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 with traverse of Group I (claims 1-15, 17, and 19-24) in the reply filed on 07/28/2026 is acknowledged. Applicant also elected the below listed species:
Polypeptide encoding one or more agents: SEQ ID NO:51, encoding Cathepsin K and Neutrophil Elastase;
ECM molecule: collagen I;
Antigen binding domain: PAP;
Co-stimulatory domain: 4-1BB; and
Immune checkpoint molecule: PD-1.
The traversal is on the ground(s) that the search for the claims of Group I will result in finding art that is applicable to the claims of Group II; Applicant alleges that, accordingly, there would be no serious search burden to examine both groups. This is not found persuasive because search burden pertains to Restriction/Election requirements under U.S. practice (i.e., applications filed under 35 U.S.C 111[a]) which require the independent and distinct analysis, whereas the instant application is filed under 35 U.S.C. 371, which falls under the unity of invention analysis.
As laid out in the Restriction/Election Requirement from 05/28/2026, Groups I and II lack unity of invention as the technical feature of the modified cell of claim 1 is not a special technical feature as it does not make a contribution over the prior art in view of US20190119636A1 (published 04/25/2019) as evidenced by Grindel et al. (Matrilysin/MMP-7 Cleavage of Perlecan/HSPG2 Complexed with Semaphorin 3A Supports FAK-Mediated Stromal Invasion by Prostate Cancer Cells, Sci Rep 8, 7262, 2018). Therefore, Groups I-II do not relate to a single general inventive concept under PCT Rule 13.1 and the restriction is proper. Thus, the arguments regarding a search burden are moot.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 16 and 18 are cancelled. Claims 1-15, 17, and 19-25 are pending.
Claims 14, 17, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim
Claims 1-13, 15, and 19-24 are currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/US2022/072981 (filed on 06/16/2022) which claims benefit of Provisional U.S. Application Nos. 63/212,303 (filed on 06/18/2021) and 63/218,020 (filed on 07/02/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-13, 15, and 19-24 have an effective filing date of 06/18/2021 corresponding to Provisional U.S. Application No. 63/212,303.
Information Disclosure Statement
The information disclosure statement filed on 12/15/2023 has been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Objections
Claims 2-4, 9-10, and 12-13 are objected to because of the following informalities:
Claims 2-4, 9-10, and 12-13: “comprise” should be replaced with “comprises”.
Claim 13: “The modified cell claim 1” should be replaced with “The modified cell of claim 1”.
Appropriate correction is required.
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 21-22 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.
Instant claim 21 is drawn to a modified cell engineered to express and secrete one or more agents targeting one or more ECM molecules, the modified cell comprising a polynucleotide encoding a CAR and a polynucleotide encoding one or more agents, wherein:
the one or more agents comprises at least one of CK, NE, and MMP7;
the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain; and
“the antigen binding domain binds a tumor antigen” (instant claim 21, lines 1-2) selected from a large list.
Instead of defining the antigen binding domain by its structure, the instant application uses the functional characteristic of binding a tumor antigen. Therefore, this language encompasses a broad genus of functionally and structurally distinct antigen binding domains that bind a tumor antigen.
It is noted that while instant claim 1 is also drawn to a polynucleotide encoding a CAR, only instant claim 21 defines the CAR by functional language i.e. the ability of the antigen binding domain to bind a tumor antigen. Therefore, only instant claim 21 and its dependent claim (instant claim 22) are included in this rejection.
Regarding the antigen binding domains of CARs, Jayaramana et al. (CAR-T design: Elements and their synergistic function, EBioMedicine, 2020) state “scFvs are the most commonly used ligand-binding domains in CAR structures, although other domains such as nanobodies, ligands to cognate receptors, native receptors against targets… and small peptides have been used” (Pg. 2, column 1, ¶ 2, lines 1-5). These antigen binding domains have distinct structures e.g. a scFv contains a VH and VL while a nanobody contains a VHH only. Furthermore, Jayaramana et al. teach “affinity, avidity, aggregation propensity, and its antigen epitope location are critical parameters that can affect CAR function” (Pg. 3, Fig. 2, legend, line 1), indicating multiple parameters that affect the functionality of the antigen binding domain. For example, membrane-proximal epitopes are difficult for CARs to target (Pg. 3, Fig. 2c, depicts binding difference with membrane-distal and membrane-proximal epitopes). Therefore, the ability of the antigen binding domain to bind a specific tumor antigen would be affected by the tumor antigen’s location on the target cell i.e. the identity of the tumor antigen. These teachings collectively demonstrate the antigen binding domains of the CAR as recited in instant claim 21 encompass a variety of species with distinct structures and functions.
Regarding an scFv antibody for the antigen binding domain, Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antigen binding domain binds a tumor antigen is not sufficient to determine its structure. This issue is only further exacerbated by the number of tumor antigens encompassed by instant claim 21.
As such, the modified cell of instant claim 21 is drawn to the CAR comprising a genus of functionally and structurally distinct antigen binding domains that bind a tumor antigen.
The instant specification teaches the CAR of the modified cell binds GCC/GUCY2C (Fig. 1-9, 18, and 20), CD19 (Fig. 12, 14-15, 17, and 19), or ACPP/PAP (Fig. 12-13 and 15-17). The instant specification does not provide examples where the CAR binds other tumor antigens as cited in instant claim 21.
However, Applicant is claiming a broad genus of functionally and structurally distinct antigen binding domains that bind a tumor antigen. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically the structure of the antigen binding domains and which tumor antigens they bind. Applicant uses functional language to define the genus which is not sufficient as detailed above (see Jayaramana et al. for information regarding the variety in CAR structure and function; see Sevy and Meiler for information regarding the difficulty in predicting antigen binding domain structure from function alone).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the 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” (MPEP 2163[II][A][2]).
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
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. As previously indicated, Applicant has disclosed three species within the genera claimed (i.e. CARs that bind GCC/GUCY2C, CD19, or ACPP/PAP). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of three adequately described species is not sufficiently representative of the entire genus.
Absent a description of the at least minimal structural features correlating with a functional ability to bind a tumor antigen which are shared by members of a genus of antigen binding domains, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish the structure of the antigen binding domains and which tumor antigens they bind.
Although screening techniques can be used to find antigen binding domains that bind tumor antigens, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly, given the difficulty associated with predicting structures of functionally described antigen binding domains, and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genera to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of instant claim 21. Instant claim 21 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Instant claim 22 is included in this rejection as it incorporates and/or depends on instant claim 21.
While instant claim 1 is also drawn to a polynucleotide encoding a CAR, only instant claim 21 defines the CAR by functional language i.e. the ability of the antigen binding domain to bind a tumor antigen. Therefore, instant claim 1 and its dependent claims, besides instant claims 21-22, are not included in this rejection.
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 6, 9, and 24 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 6 recites the limitation "the nucleic acid comprising the NFAT binding site" in line 2 and “the minimal IL2 promoter” (line 3). There is insufficient antecedent basis for these limitations in the claim.
For the purposes of claim interpretation, claim 6 will be treated as dependent on claim 4 and “the minimal IL2 promoter” will be treated as “a minimal IL2 promoter.”
Regarding claim 9, the phrase "a nucleotide encoding SEQ ID NO: 7" renders the claims indefinite because it is unclear whether the Applicant meant to refer to a nucleic acid or a nucleotide as a single nucleotide cannot encode SEQ ID NO: 7.
For the purposes of claim interpretation, the phrase "a nucleotide encoding SEQ ID NO: 7" will be treated as "a nucleic acid encoding SEQ ID NO: 7".
Regarding claim 24, the phrase “reduced expression of endogenous TRAC gene” renders the claims indefinite because the threshold for a reduction of endogenous TRAC gene expression is unclear i.e. there is no provided reference level from which TRAC gene expression is compared to. “Reduced expression of endogenous TRAC gene” is therefore a relative term. MPEP 2173.06(b) states: “Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970).” The instant specification does not provide an objective standard for reduced expression and thus is indefinite.
For the purposes of claim interpretation, the phrase “reduced expression of endogenous TRAC gene” will be treated as a reduction of endogenous TRAC gene expression to any degree.
Claim Rejections - 35 USC § 103
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 1, 8, 11, 15, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over of US20190119636A1 (published 2019-04-25, hereinafter referred to as US ‘636; IDS filed on 2023-12-15, Cite No. 2) in view of US20230348881A1 (claims priority to PRO 63/067,059 filed on 2020-08-18, hereinafter referred to as US ‘881) and Hira et al. (Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 3, 2017, Pages 594-603) as evidenced by Kafienah et al. (Cleavage of native type I collagen by human neutrophil elastase. Biochem J. 1998 Mar 1;330).
US ‘636 teaches an adoptive cell therapy (Abstract). Regarding a CAR T-cell that secretes NE and comprise polynucleotides as recited in instant claims 1, 8, 11, and 15, US ‘636 further teaches a T-cell engineered to (i) express a CAR (¶ 0005, “Modified-T cells of the disclosure include, but are not limited to, those cells that express a chimeric antigen receptor [CAR]”; instant claim 1) and (ii) express and secrete NE and CK (¶ 0214, “modified T-cells express therapeutic proteins… including a secreted human protein”; ¶ 0242, Table 1, shows exemplary secreted proteins including NE and CK; instant claims 8, 11, and 15). US ‘636 further teaches the chimeric antigen receptor, CK, and NE are encoded by a plasmid i.e. a polynucleotide (¶ 0006, “a genomic editing construct may be introduced into the modified cells of the disclosure in a transposon”; ¶ 0007, “the transposon is a plasmid DNA transposon with a sequence encoding the antigen receptor or the therapeutic protein”; instant claim 1). These teachings read on a modified cell engineered to express and secrete NE and CK (instant claims 8, 11, and 15), the modified cell comprising a polynucleotide encoding the CAR and secreted proteins, specifically NE and CK (instant claim 1).
Regarding instant claim 20, US ‘636 further teaches the CAR comprises “(a) an ectodomain comprising an antigen recognition region, wherein the antigen recognition region comprises one or more sequences that each specifically bind an antigen; (b) a transmembrane domain, and (c) an endodomain comprising at least one costimulatory domain” (¶ 0126). This teaching reads on the CAR comprises an antigen-binding domain (i.e. antigen recognition region), a transmembrane domain, and an intracellular signaling domain (i.e. endodomain comprising a co-stimulatory domain).
US ‘636 further teaches “CAR-modified T cells targeting a tumor-associated antigen (Ag) can result in robust tumor killing” (¶ 0121). This teaching gives motivation for using the CAR T-cells that bind a tumor antigen to improve tumor eradication.
US ‘636 does not explicitly teach (i) NE targets an ECM molecule (instant claim 1), specifically collagen I (instant claim 19). In addition, while US ’636 teaches the secretion of NE and CK by a CAR T-cell, NE and CK appear in a large list of secreted therapeutic proteins (¶ 0242, Table 1). Thus, US ‘636 does not give sufficient motivation for using NE and CK specifically in the disclosed modified cells. These deficiencies are remedied by US ‘881, Kafienah et al., and Hira et al.
Kafienah et al. investigated the “extracellular breakdown of fibrillar collagen helices” (Pg. 897, column 1, ¶ 2, line 4) and found “NE is capable of cleaving within the helical portion of native type I collagen” (Pg. 901, column 2, ¶ 2, lines 102). Therefore, NE inherently targets an ECM molecule (instant claim 1), specifically collagen I (instant claim 19) as evidenced by Kafienah et al.
US ‘881 teaches “serine protease enzymes are selectively toxic to cancer cells but relatively non-toxic to normal or otherwise healthy cells” (¶ 0006), specifically the serine protease “human neutrophil elastase” (¶ 0007). US ‘881 further teaches said proteases can be employed at “tumor site in vivo” (¶ 0010) and be combined with a cancer immunotherapy such as “chimeric antigen receptor (CAR)-modified T-cells” (¶ 0135). These teachings give motivation for combining CAR T-cell therapy with NE at a tumor site as NE is toxic to cancer cells while non-toxic to healthy cells.
US ‘881 does not teach the CAR T-cell secretes proteins that target the ECM and comprise polynucleotides (instant claims 1, 8, 11, 15, and 19) nor the structure of the CAR (instant claim 20). In addition, US ‘881 does not give motivation for using CK in the disclosed modified cells. These deficiencies are remedied by US ‘636, Kafienah et al., and Hira et al.
Hira et al. teach the protease cathepsin K can “have tumor suppressing effects rather than tumorigenic effects. We therefore suggest that CatK [cathepsin K] activity should be up regulated in GBM [glioblastoma] before and during chemo-irradiation, since this may sensitize GSLCs [glioma stem-like cells] to chemo-irradiation” (Pg. 602, column 2, last ¶, last 4 lines). This teaching gives motivation for combining CAR T-cell therapy with CK as the upregulation of CK has the potential to increase the effectiveness of chemo-irradiation, therefore improving therapeutic outcomes via its tumor suppressing effects.
Hira et al. do not teach the CAR T-cell secretes proteins that target the ECM and comprise polynucleotides (instant claims 1, 8, 11, 15, and 19) nor the structure of the CAR (instant claim 20). In addition, Hira et al. do not give motivation for using NE in the disclosed modified cells. These deficiencies are remedied by US ‘636, Kafienah et al., and US ‘881.
CAR T-cell therapies, NE, and CK in tumor treatments were known and used prior to the effective filing date of the application. In addition, US ‘636, US ’881, and Hira et al. are in analogous arts (i.e. tumor treatments). Since (i) US ‘881 teaches NE is toxic to cancer cells while non-toxic to healthy cells and can be combined with a CAR T-cell therapy for targeting a tumor and (ii) Hira et al. teach the upregulation of CK has the potential to increase the effectiveness of chemo-irradiation, therefore improving therapeutic outcomes via its tumor suppressing effects, there is motivation for using NE to selectively kill cancer cells as taught by US ‘881 and CK to increase effectiveness of chemo-irradiation as taught in Hira et al. in an engineered CAR T-cell that secretes therapeutic proteins for the purpose of tumor eradication as taught by US ‘636.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘881 teaches NE is toxic to cancer cells while non-toxic to healthy cells and can be combined with a CAR T-cell therapy for targeting a tumor; Hira et al. teach the upregulation of CK has the potential to increase the effectiveness of chemo-irradiation, therefore improving therapeutic outcomes via its tumor suppressing effects) would have led one of ordinary skill to modify the prior art reference (i.e. an engineered CAR T-cell that secretes therapeutic proteins for the purpose of tumor eradication as taught by US ‘636) to arrive at the claimed invention. There is a reasonable expectation of success as CAR T-cell therapies, NE, and CK in tumor treatments were known and used prior to the effective filing date of the application. In addition, US ‘636, US ’881, and Hira et al. are in analogous arts (i.e. tumor treatments). US ‘636 lists NE and CK as therapeutic proteins that can be secreted by a CAR T-cell, indicating the combination would be successful. US ‘881 and Hira et al. establish the benefits of using NE and CK respectively in tumor treatments.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use NE to selectively kill cancer cells as taught by US ‘881 and CK to increase effectiveness of chemo-irradiation as taught in Hira et al. in an engineered CAR T-cell that secretes therapeutic proteins for the purpose of tumor eradication as taught by US ‘636.
Claims 4-7 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over US20190119636A1 (published 2019-04-25, hereinafter referred to as US ‘636; IDS filed on 2023-12-15, Cite No. 2) in view of US20230348881A1 (claims priority to PRO 63/067,059 filed on 2020-08-18, hereinafter referred to as US ‘881) and Hira et al. (Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 3, 2017, Pages 594-603) as evidenced by Kafienah et al. (Cleavage of native type I collagen by human neutrophil elastase. Biochem J. 1998 Mar 1;330) as applied to claims 1 and 20 above, and further in view of WO2020106843A1 (published 2020-05-20, hereinafter referred to as WO ‘843).
US ‘636, US ‘881, Hira et al., and Kafienah et al. are as discussed above and incorporated by reference herein. An engineered CAR T-cell that secretes NE and CK (instant claim 1) and the structure of the CAR (instant claim 20) are rendered obvious over US ‘636 in view of US ‘881 and Hira et al. as evidenced by Kafienah et al. as fully described in the previous 103 rejection.
US ‘636, US ‘881, Hira et al., and Kafienah et al. do not teach (i) expression regulation of NE (instant claim 7), (ii) the CAR binds the tumor antigen PAP (instant claim 21), (iii) the co-stimulatory domain is 4-1BB (instant claim 22), the cell comprises a dominant negative form of the inhibitory immune checkpoint molecule PD-1 (instant claim 23), and (iv) the cell has reduced expression of the endogenous TRAC gene (instant claim 24). These deficiencies are remedied by WO ‘843.
WO ‘843 teaches “CAR T cell therapy for treating cancer” (Abstract) wherein the CAR T-cell comprises “an isolated nucleic acid comprising a nucleic acid and an additional nucleic acid, the nucleic acid encoding a chimeric antigen receptor (CAR), the additional nucleic acid encoding a therapeutic agent… The cells may conditionally express and secrete the therapeutic agent” (¶ 0005). This teaching reads on an engineered CAR T-cell that secretes a therapeutic agent and comprising polypeptides (i.e. nucleic acids) that encode the CAR and therapeutic agent.
Regarding instant claims 4-5 and 7, WO ‘843 further teaches “a VHL-interaction domain of Hifla [ODD domain” can be linked to a therapeutic protein for its expression in hypoxic tumor environments (¶ 00250; instant claim 4) wherein the sequence of the ODD domain is in SEQ ID NO: 458, encompassed instant SEQ ID NO: 57 (instant claim 5). WO ‘843 further teaches the polypeptides comprise “a promoter comprising a binding site for a transcription modulator that modulates the expression and/or secretion of the therapeutic agent in the modified cell. In embodiments, the transcription modulator is or comprises Hifla, NFAT, FOXP3, or NFkB” (¶ 00143; instant claims 4 and 7). These teachings read on (i) the therapeutic protein sequence has both the NFAT binding site (i.e. NFAT promoter) and nucleic acid sequence of ODD domain (instant claim 4), (ii) the ODD domain comprises instant SEQ ID NO: 57 (instant claim 5), and (iii) the expression of the therapeutic agent is regulated by Hifla, NFAT, FOXP3, or NFkB (instant claim 7).
Regarding instant claim 6, WO ‘843 further teaches a ”promoter is operably linked to the polynucleotide encoding the therapeutic agent” and comprises SEQ ID NO: 341 (¶ 00261, exemplary embodiment 243), identical to instant SEQ ID NO: 5. The instant specification indicates instant SEQ ID NO: 5 is the minimal IL2 promoter (¶ 0217, Table 2). WO ‘843 further teaches “the promoter is divided into two parts, a specific regulatory region containing a transcription factor binding site, plus a minimal promoter” (¶ 00168). Therefore, this teaching reads on the nucleic acid comprises the NFAT binding site (see instant claim 7) followed by the minimal IL2 promoter.
Regarding instant claim 21, WO ‘843 further teaches the CAR T-cell comprises an “antigen binding domain [that] binds an antigen, on the surface of a tumor… Tumor antigens are well known in the art and include… PAP” (¶ 00115). This teaching reads on the antigen binding domain binds the tumor antigen PAP.
Regarding instant claim 22, WO ‘843 further teaches the CAR comprises a cytoplasmic domain that includes a co-stimulatory domain (¶ 00118) and “the co-stimulatory domain includes the intracellular domain of… 4-1BB” (¶ 00119). This teaching reads on the intracellular domain (i.e. cytoplasmic domain) comprises a co-stimulatory signaling domain wherein the co-stimulatory signaling domain is 4-1BB.
Regarding instant claim 23, WO ‘843 further teaches “the modified cell may express a dominant negative form of a checkpoint inhibitor (e.g., PD-1)” (¶ 00134). This teaching reads on the modified cell comprises a dominant negative form of the inhibitory immune checkpoint molecule PD-1.
Regarding instant claim 24, WO ‘843 further teaches “the TRAC gene of the modified cell is inactivated” (¶ 00261, exemplary embodiment 108). This teaching reads on the modified cell has reduced expression of the endogenous TRAC gene.
As WO ‘843 teaches these modifications are suitable for CAR T-cells in a cancer treatment to “enhance T cell response in a subject” (¶ 00236), there is motivation for including said modifications in order to increase the effectiveness of the treatment.
WO ‘843 does not teach the CAR T-cell secretes NE and CK (instant claims 1 and 20) nor the NFAT binding site and nucleic acid encoding the ODD domain flank the nucleic acid encoding the secreted proteins (instant claim 4). These deficiencies are remedied by the combined teachings of US ‘636, US ‘881, Hira et al., and Kafienah et al. (instant claims 1 and 20) and routine optimization (instant claim 4).
MPEP 2144.05(II)(A) states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. the placement of promoters like the NFAT binding site and nucleic acids encoding reporter tags like the ODD domain), so as to achieve optimal effect and maximal benefit (i.e. promoters can be placed before a protein sequence to increase protein production and nucleic acids encoding a reporter domain can be placed after a protein sequence if the positioning does not affect protein folding to create a hypoxia-inducible tag). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of the positioning of the NFAT binding site and the nucleic acid encoding the ODD domain would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed positioning to achieve it without undue experimentation in order to increase protein production and create a hypoxia-inducible tag (instant claim 4).
CAR T-cell therapies and their modifications (e.g. expression regulation of secreted agent, recognition of the tumor antigen PAP, use of 4-1BB as a co-stimulatory signaling domain, expression of dominant negative PD-1 immune checkpoint inhibitor, and reduction of TRAC gene expression) were known and used prior to the effective filing date of the application. In addition, US ‘636, US ’881, Hira et al., and WO ‘843 are in analogous arts (i.e. tumor/cancer treatments). Since WO ‘843 teaches modifications to CAR T-cells and their use in a method of treating cancer to enhance T cell response, there is motivation for including said modifications in order to increase the effectiveness of the treatment as taught by WO ‘843 in the engineered CAR T-cell that secretes NE and CK as taught by US ‘636, US ‘881, and Hira et al.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. WO ‘843 teaches modifications to CAR T-cells and their use in a method of treating cancer to enhance T cell response) would have led one of ordinary skill to modify the prior art reference (i.e. an engineered CAR T-cell that secretes NE and CK as taught by US ‘636, US ‘881, and Hira et al.) to arrive at the claimed invention. There is a reasonable expectation of success as CAR T-cell therapies and their modifications were known and used prior to the effective filing date of the application. In addition, US ‘636, US ’881, Hira et al., and WO ‘843 are in analogous arts (i.e. tumor/cancer treatments). WO ‘843 teaches expression regulation of secreted agent, recognition of the tumor antigen PAP, use of 4-1BB as a co-stimulatory signaling domain, expression of dominant negative PD-1 immune checkpoint inhibitor, and reduction of TRAC gene expression. These features are known modifications of CAR T-cells in general as taught by WO ‘843 and therefore applicable to the modified CAR T-cell taught by US ‘636, US ‘881, and Hira et al., giving a reasonable expectation that said modifications would be successful.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to include known CAR T-cell modifications in order to increase the effectiveness of the cancer treatment as taught by WO ‘843 in the engineered CAR T-cell that secretes NE and CK as taught by US ‘636, US ‘881, and Hira et al.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over US20190119636A1 (published 2019-04-25, hereinafter referred to as US ‘636; IDS filed on 2023-12-15, Cite No. 2) in view of US20230348881A1 (claims priority to PRO 63/067,059 filed on 2020-08-18, hereinafter referred to as US ‘881) and Hira et al. (Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 3, 2017, Pages 594-603) as evidenced by Kafienah et al. (Cleavage of native type I collagen by human neutrophil elastase. Biochem J. 1998 Mar 1;330) as applied to claim 1 above, and further in view of Zhang et al. (Alteration in the IL-2 signal peptide affects secretion of proteins in vitro and in vivo, J. Gene Med., 7: 354-365, 2005), GenBank Accession No. AB451325.1 (Homo sapiens IL2 mRNA for interleukin 2 precursor, complete cds, clone: FLJ08206AAAN, NCBI, 2008, Pg. 1-2), and GenBank Accession No. AF117205.1 (Synthetic construct neutrophil elastase precursor (NE) mRNA, partial cds, NCBI, 1998, Pg. 1).
US ‘636, US ‘881, Hira et al., and Kafienah et al. are as discussed above and incorporated by reference herein. An engineered CAR T-cell that secretes NE and CK (instant claim 1) is rendered obvious over US ‘636 in view of US ‘881 and Hira et al. as evidenced by Kafienah et al. as fully described in the previous 103 rejection.
US ‘636, US ‘881, Hira et al., and Kafienah et al. do not teach (i) an IL2 signal peptide (instant claim 12) and a nucleic acid sequence encoding instant SEQ ID NO: 42 (instant claim 13) nor (ii) a nucleic acid sequence of NE encoding instant SEQ ID NO: 10 (instant claim 13). These deficiencies are remedied by Zhang et al., GenBank Accession No. AB451325.1, and GenBank Accession No. AF117205.1.
Regarding instant claim 12, Zhang et al. teach “a commonly used signal peptide from interleukin-2 (IL-2)” (Pg. 354, Abstract, lines 7-8) for the purpose of increasing protein secretion in “commercial protein production and gene therapy research” (Pg. 355, column 2, ¶ 1, line 7). This teaching gives motivation for adding the signal peptide of IL-2 to a therapeutic protein as it is routinely used to increase protein secretion in commercial and research settings.
Zhang et al. do not teach a CAR T-cell that secretes NE and CK (instant claim 1) nor a nucleic acid sequence encoding instant SEQ ID NOs: 42 and 10 for the IL-2 signal peptide and NE respectively (instant claim 13). These deficiencies are remedied by US ‘636, US ‘881, Hira et al., Kafienah et al., GenBank Accession No. AB451325.1, and GenBank Accession No. AF117205.1.
Regarding instant claim 13, GenBank Accession No. AB451325.1 and GenBank Accession No. AF117205.1 teach nucleic acid sequences encoding instant SEQ ID NOs: 42 (IL-2 signal peptide) and 10 (NE) respectively.
GenBank Accession No. AB451325.1 and GenBank Accession No. AF117205.1 do not teach a CAR T-cell that secretes NE and CK (instant claim 1) nor a motivation for including an IL-2 signal peptide in a polynucleotide (instant claim 12). These deficiencies are remedied by US ‘636, US ‘881, Hira et al., Kafienah et al., and Zhang et al.
US ‘636, US ’881, and Hira et al. are in analogous arts (i.e. tumor treatments). Since US ‘636 and US ’881 teach the secreted protein NE, this allows for the addition of an IL-2 signal peptide to facilitate secretion and increase protein production as taught by Zhang et al. Furthermore, nucleic acid sequences encoding instant SEQ ID NOs: 42 (IL-2 signal peptide) and 10 (NE) were known and used prior to the effective filing date of the instant application as taught by GenBank Accession No. AB451325.1 and GenBank Accession No. AF117205.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the application to add the signal peptide of IL-2 to NE in an engineered CAR T-cel that secretes NE and CK because:
US ‘636, US ’881, and Hira et al. render obvious an engineered CAR T-cell that secretes NE and CK as evidenced by Kafienah et al.;
Zhang et al. teach adding the signal peptide of IL-2 to a therapeutic protein, applicable to NE, as it is routinely used to increase protein secretion in commercial and research settings; and
GenBank Accession No. AB451325.1 and GenBank Accession No. AF117205.1 teach nucleic acid sequences encoding instant SEQ ID NOs: 42 (IL-2 signal peptide) and 10 (NE) respectively.
MPEP 2143(I)(A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950).”
The prior art includes each element prior to the effective filing date of the application, the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person having ordinary skill in the art prior to the effective filing date of the application would be motivated to add the signal peptide of IL-2 as taught by Zhang et al. to NE in an engineered CAR T-cell that secretes NE and CK as taught by US ‘636, US ’881, and Hira et al. in order to improve protein production, leading to an increase in therapeutic delivery of NE to tumor cells. Furthermore, the nucleic acid sequences encoding the IL-2 signal peptide and NE were known and used in the prior art as taught by GenBank Accession No. AB451325.1 and GenBank Accession No. AF117205.1. A person having ordinary skill in the art could use said sequences for the purposes of producing an IL-2 signal peptide and NE fusion construct.
A person having ordinary skill in the art would recognize the results of the combination were predictable and have a reasonable expectation of success because (i) addition of an IL-2 signal peptide to a therapeutic protein is routine in the art, used commonly in commercial and research settings, and (ii) nucleic acids encoding the therapeutic protein NE and IL-2 signal peptide can be fused reliably to produce a construct that has dual properties.
Art-Free Subject Matter
All species of instant claims 2-3 and 9-10 (corresponding to the polynucleotides encoding one or more agents) were searched, not just the elected species (see Election/Restriction section for more information), as the elected species did not have prior art.
The closest prior art to instant claims 2-3 and 9-10 is the combined teachings of US20190119636A1 (published 2019-04-25, hereinafter referred to as US ‘636; IDS filed on 2023-12-15, Cite No. 2), US20230348881A1 (claims priority to PRO 63/067,059 filed on 2020-08-18, hereinafter referred to as US ‘881), Hira et al. (Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 3, 2017, Pages 594-603), and Kafienah et al. (Cleavage of native type I collagen by human neutrophil elastase. Biochem J. 1998 Mar 1;330). An engineered CAR T-cell that secretes NE and CK (instant claim 1) is rendered obvious over US ‘636 in view of US ‘881 and Hira et al. as evidenced by Kafienah et al. as fully described in the previous 103 rejection.
However, US ‘636, US ‘881, Hira et al., and Kafienah et al. do not teach the polynucleotide sequences as recited in instant claims 2-3 and 9-10. It is noted that instant SEQ ID NOs of instant claims 2-3 and 9-10 were thoroughly searched corresponding to the limitations of the claims and are free of prior art.
Therefore, instant claims 2-3 and 9-10 are not anticipated by the prior are because the prior art fails to disclose each and every element of the claimed invention. In addition, instant claims 2-3 and 9-10 cannot be rendered obvious. While US ‘636, US ‘881, Hira et al., and Kafienah et al. teach an engineered CAR T-cell that secretes NE and CK, the prior art does not provide a teaching, suggestion, or motivation to produce the polynucleotide sequences as recited in instant claims 2-3 and 9-10.
Allowable Subject Matter
Claims 2-3 and 10 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-13, 15, and 19-24 are currently under consideration for patentability. Claims 2-4, 9-10, and 12-13 are objected to. Claims 1, 4-9, 11-13, 15, and 19-24 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
