DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 08 December 2025 have been entered. Claims 289, 291-292, 294-299, and 303-312 were previously pending in the application. Claim 307 has been cancelled by Applicant. Claims 289, 291-292, 294-299, 303-306, and 308-312 are currently pending in the application. Claims 289, 306, 308, and 310 are independent claims.
The following election of species remains in effect in the instant application:
1) Transmembrane domains: b. A transmembrane domain of CD3 epsilon,
2) Extracellular antigen binding domains: b. A single chain variable fragment (scFv),
3) B cell surface antigens: a. CD19,
4) Intracellular domains: d. Intracellular signaling domain of CD3 epsilon.
Claims 289, 291-292, 294-299, 303-306, and 308-312 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/030837, filed 30 April 2020, which claims priority
as a continuation in part to U.S. Patent Application No. 16/827,381, filed 23 March 2020,
as a continuation in part to U.S. Patent Application No. 16/827,302, filed 23 March 2020,
to U.S. provisional Application No. 62/841,190, filed 30 April 2019, and
to U.S. provisional Application No. 62/841,183, filed 30 April 2019.
Thus, the earliest possible priority for the instant application is 30 April 2019. Note that U.S. provisional Application No. 62/841,183 provides the requisite adequate support under 35 U.S.C. 112(a) for the claimed subject matter.
Information Disclosure Statement
The information disclosure statement filed 31 December 2025 has been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 31 December 2025, as required under 37 CFR 1.98, indicating that no IDS size fee is required under 37 CFR 1.17(v) at this time.
37 CFR 1.121
The substitute specification filed 08 December 2025 has not been entered because it does not conform to 37 CFR 1.121(b) and (c) because: the marked up copy of the amended specification filed 08 December 2025 does not include all the necessary markings. For example, the SEQ ID NOs inserted in paragraphs [0287, 0288, 0291, 0378, 0379, 0385, 0427, 00618, 00774, 00780] are not underlined.
The drawings replacements sheets filed 08 December 2025 has not been entered because it does not conform to 37 CFR 1.84(u) because: the replacement sheets for Figure 10D have been amended to recite “FIG. 10Di” and “FIG. 10Dii”, which is not an acceptable format for Figures, as described in 37 CFR 1.84(u)(1), which states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” 37 CFR 1.84(u)(1) does not provide for use of Roman numerals to differentiate partial views.
37 CFR 1.821-1.825
Note that the specification amendment filed 08 December 2025 is not in compliance with 37 CFR 1.121, as discussed above, and so has not been entered. As such, the sequence compliance issues remain outstanding.
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), see for example paragraphs [0287, 0288, 0291, 0378, 0379, 0385, 0427, 00618, 00774, 00780] of the instant specification. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice to Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to this communication. Specifically, paragraphs [0287, 0288, 0291, 0378, 0379, 0385, 0427, 00618, 00774, 00780] disclose amino acid and/or nucleotide sequences but do not include any sequence identifiers. If the unidentified sequences of paragraphs [0287, 0288, 0291, 0378, 0379, 0385, 0427, 00618, 00774, 00780] are included in the submitted sequence listing, Applicant must amend the specification to comply with the sequence identification requirements. Alternatively, if the unidentified sequences of paragraphs [0287, 0288, 0291, 0378, 0379, 0385, 0427, 00618, 00774, 00780] are not included in the presently submitted sequence listing, Applicant must submit an updated sequence listing in compliance with 37 CFR 1.821(c)-(d) and 37 CFR 1.825(b). See also the attached Notice to Comply.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice to Comply with the response.
Note that Examiner has not inspected the disclosure sufficiently to ensure identification of all instances of non-compliance with the sequence requirements. It is Applicant’s responsibility to ensure full compliance.
Drawings
The objection to the drawings of the disclosure for the partial views for Figure 8 that appear on multiple sheets are followed by "(continued)" instead of a capital letter such as FIG. 8A, FIG. 8B, etc. and the view numbers for the partial views for Figures 10D, 12D, 18C, 19C, and 21C are followed by “(continued)” instead of a subsequent capital letter (e.g., 10E, 12E, 18D, 19C, 19D, 21D), is maintained in view of the replacement sheets filed 08 December 2025 having not been entered.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Note that appropriate correction of the “Brief Description of the Drawings” in the Specification providing individual descriptions of each panel of the Drawings must also accompany the corrected Drawings. Each figure should be sufficiently described to identify each display, figure, graph, image, and/or view being presented within each panel.
Specification
The objection to the specification of the disclosure for the use of the terms “Histopaque 1077”, “CliniMACS”, Alburex”, “GraphPad Prism 6”, “TexMACS”, “TruCount”, “Sysmex XP-300”, “MACSQuant 10”, “Matrigel”, “CryoStor CS10”, “EVOS”, and “IVIS” at least in [00720-0721, 07250726, 0728, 0739, 0741-0742], which are a trade names or a marks used in commerce, have been noted in this application, is maintained in view of the specification amendment filed 08 December 2025 having not been entered.
The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that Examiner has not inspected the disclosure sufficiently to ensure identification of all instances of trade names or a marks used in commerce. It is Applicant’s responsibility to ensure full compliance.
Claim Objections
**The following new objection is necessitated by Applicant’s amendments to the claims.**
Amended independent claim 289 is newly objected to because of the following informalities: claim 289 recites, “cells; and” in line 12 which appears to be a typographical error for “cells, and”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claim 291 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “polar” and “nonpolar”, is withdrawn in view of Applicant’s amendments to claim 291 such that “polar” and “nonpolar” are no longer recited.
**The following new rejection is necessitated by Applicant’s amendments to the claims.**
Amended claims 291 and 309 are newly 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 291 was amended to newly recite, “wherein the lipid nanoparticle further comprises a lipid PEG lipid”, which is indefinite because it is unclear whether the first recitation of “lipid” is meant to be an additional or alternative component to “PEG lipid”, whether “PEG lipid” is meant to exemplify or further limit the first recitation of “lipid”, or whether the first recitation of “lipid” is a typographical duplication wherein Applicant meant to only recite “PEG lipid”. As such, the metes and bounds of the claim cannot be determined.
Claim 309 newly recites, “the systemic delivery” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 309 depends on claim 308, which encompasses independent claim 289. None of claims 289, 308, nor 309 have any prior recitation of a systemic delivery. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(a)- New Matter
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.
Amended and previously presented claims 289, 291-292, 294-299, and 303-306, 308-312 are newly 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. This is a new matter rejection. 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.
The Applicant is reminded that an amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972).
Amended independent claims 289 and 306 newly recite, “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells” in lines 9-13 and 8-11, respectively. Note that “expresses” or “express” as written in claims 289 and 306 has been afforded a broadest reasonable interpretation of any expression from the mRNA and is not limited to cell surface expression/occupancy of the CFP. However, the instant disclosure does not provide any teachings, explicitly or implicitly, to support this new limitation.
The specification teaches that the instant invention is an improvement over CAR-T cells (thereby teaching T cells expressing a chimeric fusion protein) [0002-0003] and that cells comprising the composition of the instant invention include lymphocytes [0202, 00624, Embodiment 197]. The specification also teaches transfecting and/or transducing (e.g., contacting compositions of the invention with) macrophages, monocytes, myeloid cells (e.g., macrophages), phagocytic cells, and CD14+ cells, including cell lines or isolated primary cells [0005, 0007, 0011, 0028-0038, 0043, 0063, 0067, 0071-0072, 0075-0086, 0091-0106, 0116, 0120-0123, 0126, 0384, 0418, 0422, 0632, 0641, 0672-0673, 0697, 0710, 0715, 0718, 0730, 0743, 0752-0754, 0762, 0763, 0767, 0769, 0770, 0772, 0779, Figure 5, 6, 10, 20, 21, 22, 26, 27, 28, 31, 32, 33]. The specification further teaches an NF-kB response element preceding a promoter, wherein the NF-kB element allows for activation in a phagocyte for selective expression in actively phagocytosing macrophages [0772]. The specification also teaches inclusion of an ARE protein binding sequence in the 3’ UTR of a construct to regulate its expression in selective macrophages [0772]. The specification also teaches inclusion of FcR-alpha receptor TM domains, which dimerize with either endogenous FcR-gamma receptors in myeloid cells, such as macrophages, or FcR-beta receptors in mast cells, to ensure myeloid or mast cell-specific expression of a recombinant construct [0341, 0400, 0452, 0775, 0777, Figure 31A].
However, the instant disclosure does not teach nor exemplify any contacting of any T cells or NK cells with any composition, nor does the disclosure teach nor exemplify contacting a composition of the instant invention with any population of heterogenous cells. Further, the disclosure does not teach nor exemplify any cell-type specific targeting of LNPs, any cell-type specific expression controls, nor any cell-type specific mechanisms which would allow for expression in only T cells or only NK cells of an LNP-transfected heterologous population.
Therefore, the disclosure does not provide support for the limitations newly added to amended independent claims 286 and 306 of “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells”, and the limitations represent new matter.
Claim Rejections - 35 USC § 112(a)- Enablement
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.
Amended and previously presented claims 289, 291-292, 294-299, and 303-306, 308-312 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to a composition comprising an mRNA encoding a chimeric fusion protein, wherein the chimeric fusion protein comprises an extracellular binding domain that binds to a B cell surface antigen (e.g., CD19 as elected and recited in independent claim 306), and a transmembrane domain that is a transmembrane domain of a T cell Receptor subunit CD3 epsilon, wherein the engineered mRNA is encapsulated in a lipid nanoparticle. Independent claims 289 and 306 have each been amended to recite, “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells” in lines 9-13 and lines 8-11, respectively. Note that “expresses” or “express” as written in claims 289 and 306 has been afforded a broadest reasonable interpretation of any expression from the mRNA and is not limited to cell surface expression/occupancy of the CFP.
The specification teaches that the instant invention is an improvement over CAR-T cells (thereby teaching T cells expressing a chimeric fusion protein) [0002-0003] and that cells comprising the composition of the instant invention include lymphocytes [0202, 00624, Embodiment 197]. The specification also teaches transfecting and/or transducing (e.g., contacting compositions of the invention with) macrophages, monocytes, myeloid cells (e.g., macrophages), phagocytic cells, and CD14+ cells, including cell lines or isolated primary cells [0005, 0007, 0011, 0028-0038, 0043, 0063, 0067, 0071-0072, 0075-0086, 0091-0106, 0116, 0120-0123, 0126, 0384, 0418, 0422, 0632, 0641, 0672-0673, 0697, 0710, 0715, 0718, 0730, 0743, 0752-0754, 0762, 0763, 0767, 0769, 0770, 0772, 0779, Figure 5, 6, 10, 20, 21, 22, 26, 27, 28, 31, 32, 33]. The specification further teaches an NF-kB response element preceding a promoter, wherein the NF-kB element allows for activation in a phagocyte for selective expression in actively phagocytosing macrophages [0772]. The specification also teaches inclusion of an ARE protein binding sequence in the 3’ UTR of a construct to regulate its expression in selective macrophages [0772]. The specification also teaches inclusion of FcR-alpha receptor TM domains, which dimerize with either endogenous FcR-gamma receptors in myeloid cells, such as macrophages, or FcR-beta receptors in mast cells, to ensure myeloid or mast cell-specific expression of a recombinant construct [0341, 0400, 0452, 0775, 0777, Figure 31A].
However, the instant disclosure does not teach nor exemplify any contacting of any T cells or NK cells with any composition, nor does the disclosure teach nor exemplify contacting a composition of the instant invention with any population of heterogenous cells. Further, the disclosure does not teach nor exemplify any cell-type specific targeting of LNPs, any cell-type specific expression controls, nor any other cell-type specific mechanisms which would allow for expression in only T cells or only NK cells of an LNP-transfected heterologous population. As such, the specification does not provide an enabling disclosure for expressing a CFP of the instant invention exclusively in T cells or exclusively in NK cells.
The art at the time of filing teaches that T cells are notoriously difficult to transfect [Ramishetti et al. 2015, ACS Nano, 9(7), 6706-6716, column 2 ¶ 1], and that T cell-specific RNA delivery requires additional layers of specificity beyond nanoparticle formulation, such as active targeting approaches wherein the nanoparticle is coated with a nonclonal antibody directed to a surface protein of the target T cell (e.g., CD4) which will induce intracellular uptake of the nanoparticle [column 3 ¶ 3]. Ramishetti teaches that non-targeted LNPs are able to deliver RNA to leukocytes, including T cells, but that they are not cell type specific [column 3 ¶ 2]. Thus, at the time of filing, the ordinarily skilled artisan did not consider the exclusive targeting of T cells or NK cells by LNPs to be predictable.
Applicant’s disclosure does not overcome this art recognized unpredictability as the disclosure does not provide sufficient guidance for expression of the claimed mRNA exclusively in T cells or NK cells when a heterologous population of cells is contacted with a composition comprising the mRNA.
Therefore, in view of the state of the art at the time of filing for cell-type specific targeting of LNPs delivering RNA to T cells requiring additional targeting mechanisms, the art recognized unpredictability for exclusive targeting of T cells or NK cells by LNP delivery of RNA, the complete lack of teachings in the disclosure regarding specific targeting of T cells or NK cells for the expression of the claimed mRNA exclusively within the T cells or NK cells, neither by delivery mechanisms nor by expression control mechanisms, and the breadth of the claims, an ordinarily skilled artisan would have considered making the composition comprising an engineered mRNA encoding a CFP and/or practicing the method of treating a B cell cancer, an inflammatory disease, or autoimmune disease by administering the composition comprising the engineered mRNA encoding a CFP encompassed by the claims, wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells, as highly unpredictable. As such, it would have required undue experimentation to practice Applicant’s invention as claimed.
Claim Rejections - 35 USC § 102
The rejection of amended, previously presented, and cancelled claims 289, 292, 294, 296-299, and 303-309 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Suri et al. (WO2018160993A1, filed 2 March 2018, published 07 September 2018), is withdrawn in view of Applicant’s claims which now recite “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells” in amended independent claims 289 and 306.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 289, 291-292, 294-299, and 303-312 under 35 U.S.C. 103 as being unpatentable over Suri et al. (WO2018160993A1, filed 2 March 2018, published 07 September 2018); in view of Bridgeman et al. (2010, Current Gene Therapy, 10(2), 77-90); Fenton et al. (2016, Advanced Materials, 28, 2939-2943); Sommermeyer et al. (2017, Leukemia, 31, 2191-2199); Mei et al. (2012, Arthritis Research & Therapy, 14(Suppl 5), S1, 1-16); and Hale et al. (2018, Current Opinions in Immunology, 55, 81-88), is withdrawn in view of Applicant’s claims which now recite “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells; and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells” in amended independent claim 289.
***The following new rejection is necessitated by Applicant’s amendments to the claims.***
Amended and previously presented claims 289, 291-292, 294-299, and 303-306, 308-312 are newly rejected under 35 U.S.C. 103 as being unpatentable over Suri et al. [US20200172879A1, filed 02 September 2019, with priority to 03 March 2017]; in view of Bridgeman et al. [2010, Current Gene Therapy, 10(2), 77-90, cited in a prior action]; Fenton et al. [2016, Advanced Materials, 28, 2939-2943, cited in a prior action]; Ramishetti et al. [2015, ACS Nano, 9(7), 6706-6716]; and Sommermeyer et al. [2017, Leukemia, 31, 2191-2199, cited in a prior action].
Regarding claims 289, 291-292, 294, 298-299, and 303, Suri discloses a composition comprising an engineered mRNA encoding a chimeric antigen receptor (CAR), e.g., a chimeric fusion protein (CFP) [0043, 0048, 0741, 0748, 0830-0831, 0976, 0979, 1108, 1538], the CFP comprising (i) an extracellular antigen binding domain comprising a single chain variable fragment (scFv) that binds to the B cell surface antigen CD19 [0051-0052, 1362-1368, 1522], (ii)a transmembrane domain that is a transmembrane domain of T cell Receptor subunit CD3 epsilon [0057, 1527], and (iii) an intracellular signaling domain of the T cell Receptor subunit CD3 epsilon [0053, 0169, 1524], wherein the engineered mRNA is encapsulated in a lipid nanoparticle [0087, 0121, 0153, 0197, 0790, 0823-0824, 1002-1003]. Suri specifically teaches i) that the extracellular antigen binding domain of the CAR comprises an scFv that binds to CD19 [0051, 0491-0494, Table 9], and ii) that the transmembrane domain of the CAR may be derived from the CD3 epsilon chain of a T-cell receptor [0057]. Suri teaches to select the intracellular domain of the CAR from a short list of ten intracellular signaling domains, which includes the CD3 epsilon intracellular domain [0053]. Therefore, an ordinarily skilled artisan would immediately envision a CAR construct comprising the CD19 scFv, CD3ε transmembrane domain, and the CD3ε intracellular signaling domain as one of a limited number of options taught by Suri.
Additionally, Bridgeman teaches an anti-CEA CAR comprising a CD3ε transmembrane (TM) domain and a CD3ε intracellular signaling (IS) domain, which is expressible in T cells [column 12 ¶ 2, Tables 2-3] . Bridgeman further teaches that the CD3ε CAR could activate engrafted T cells equivalently to CD3ζ CAR-expressing cells [column 14 ¶ 2], and that one advantage of a CD3ε-TM/ CD3ε-IS approach is that such CARs would preferentially heterodimerize with CD3δ and CD3ɣ which would not only increase the number of functional CAR molecules on the cell surface, but would also give a more rounded T cell response as, compared to the CD3ζ-based CAR, there would be more diverse array of ITAM signaling domains involved [column 15 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to specifically construct the CAR with both the transmembrane domain and a signaling domain derived from CD3ε to promote a more rounded T cell response.
Suri further teaches that the nanoparticles may comprise at least one lipid selected from a list comprising cationic and amphipathic lipids: DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, DLin-D-DMA, and PEGylated lipids [0823-0824, 1002-1003].
Fenton teaches that lipid nanoparticles (LNPs) are viable delivery vehicles for mRNA, and that LNPs typically comprise cholesterol, a phospholipid, a polyethylene glycol derivative, and an ionizable lipid [column 2 ¶ 1-2]. Fenton also teaches that cholesterol aids in stability, a phospholipid modifies bilayer structure, a PEG derivative decreases aggregation and nonspecific uptake, and an ionizable lipid complexes negatively charged RNA and enhances endosomal escape [column 2 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to include at least one ionizable lipid and at least one PEG lipid (e.g., a PEG derivative) in a lipid nanoparticle for mRNA delivery.
Suri also teaches that the transfection of a population of cells such that the chimeric fusion protein is expressed in a T cell or an NK cell within the population of cells [0791-0792, 0800-0801, 0807, 0823-0824, 1002-1003, 1113, 1312, 1462, 1538, 1545-1546]. Suri teaches the use of tissue or cell specific promoters to control spatial and temporal expression of genes of interest [0267, 0945, 1077]. Suri further teaches the use of activation-conditional chimeric antigen receptors, which are only expressed in an activated immune cell through coupling of the CAR to activation conditional control regions which induce the transcription and/or expression of a sequence under its control, such as promoters that are upregulated during the activation of the immune effect cell (e.g., IL2 promoter or NFAT binding sites) [0563].
Suri does not teach that when a composition comprising an mRNA encoding the CFP is contacted with a population of heterogenous cells, the CFP does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells.
Ramishetti teaches that CD4+ T cells are an attractive target for a range of therapeutic interventions, but that T lymphocytes are notoriously difficult to transfect [column 1 ¶ 1- column 2 ¶ 1]. Ramishetti also teaches that for LNP-based RNA delivery technology to be effectively applied for the therapeutic manipulation of gene expression in T cells, it requires a level of specificity beyond modifying the LNP composition, such as an active targeting approach coating the LNPs with monoclonal antibodies against the T cell surface CD4 receptor [column 3 ¶ 3]. Ramishetti teaches the specific delivery of RNA to T lymphocytes using targeted lipid nanoparticles (tLNPs), wherein the tLNP were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the RNAs specifically to CD4+ T lymphocytes [abstract]. Ramishetti further teaches that ex vivo, the tLNPs demonstrated specificity by targeting only primary CD4+ T lymphocytes and no other cell types in a heterogenous population of primary splenocytes [abstract, column 5 ¶ 1], and that systemic intravenous injection of the tLNP particles led to efficient binding and uptake into CD4+ T lymphocytes in several anatomical sites [abstract, column 6 ¶ 2]. Ramishetti additionally teaches that the functional effect of the RNA delivery (e.g., CD45 silencing) was restricted to the CD4+ T cells and was not observed in other lymphocyte subsets [column 16 ¶ 5].
Therefore, given the teachings of Ramishetti that CD4+ T cells are an attractive target for a range of therapeutic interventions and the ability to specifically deliver RNA to the CD4+ T cells using targeted lipid nanoparticles, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a nanoparticle which is specifically targeted to T cells for the delivery of RNA to T cells. In using the targeted lipid nanoparticles taught by Ramishetti to deliver composition comprising an engineered mRNA encoding the CAR-19/CFP taught by Suri to a heterogenous cell population (e.g., a heterogenous population of splenocyte ex vivo or a heterogenous population of cell in vivo), the ordinarily skilled artisan would thereby reasonably expect expression of the CAR-19/CFP exclusively in the targeted T cells without expressing the CAR-19/CFP in a cell other than a T cell.
Regarding claim 295, Suri does not teach the affinity of the CD19 scFv towards CD19.
However, Sommermeyer teaches the binding affinities (EC50 value) of five CD19 scFvs (one mouse, four human) which range from 4.1 nM to 11.6 nM as well as a sixth CD19 scFv with a binding affinity of >200 nM [column 4 ¶ 8- column 5 ¶ 2, Table 1]. Sommermeyer also teaches that adoptive immunotherapy with gene-modified T-cells expressing a tumor-reactive CAR has rapidly evolved with the most impressive clinical results using autologous T-cells expressing a CD19-specific CAR to treat B-cell malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma [column 1 ¶ 1]. Sommermeyer further teaches that one mechanism for loss of CAR T-cells after treatment is the development of an HLA-restricted T-cell mediated immune response against epitopes derived from murine scFv used as the antigen-binding domain of the CAR [column 1 ¶ 1]. Therefore, Sommermeyer developed fully human CD19-specific CARs for T-cell therapy to reduce the immunogenicity of CARs and thereby improve the longevity of CAR T-cell persistence and enhance their therapeutic efficacy in patients [column 2 ¶ 1], which they show have improved in vitro functions against tumor cell lines and primary CLL and were more efficient in eliminating lymphoma xenografts in immunodeficient mice than the murine FMC63-CAR used in prior human clinical trials [column 2 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an scFv that binds to CD19 with an affinity similar to the affinities of the CD19 scFvs taught by Sommermeyer (e.g., from 4.1 nM to 11.6 nM, which are less than 100 nM) for T-cell therapy.
Regarding claims 296-297, Suri also discloses that the chimeric fusion protein comprises one or more linker sequences comprising glycine and serine residues [0431, 0456].
Regarding claims 304-305, Suri teaches that the CFP comprises two or more intracellular domains, such as two or more intracellular signaling domains, such as a primary signaling domain and a co-stimulatory signaling domain [0212-0213, 0512, 0527-0535, Table 14, Figure 13-14].
Regarding claim 306, Suri, Bridgeman, Ramishetti, and Fenton teach all the limitations of independent claim 289. Suri also teaches wherein the composition is formulated for systemic delivery (e.g., intravenous injection, transdermal, infusion, inhalation, etc.) [0829, 0995-0996].
Regarding claims 308-309, Suri also teaches a pharmaceutical composition comprising the composition comprising the mRNA encoding the CFP and the lipid nanoparticle [0430, 0818-0824, claim 89]. Suri also teaches that the pharmaceutical compositions are administered via injection, e.g., intravenously, or infusion [0829, 0995-0996].
Regarding claims 310-312, Suri also teaches a method of treating various carcinomas, including B-cell lymphoma, and various autoimmune diseases in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition comprising the mRNA encoding the CFP and a lipid nanoparticle [1012, 1029, 1041], wherein the administering is via any route to achieve a therapeutically effective outcome, including an infusion or an intravenous injection, intravenous bolus, intravenous drip/infusion [00460-00461, 0829, 0995-0996], and wherein the subject is human [0821]. Suri also specifically teaches to use the CD19-targeted CAR (as elected) in a composition for treating a B cell cancer in a subject in need thereof [0491-0493].
Given the motivation taught by Bridgeman to specifically construct the CAR with both the transmembrane domain and a signaling domain derived from CD3ε to promote a more rounded T cell response; the motivation taught by Fenton to include at least one ionizable lipid and at least one PEG lipid (e.g., a PEG derivative) in a lipid nanoparticle for mRNA delivery; the motivation taught by Ramishetti to use a nanoparticle which is specifically targeted to T cells for the delivery of RNA to T cells; and the motivation taught by Sommermeyer to use an scFv that binds to CD19 with an affinity similar to the affinities of the CD19 scFvs taught by Sommermeyer (e.g., from 4.1 nM to 11.6 nM, which are less than 100 nM) for T-cell therapy; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the composition and method of Suri to formulate a CD19 CAR to comprise both a transmembrane domain derived from CD3e and a signaling domain derived from CD3e, wherein the CD19 scFv has an affinity for CD19 less than 100 nM, and to administer a pharmaceutical composition comprising the CD19 CAR to treat an autoimmune disease in a subject in need thereof, wherein when the composition is contacted with a population of heterogenous cells, the CFP express exclusively in a T cell with a reasonable expectation of success.
Insofar as applicant’s arguments apply to this new grounds of rejection, Applicant argues that:
Suri does not teach any specific mechanism by which the CAR is selectively expressed in a T cell or an NK cell within a heterogenous population of cells;
Suri teaches a long list of transmembrane domains and a long list of intracellular signaling domains;
Bridgeman teaches that CD3ε-CAR failed to engage its cognate ligand, and so Bridgeman does not provide a skilled artisan with a reasonable expectation of success; and
Sommermeyer does not cure the deficiencies of Suri and Bridgeman because Sommermeyer does not teach an anti-CD19 binding CAR that comprises a CD3ε TM domain and a CD3ε intracellular domain.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), note that Ramishetti was cited for teaching the specific delivery of RNA to T lymphocytes using targeted lipid nanoparticles (tLNPs) for specifically targeting T cells for therapeutic purposes, wherein the RNA is delivered to CD4+ T cells and not to other cell types.
Regarding Applicant’s argument 2), Suri specifically teaches that the transmembrane domain of the CAR may be derived from the CD3 epsilon chain of a T-cell receptor [0057]. Given the teachings of Suri to specifically use a CD3ε transmembrane domain and of a list of 11 intracellular signaling domains which include a CD3ε intracellular signaling domain, it would have been obvious to an ordinarily skilled artisan to combine the CD3ε transmembrane domain with any of the intracellular signaling domains taught by Suri as selecting from 11 options is a very limited number of options from which to choose.
Additionally, Bridgeman was cited for teaching that one advantage of using a CAR comprising both a CD3ε transmembrane domain and a CD3ε intracellular domain is that such CARs would preferentially heterodimerize with CD3δ and CD3ɣ which would not only increase the number of functional CAR molecules on the cell surface, but would also give a more rounded T cell response as, compared to the CD3ζ-based CAR, there would be more diverse array of ITAM signaling domains involved [column 15 ¶ 1].
Regarding Applicant’s argument 3), Bridgeman additionally teaches that the lack of engagement with the cognate ligand in the context of cell membrane antigen may have been related to the natural extracellular Ig-spacer in that CAR, and may be an observation specific to the CEA target antigen, or the scFv binding epitope, as has been demonstrated previously with CEA and CD22 [column 14 ¶ 2- column 15 ¶ 1]. Bridgeman also teaches that it would be interesting to investigate whether removing this natural Ig-spacer would permit CEA targeting with CD3ε-based CARs [column 16 ¶ 1]. Therefore, Bridgeman suggests that the lack of engagement with the antigen in a cell membrane context is not attributable to the CD3ε components themselves, but to the specific scFv used to detect a target antigen. By teaching that the same CD3ε-based CAR-CEA was able to activate engrafted T-cells equivalently to the CD3ζ-CAR expressing cells on immobilized antigen, Bridgeman is teaching that the CD3ε construct is functional to carry out the desired function with a reasonable expectation of success.
Regarding Applicant’s argument 4), Sommermeyer was cited for teaching binding affinities of CD19 CARs, which is attributable to the scFv domain [column 4 ¶ 8- column 5 ¶ 2, Table 1], and as such, an ordinarily skilled artisan at the time of filing the instant application would understand that the other domains of the CAR could be exchanged without substantially altering the binding affinity. Sommermeyer was not cited for teaching to use the CD3ε transmembrane domain nor the CD3ε intracellular signaling domain.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Suri, Bridgeman, Ramishetti, and Sommermeyer under 35 U.S.C. 103.
Double Patenting
The rejection of amended, previously presented, and cancelled claims 289, 291-292, 294-299, and 303-309 on the ground of nonstatutory double patenting as being unpatentable over claims 126-145 of copending Application No. 17/604,857 (claims dated 06 July 2022), hereinafter referred to as the ‘857 application, in view of Fenton et al. (2016, Advanced Materials, 28, 2939-2943); Sommermeyer et al. (2017, Leukemia, 31, 2191-2199); and Suri et al. (WO2018160993A1, filed 2 March 2018, published 07 September 2018), is withdrawn over cancelled claim 307 and maintained over amended and previously presented claims 289, 291-292, 294-299, 303-306, and 308-309. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claims 289 and 306 to recite, “wherein when the composition is contacted with a population of heterogenous cells, the CFP expresses in a T cell or an NK cell within the population of heterogenous cells, and does not express in a cell other than a T cell or an NK cell within the population of heterogenous cells”. The ‘857 application claims recite wherein the chimeric fusion protein is expressed in a T cell and does not recite expression in any other cell type. Therefore, the ‘857 claims still encompass and render obvious the claims of the instant application.
The Applicant requests that the rejection be held in abeyance until the indication of allowable subject matter. However, the instant rejection may not be held in abeyance. As set forth in MPEP 804, only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. A complete response to a nonstatutory double patenting (NDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (MPEP 804 (I)(B)(1)). Such a response is required even when the nonstatutory double patenting rejection is provisional.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634