems encompassed by the highly general structural requirements of the claims would also possess the required functional activity. 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, the Applicant did not possess the full genus as broadly claimed at the time the application was filed.
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.
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.
Claims 21, 23, and 41-45 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chu (US 2011/0023137 A1).
Chu describes fusion proteins comprising a Caspase domain and a ligand-binding domain of a nuclear hormone receptor, as well as medicaments comprising said fusion proteins and their use in the treatment of cancer or for/after transplantation (e.g., Abstract). In embodiments of the invention, Chu provides for fusion proteins in which a domain of Caspase 9 and a ligand-binding domain of a mutant mammalian estrogen receptor ER(T2), which upon expression in mammalian cells conditionally induces apoptosis in said cells upon exposure to a ligand for said ligand-binding domain (e.g., ¶ 0034-0050; claims 1-11). Chu teaches that the ER(T2) domain dimerizes upon administration of the synthetic ligand 4-OT-tamoxifen ligand and activates Caspase to induce apoptosis (e.g., ¶ 0079; Example 1 at ¶ 0200-0213; Examples 3-4 at ¶ 0221-0231). Regarding claims 21, 23, 41, 43, and 45, Chu teaches methods for treating a disease by administering to a patient an effective amount of a fusion protein of the invention or a nucleic acid encoding the same (e.g., ¶ 0163-0173). Regarding claim 42, Chu teaches that in a preferred embodiment the nuclear hormone receptor LBD comprises an amino acid sequence of SEQ ID NO: 80 (e.g., ¶ 0088, 0107), which comprises the ER LBD comprising instant SEQ ID NO: 42. See Office Action Appendix. Regarding claim 44, Chu teaches that tamoxifen can be used as the ligand for ER(T2) LBD in in vivo applications and that tamoxifen is metabolized in the liver into the ER(T2) ligand 4-OH-tamoxifen (e.g., ¶ 0086).
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.
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.
Claims 21, 23, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Chu (US 2011/0023137 A1; supra) as applied to claims 21, 23, and 41-45 above, further in view of Bamber (US 2022/0380801 A1; earliest priority date: July 15, 2019) and NCBI (Entry: “caspase 9, apoptosis-related cysteine protease [Homo sapiens]”, GenBank: AAO21133.1; January 18, 2003).
The teachings of Chu are recited in the 35 U.S.C. § 102 rejection above.
While Chu teaches selected caspase-9 sequences, Chu does not expressly teach a caspase-9 domain comprising the amino acid sequence of instant SEQ ID NO: 39.
Bamber describes compositions that make use of a target protein capable of binding to a small molecule in order to form a complex and a binding member that specifically binds to the complex, which can be used to control the activity of dimerization-inducible proteins (e.g., Abstract). Bamber states, “In particular, it was realised that the approach [described herein] could be implemented to control the activity of proteins that require dimerization or clustering to drive their activity. Such proteins are termed herein as “dimerization-inducible proteins” and include “split proteins”, “dimerization-deficient proteins” and “split complexes”. (…) Dimerization-deficient proteins are proteins that require dimerization for activity, but their endogenous dimerization capacity has been disabled e.g. via mutation or removal of the dimerization domain(s). One such example is the iCasp9 molecule, a caspase 9 protein that has had its dimerization (CARD) domain removed” (¶ 0027). Bamber teaches that the dimerization-inducible protein may be a split apoptotic protein (i.e., a protein capable of inducing apoptosis when the first and second component polypeptides dimerize) such as split caspase 9, e.g., where both the first and second components comprise caspase 9 activation domains as provided in amino acids 152-414 of the human caspase 9 amino acid sequence provided as NCBI accession number AAO21133.1 (e.g., ¶ 0378-0381).
Residues 2-416 of the human caspase 9 amino acid sequence provided by NCBI comprise 100% sequence identity to instant SEQ ID NO: 39. The CARD domain of caspase 9 corresponds to residues 17-90 of the human caspase 9 sequence set forth by NCBI.
In view of the further teachings of Bamber, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the caspase-9/ER fusion proteins described by Chu by substituting the caspase-9 domain taught by Bamber and NCBI. The skilled artisan would have been motivated to do so because a caspase-9 comprising at least both of the CARD domain and the activation domain would be expected to have the ability to dimerize and thus promote cell death. Bamber notes that an exemplary caspase-9 which has had its CARD domain removed (iCasp9) loses its endogenous dimerization activity. There would have been a reasonable expectation of success because the caspase-9 domains described by Chu and by Bamber and NCBI are functional equivalents suitable for use for the same purpose.
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.
(1)
Claims 21, 23, 41, and 43-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of co-pending Application No. 19/287,644 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
The ‘644 reference application recites a method of treating a patient in need thereof, comprising administering a gene-edited target cell comprising a nucleic acid encoding a fusion polypeptide comprising (1) a modified ER ligand-binding domain with mutations of G400V, M543A, and L544A relative to SEQ ID NO: 1 (which are comprised in the ligand-binding domain having the amino acid sequence of instant SEQ ID NO: 42) and one or more additional amino acid substitutions, and (2)a caspase-9 domain or functional fragment thereof (e.g., co-pending claims 12-15 and 18), wherein the inducer of the ER-LBD is tamoxifen or a tamoxifen metabolite (e.g., co-pending claim 16).
(2)
Claims 21, 23, 41, 43, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of co-pending Application No. 19/288,667 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
The ‘667 reference application recites a method of inducing oligomerization of a chimeric protein, which comprises contacting a transformed cell encoding a heterologous construct encoding the inducible cell death system of co-pending claim 1 with a non-endogenous ligand (4-hydroxytamoxifen, endoxifen, i.e., tamoxifen metabolites), which is administered to the human or animal (e.g., co-pending claim 14). (By virtue of the contacting, the engineered cell must have been delivered to the human/animal in order to be contacted with the non-endogenous ligand.) The inducible cell death system comprises a first polypeptide monomer and a second polypeptide monomer, each comprising (1) a ligand-binding domain comprising a modified ER ligand-binding domain with mutations of G400V, M543A, and L544A relative to SEQ ID NO: 1 (which are comprised in the ligand-binding domain having the amino acid sequence of instant SEQ ID NO: 42) and one or more additional amino acid substitutions, and (2) a cell death inducing domain, which is caspase 9 (e.g., co-pending claims 1, 5, 7, 8).
(3)
Claims 21, 23, and 44-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-21 of co-pending Application No. 19/288,667 further in view of Chu (US 2011/0023137 A1; supra), Bamber (US 2022/0380801 A1; supra), and NCBI (GenBank: AAO21133.1; supra).
The teachings of the ‘667 reference application are recited in the provisional non-statutory double patenting rejection above.
The co-pending reference application does not expressly teach a caspase-9 domain comprising the amino acid sequence of instant SEQ ID NO: 39, or that the cognate ligand administered is tamoxifen.
The teachings of Chu, Bamber and NCBI are recited in the 35 U.S.C. § 103 rejection above.
In view of the further teachings of Chu, Bamber, and NCBI, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the caspase-9/ER fusion proteins described in the co-pending claims by incorporating the caspase-9 domain taught by Bamber and NCBI, and to use tamoxifen as the cognate ligand based on the teachings of Chu. The skilled artisan would have been motivated to do so because a caspase-9 comprising at least both of the CARD domain and the activation domain would be expected to have the ability to dimerize and thus promote cell death. Bamber notes that an exemplary caspase-9 which has had its CARD domain removed (iCasp9) loses its endogenous dimerization activity. With respect to using tamoxifen instead of the metabolite 4-OH-tamoxifen, Chu teaches that tamoxifen is metabolized to 4-OH-tamoxifen in vivo. There would have been a reasonable expectation of success because the caspase-9 domains described in the co-pending claims and by Bamber and NCBI are functional equivalents suitable for use for the same purpose.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Chu (Genesis (2008) 46: 530-536; cited in IDS), authored by the same inventor as Chu (US 2011/0023137 A1) above, describes fusion proteins comprising Caspase-9 and a mutant ER ligand-binding domain (ERT2) which induce apoptosis upon introduction of a ligand. The mechanism by which dimerization of the fusion proteins induces apoptosis upon binding of the ligand to the ERT2 LBD is illustrated in Figure 1A, reproduced below:
PNG
media_image1.png
278
400
media_image1.png
Greyscale
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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, Julie Wu can be reached at (571) 272-5205. 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.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 While Applicant submits that claim 22 reads on the elected invention, it is noted that the alternative embodiments recited in the claim all appear to be drawn to polypeptide monomers in which the first ligand-binding domain differs from the second ligand-binding domain. Because Applicant has elected ligand-binding domains which are the same (see Remarks filed May 5, 2026 at page 10), it is believed that the limitations in claim 22 do not read on the elected species.
Prosecution Insights