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 amended claims filed August 14, 2024 are acknowledged. Claims 3-4, 9, 11-20, 24-28, 30, 32-41, 45, and 47 are canceled. Claims 2, 5, 8, 10, 21-23, 29, 31, 42, 44, 46, 48-49, and 51-53 are amended. Claim 55 is newly added.
Claims 1-2, 5-8, 10, 21-23, 29, 31, 42-44, 46, and 48-55 are pending and under examination herein.
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 2, 8, 10, 23, 29, 31, 43-44, and 51 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.
Regarding claims 2, 8, 10, 23, 29, 31, and 43, the phrase “optionally” renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Claim 44, which depends from claim 43 and does not remedy this deficiency, is similarly rejected.
It is noted for Applicant that limitations designated as “optional” will not be considered required for the purposes of applying prior art under 35 U.S.C. §§ 102 and 103.
Claim 51 recites a method of making an immune effector cell, wherein a composition is introduced into an immune cell that comprises “two or more nucleic acids each encoding one or two of p40 subunit of IL-12, CCL-19; and a functional exogenous receptor” or “two or more nucleic acids each encoding one or two of p40 subunit of IL-12, CCL-21; and a functional exogenous receptor”. The phrasing and punctuation used in the claim does not make it clear whether the respective compositions are intended to comprise (1) one or two nucleic acids each encoding a IL-12p40 subunit, one or two nucleic acids each encoding CCL-19/CCL-21, and one nucleic acid encoding a functional exogenous receptor, or (2) one or two nucleic acids encoding a IL-12p40 subunit, one nucleic acid encoding CCL-19/CCL-21, and one nucleic acid encoding a functional exogenous receptor.
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 2, 5-7, 23, 43, and 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 an immune effector cell expressing (1) an exogenously introduced IL-12 p40 subunit fragment or a variant of the IL-12 p40 subunit having at least 75% to at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 5 (as in claim 2) and (2) an exogenously introduced CCL-19 fragment or a variant of CCL-19 having at least 75% to at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 6, or an exogenously introduced CCL-21 fragment or a variant of CCL-21 having at least 75% to at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 22 (as in claims 5-7). The instant claims are further drawn to a polypeptide comprising the same (as in claim 23), wherein a domain expressing the p40 subunit and CCL-19 may comprise an amino acid sequence having at least 75% to at least 99% sequence identity to SEQ ID NO: 4 or wherein a domain expressing the p40 subunit and CCL-21 may comprise an amino acid sequence having at least 75% to at least 99% sequence identity to SEQ ID NO: 20. In addition, the scope of claim 43 is drawn to variants of the 2A self-cleaving peptides F2A, E2A, P2A, and T2A.
IL-12 p40, CCL-19, CCL-21, and 2A peptides each have recognized functions and activities in the art. Accordingly, one of ordinary skill in the art would recognize that absent a showing otherwise, fragments or variants thereof would not be expected to possess the same or equivalent levels of functionality.
State of the prior art. Moelling (WO 2006/032525 A2; cited in IDS) teaches that IL-12, a heterodimeric cytokine comprising p35 and p40 subunits, enhances T cell- and natural killer (NK)-cell-mediated cytotoxicity and proliferation, stimulates IFN-γ and IL-2 secretion, and, when administered in vivo, exerts anti-tumor activity (e.g., pages 1-4). Ma (Nature Biotechnology (2020) 38(4): 448-459; cited in IDS) provides that the IL-12p40 subunit is also a component of IL-23, and that engineering expression of the p40 subunit in CAR T cells resulted in selective proliferative activity in activated T cells via autocrine IL-23 signaling and yielded improved anti-tumor activity in vitro and in vivo (e.g., Abstract; Results; Figures 3-6). Modified immune effector cells expressing a CAR and exogenous IL-12p40 are also described by, e.g., Li (US 2022/0056408 A1, English language equivalent of WO 2020/118634 A1, cited in IDS) and Dotti (WO 2021/055915 A1; cited in IDS).
Moelling further teaches that CCL19 and CCL21 are both ligands of the CCR7 receptor, which is expressed on naïve T cells and dendritic cells (page 3). Moelling discloses that CCL19 and CCL21 act as chemo-attractants for naïve T cells and dendritic cells, and demonstrate anti-tumor activity (e.g., page 3; Examples). Moelling further discloses that the combination of IL-12 with CCL19 or CCL21 produces a synergistic effect (e.g., pages 3, 9; Examples). Adachi (Nature Biotechnology (2018) 36(4): 346-351) describes CAR T cells which were further engineered to express IL-7 and CCL19, connected via a 2A peptide, which promoted increased infiltration of dendritic cells and T cells into the tumor site and generated memory responses against tumors (e.g., whole document).
2A peptides are among several means of facilitating the cloning of multiple genes (e.g., IL-12 and CCL19 or CCL21) into a single vector. Liu (Scientific Reports (2017) 7: Article 2193) teaches that 2A “self-cleaving” peptides have attracted considerable interest for this purpose because of their polycistronic nature, small size, and high “cleavage” efficiency (e.g., Abstract). Liu discloses that 2A peptides are 18-22 amino acid residue-long oligopeptides that mediate “cleavage” of polypeptides during translation in eukaryotic cells, the mechanism of which was determined to be ribosome skipping the formation of a glycyl-prolyl peptide bond at the C-terminus of the 2A (e.g., Introduction; Figure 1A). Liu notes, “A highly conserved sequence GDVEXNPGP is shared by different 2As at the C-terminus (Fig. 1B), and is essential for the creation of steric hindrance and ribosome skipping” (Introduction). Liu also notes that studies have suggested that either P2A (comprising the amino acid sequence of instant SEQ ID NO: 13) or T2A (comprising the amino acid sequence of instant SEQ ID NO: 14), as shown in Figure 1B, show the strongest efficiency (e.g., Introduction).
Scope of species disclosed in original specification. The Examples describe exemplary embodiments of the invention comprising anti-GPC3 CAR-T cells expressing exogenously introduced IL-12 p40 and CCL-19 (e.g., Examples 1-4) or IL-12p40 and CCL-21 (e.g., Examples 5-10). With respect to the CAR, a humanized anti-GPC3 CAR (“H93 CAR”) comprising an anti-GPC3 scFv, a CD8α hinge, a CD8α transmembrane domain, a CD137 co-stimulatory signaling domain, and a CD3ζ cytoplasmic domain was synthesized and linked to a CD8α signal peptide (e.g., Example 1; Figure 1).
Example 1 discloses that multi-cloning sites (MCS) in H93M CAR allowed for the insertion of a nucleic acid sequence encoding human IL-12 p40 (SEQ ID NO: 5) and human CCL-19 (SEQ ID NO: 6) linked by a 2A self-cleaving peptide (e.g., a T2A peptide having the amino acid sequence of SEQ ID NO: 14) to produce a IL12p40-T2A-CCL-19 peptide which was cloned into the CAR backbone, generating the “H93M CAR” (pages 128-129). The H93 and H93M CARs were transduced into T cells purified from PBMCs (Example 1, pages 129-130). Example 2 recites that only the H93M CAR T cells secreted IL-23 and CCL-19. See also Figure 3. H93M CAR T cells showed higher cytotoxicity, secreted higher levels of TNF-α and IFN-γ, and secreted lower levels of PD1 and LAG3 (exhaustion markers) than H93 CAR T cells (e.g., Examples 2 and 4; Figures 5, 7, 9). Example 4 also discloses that H93M CAR T cells improved T cell infiltration into tumor site and induced more macrophage and dendritic cell (DC) recruitment in the tumor tissues (e.g., Figures 12-13).
Example 5 discloses the preparation of “H93P” CAR T cells comprising a CAR as described above, a human IL-12p40 subunit, a 2A self-cleaving peptide linker, and CCL-21, and having the amino acid sequence of SEQ ID NO: 18 (e.g., Figure 1). SEQ ID NO: 18 comprises the human IL-12p40 amino acid sequence of SEQ ID NO: 5 at residues 516-843, the T2A self-cleaving peptide comprising the amino acid sequence of SEQ ID NO: 14 at residues 844-864, and the human CCL-21 amino acid sequence of SEQ ID NO: 22 at residues 865-998. The H93P CAR T cells secreted IL-23 and CCL-21 (e.g., Example 6; Figure 14) and had anti-tumor efficacy (e.g., Example 8; Figure 17).
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.
As summarized above, the exemplary embodiments set forth in the specification comprise (1) a full-length, wild-type human IL-12p40 subunit having the amino acid sequence of SEQ ID NO: 5 and a full-length, wild-type human CCL-19 peptide comprising the amino acid sequence of SEQ ID NO: 6, linked to one another via a wild-type T2A peptide linker, or (2) a full-length, wild-type human IL-12p40 subunit having the amino acid sequence of SEQ ID NO: 5 and a full-length, wild-type human CCL-21 peptide comprising the amino acid sequence of SEQ ID NO: 22, linked to one another via a wild-type T2A peptide linker. Further, the use of wild-type 2A peptide linkers such as P2A and T2A are well within the skill of one of ordinary skill in the art, and it is recognized that a conserved C-terminal sequence is essential among 2A peptides for their function. The disclosure does not provide a showing of how portion(s) of or amino acid residues within any of these peptides, or which ones, may be mutated (to generate a variant) or deleted (to create a fragment) while retaining their respective functions. Accordingly, Applicant's disclosure does not provide adequate written description support for fragments or variants of IL-12p40, CCL-19, and CCL-21, or for variants of a 2A self-cleaving peptide.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless IL-12p40 subunit, CCL-19 or CCL-21 peptide, and 2A peptide fragments/variants encompassed by the highly general structural requirements of the claims would also possess the requisite functional activity. Given 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 of IL-12p40 subunit, CCL-19/CCL-21, and 2A peptide linker fragments and variants 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 1-2, 5-8, 10, 21-23, 29, 31, 42-44, 46, and 48-55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fan (WO 2021/170100 A1; earliest priority date: February 27, 2020; cited in IDS).
The applied reference has common inventors (X. FAN, J. MAO, Q. ZHUANG) and a common applicant (NANJING LEGEND BIOTECH CO., LTD.) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Fan discloses anti-glypican-3 (GPC3) chimeric antigen receptors (CARs) containing an anti-GPC3 extracellular antigen-binding domain, a transmembrane domain, and intracellular domain, and immune effector cells transduced with said anti-GPC3 CARs which can be used for cancer immunotherapy (e.g., Abstract; ¶ 0005-0033). Regarding claims 1-2, 5-8, 22-23, and 29, Fan teaches that an anti-GPC3 CAR of the invention may comprise a polypeptide comprising an exogenously introduced human IL-12 p40 subunit comprising the amino acid sequence of SEQ ID NO: 135 (which shares 100% sequence identity to instant SEQ ID NO: 5) and an exogenously introduced human CCL-19 having the amino acid sequence of SEQ ID NO: 136 (which shares 100% sequence identity to instant SEQ ID NO: 6) (e.g., ¶ 0026-0034, 00286-00327). (While claims 7 and 23 set forth further limitations with respect to the exogenous CCL-21, the claims do not require that the CCR7 ligand is CCL-21 if the other condition (i.e., that the ligand is CCL-19) is satisfied.) Regarding claims 42-44 and 46, Fan recites that in some embodiments the p40 and CCL-19 are present on a domain comprising the amino acid sequence of SEQ ID NO: 134 (which shares 100% sequence identity to instant SEQ ID NO: 4) and are linked by a self-cleaving peptide such as a T2A fragment comprising the amino acid sequence of SEQ ID NO: 139 (which shares 100% sequence identity to instant SEQ ID NO: 14) or a P2A fragment comprising the amino acid sequence of SEQ ID NO: 138 (which shares 100% sequence identity to instant SEQ ID NO: 13) (e.g., ¶ 0027).
Regarding claims 10 and 31, Fan teaches that (i) the transmembrane domain of the CAR is derived from the group consisting of CD8α and others, (ii-iii) the intracellular domain of the CAR comprises a primary intracellular signaling domain derived from CD3ζ and a co-stimulatory signaling domain derived from CD28 or CD137, (iv) a hinge domain derived from CD8α, and (v) a signal peptide located at the N-terminus of the polypeptide, also derived from CD8α (e.g., ¶ 0019-0025, 00286-00327).
Regarding claim 21, the immune effector cell is a T cell (e.g., ¶ 0029).
Fan further describes vectors comprising nucleic acids encoding the CARs or polypeptides of the invention, as well as methods for introducing said vectors into immune effector cells using methods known in the art (e.g., ¶ 0028-0030, 00331-00356), anticipating claims 48-52 and 55. Regarding claim 53, Fan discloses therapeutic compositions comprising the immune effector cells of the invention (e.g., ¶ 0031-0033).
Fan also describes a method of treating a GPC3-expressing cancer that comprises administering a composition of the invention (e.g., Abstract; ¶ 0032), anticipating claim 54.
This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 5-8, 10, 21-23, 29, 31, 42-44, 46, and 48-55 are rejected under 35 U.S.C. 103 as being unpatentable over Klingemann (US 2020/0038441 A1) in view of Ma (WO 2020/077356 A1; published April 16, 2020; cited in IDS) and Moelling (WO 2006/032525 A2; supra), and as evidenced by Liu (Scientific Reports (2017) 7: Article 2193; supra).
Klingemann discloses quadricistronic systems comprising NK-92® cells, wherein the NK-92® cells comprise one or more nucleic acids encoding a homing receptor, a CAR that specifically binds to a target antigen, and/or a cytokine, wherein the nucleic acid sequence is operably linked to a promoter (e.g., Abstract). Klingemann teaches that the homing receptor is selected from, inter alia, CCL19 and CCL21, and the cytokine is IL-12, the latter of which Klingemann teaches improves the function of NK-92® cells as immunotherapeutic agents (e.g., ¶ 0009-0042). Klingemann discloses that the IL-12 may comprise the amino acid sequence of SEQ ID NO: 60 (which shares 100% sequence identity to instant SEQ ID NO: 5), that the CCL19 comprises the amino acid sequence of SEQ ID NO: 45 (which shares 100% sequence identity to instant SEQ ID NO: 6), and that the CCL21 comprises the amino acid sequence of SEQ ID NO: 46 (which shares 100% sequence identity to instant SEQ ID NO: 22) (e.g., ¶ 0123, 0137), relevant to claims 1-2, 5-7, and 22-23. Relevant to claims 8, 10, 29, and 31, the CARs expressed by the NK-92® cells of the invention comprise an intracellular signaling domain, a CD8α hinge region, and a CD28 transmembrane domain (e.g., ¶ 0025-0031).
Relevant to claims 42-44 and 48-49, Klingemann discloses that nucleic acid constructs of the invention may comprise a 2A peptide such as a T2A or P2A peptide to string together multiple genes under the control of a single promoter (e.g., ¶ 0031, 0116-0141). As evidenced by Liu, the T2A and P2A peptides comprise the amino acid sequences corresponding to SEQ ID NO: 14 and 13, respectively (e.g., Figure 1B). Relevant to claims 50-52 and 55, Klingemann teaches expression vectors comprising nucleic acid constructs of the invention, as well as methods of producing the NK-92® cells of the invention by transforming NK-92® cells with an expression vector comprising a nucleic acid construct of the invention operably linked to a promoter (e.g., ¶ 0144-0151).
Relevant to claims 53-54, Klingemann further provides methods of treating cancer that comprise administering compositions comprising the engineered NK-92® cells of the invention (e.g., ¶ 0152-0169; claims 14-16).
While Klingemann discloses modified NK-92® cells co-expressing a polypeptide comprising a CAR and IL-12p40 or a CAR and one of CCL19 and CCL21, Klingemann does not expressly disclose an embodiment in which the immune effector cell or polypeptide comprises a CAR, IL-12p40, and one of CCL19 or CCL21.
Ma describes engineered cells having at least one CAR polypeptide and at least one of a cytokine and chemokine (Abstract). Relevant to claims 1, 8, and 21-22, Ma discloses an engineered cell (e.g., T cell, natural killer (NK) cell) comprising (i) a CAR polypeptide, (ii) at least one heterologously expressed cytokine such as IL-12 (which comprises a p40 subunit), and (iii) at least one heterologously expressed chemokine such as CCL19 or CCL21, as well as engineered polypeptides comprising a CAR and at least one enhancer (e.g., IL-12) (e.g., claims 1-14; ¶ 0013-0023, 0302-0333). Relevant to claim 10, Ma discloses CAR polypeptide constructs of the invention comprising a signal peptide, an antigen-binding domain, a hinge region (e.g., CD8α), a transmembrane domain (e.g., CD28), an intracellular co-stimulatory domain (e.g., CD137), and an intracellular signaling domain, as well as polynucleotides encoding said CAR polypeptides (e.g., CD3ζ) (e.g., ¶ 0247-0274). Relevant to claims 53-54, Ma provides method of treating cancer or an autoimmune disease by administering a composition comprising the immune effector cells of the invention (e.g., ¶ 0013-0018; claims 20-25).
As set forth previously, Moelling teaches that IL-12, a heterodimeric cytokine comprising p35 and p40 subunits, enhances T cell- and natural killer (NK)-cell-mediated cytotoxicity and proliferation, stimulates IFN-γ and IL-2 secretion, and, when administered in vivo, exerts anti-tumor activity (e.g., pages 1-4). Moelling further teaches that CCL19 and CCL21 are both ligands of the CCR7 receptor, which is expressed on naïve T cells and dendritic cells (page 3). Moelling discloses that CCL19 and CCL21 act as chemo-attractants for naïve T cells and dendritic cells, and demonstrate anti-tumor activity (e.g., page 3; Examples). Moelling further discloses that the combinations of IL-12 with CCL19 and IL-12 with CCL21 produce a synergistic effect (e.g., pages 3, 9; Examples). As illustrated in Figures 1-3, intratumoral combination treatments of IL-12/CCL19 and IL-12/CCL21 in murine cancer models decreased mean tumor volume and prolonged survival relative to monotherapy regimens comprising the same.
In view of the teachings above, 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 engineered immune effector cells taught by Klingemann to express both an IL-12p40 subunit and one of CCL19 or CCL21. The skilled artisan would have been motivated to do so because Moelling teaches that the combination of IL-12 (which comprises the IL-12p40 subunit) and one of CCL19 or CCL21 demonstrates favorable anti-tumor activity. Expressing these peptides in a single nucleic acid construct with a CAR, linked via a 2A peptide (as demonstrated by Klingemann and Ma), would localize the peptides to the tumor microenvironment, thereby furthering their anti-tumor activities. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that CARs, IL-12p40, and CCL19/CCL21 each have utility in the treatment of cancer, and, as noted in MPEP § 2144.06(I): “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Furthermore, Ma provides a proof-of-concept that a polypeptide having multi-gene co-expression (i.e., expressing a CAR, a cytokine, and a chemokine), as well as immune effector cells comprising said polypeptide, can be generated and used in a method of treatment by a skilled artisan.
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.
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Claims 1, 8, 22, 29, 42, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-14, 18, 29-30, 32, 35, 43-45, and 50-53 of co-pending Application No. 17/798,541 (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.
Regarding claims 22, 29, and 42, the co-pending reference application recites a polypeptide comprising a CAR (comprising an extracellular antigen-binding domain comprising the anti-GPC3 antibody of co-pending claim 1, a transmembrane domain, and an intracellular signaling domain), a p40 subunit of IL-12, and CCL-19, wherein the p40 and CCL-19 are linked by a self-cleaving peptide (co-pending claims 1, 18, 30, 32). Regarding claims 1 and 8, co-pending claims 18 and 43 recite an immune effector cell expression the CAR of co-pending claim 18, an exogenously introduced p40 subunit, and exogenously introduced CCL-19.
Regarding claim 53, co-pending claim 44 recites a pharmaceutical composition comprising the immune effector cell of co-pending claim 43. Regarding claim 54, co-pending claim 45 recites a method of treating a patient having a GPC3-expressing cancer by administering said pharmaceutical composition.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 5-8, 10, 21-23, 29, 31, 42-44, 46, and 48-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-14, 18, 29-30, 32, 35, 43-45, and 50-53 of co-pending Application No. 17/798,541 as applied to claims 1, 8, 22, 29, 42, and 53-54 above, further in view of Klingemann (US 2020/0038441 A1; supra), Ma (WO 2020/077356 A1; supra), Moelling (WO 2006/032525 A2; supra), and Liu (Scientific Reports (2017) 7: Article 2193; supra).
The teachings of the co-pending reference application as they relate to instant claims 1, 8, 22, 29, 42, and 53-54 are described above.
In addition, the co-pending reference application teaches that the p40 and CCL-19 are linked by a self-cleaving peptide (co-pending claim 32), relevant to claims 43-44. Relevant to claims 48-50 and 55, co-pending claims 50-52 recite a cell and a vector comprising a nucleic acid comprising a sequence encoding the CAR of co-pending claim 18.
However, the co-pending reference application does not expressly teach that the p40 is a human IL-12 p40 comprising the amino acid sequence of instant SEQ ID NO: 5 and that the CCL-19 is a human CCL-19 comprising the amino acid sequence of instant SEQ ID NO: 6 (as set forth in claims 2, 5-7, 23, and 46), or that the self-cleaving peptide connecting the two is a T2A self-cleaving peptide comprising the amino acid sequence of instant SEQ ID NO: 14 (as set forth in claims 43-44). The co-pending reference application also does not teach that the CAR comprises a transmembrane domain, intracellular signaling domain, hinge, and/or signal peptide (as set forth in claims 8, 10, 29, and 31), or that the immune effector cell expressing said CAR is a T cell (as recited in claim 21).
These deficiencies are remedied by the teachings of Klingemann, Ma, Moelling, and Liu, which are summarized in the rejections above.
Based on the further teachings of Klingemann, Ma, Moelling, and Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to co-express an exogenous human IL-12p40 subunit comprising the amino acid sequence of instant SEQ ID NO: 5 and one of a human CCL19 peptide comprising the amino acid sequence of instant SEQ ID NO: 6 or a human CCL21 peptide comprising the amino acid sequence of instant SEQ ID NO: 22, joined via a T2A or P2A peptide, alongside a CAR (e.g., a CAR comprising the components set forth in claims 10 and 31) in an immune effector cell (e.g., a T cell). The skilled artisan would have been motivated to do so because Moelling teaches that the combination of IL-12 (which comprises the IL-12p40 subunit) and one of CCL19 or CCL21 demonstrates favorable anti-tumor activity, while Klingemann and Ma set forth that immune effector cells comprising multi-gene constructs including a CAR, IL-12p40, and/or CCL19/CCL21 are efficacious in the treatment of various cancers. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that CARs, IL-12p40, and CCL19/CCL21 each have utility in the treatment of cancer, and, as noted in MPEP § 2144.06(I): “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Furthermore, Ma provides a proof-of-concept that a polypeptide having multi-gene co-expression (i.e., expressing a CAR, a cytokine, and a chemokine), as well as immune effector cells comprising said polypeptide, can be generated and used in a method of treatment by a skilled artisan.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643