DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 10/25/2023, has been entered.
Claims 78-97 are pending.
Election/Restrictions
Applicant’s election of Group I and species “reduced interaction between PD1 and PDL1” in the reply filed on 07/13/2026 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 80 and 82-97 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Inventions/species, there being no allowable generic or linking claim.
Claims 78, 79 and 81 are currently under examination as they read on a method for manufacturing engineered therapeutic immune cells expressing an anti-MUC1 CAR and introducing at least one mutation leading to an enhanced IL-2, IL-12, IL-15 or IL-18 expression.
Claim Rejections - 35 USC § 112
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 78, 79 and 81 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.
The present claims recite introducing at least one genetic modification in the genome of an immune cell, wherein the modification is selected from modifications “leading to an enhanced IL-2, IL-12, IL-15 or IL-18 expression.” The claimed genus is therefore defined principally by the biological result achieved by the genetic modification rather than by structural characteristics of the modification itself.
The specification discloses particular embodiments involving cytokine expression, including IL-12, and provides certain cytokine sequences and expression constructs. However, claim 78 is not limited to those disclosed embodiments. Rather, the claim encompasses any genomic modification, irrespective of its genomic locus, nucleotide alteration, regulatory element, mechanism, or structural configuration, provided that the modification results in enhanced expression of one of IL-2, IL-12, IL-15, or IL-18. The disclosed examples therefore represent only particular species within the substantially broader claimed genus.
Furthermore, the specification does not disclose a representative number of structurally diverse genomic modifications commensurate with the breadth of the claimed genus, nor does it establish a correlation between the structure of a genomic modification and its ability to enhance expression of IL-2, IL-12, IL-15, or IL-18 such that one skilled in the art could recognize which undisclosed genomic modifications would possess the claimed function. Accordingly, disclosure of particular cytokine-expression embodiments does not demonstrate possession of the full genus of genomic modifications defined solely by the desired enhancement of cytokine expression.
Similarly, claim 79 presents the same deficiency in the recitation of further genetic modifications “leading to” reduced or inactivated TCR expression, reduced or inactivated B2M, reduced interaction between TGFβ and TGFβR2, and/or reduced interaction between PD1 and PDL1. The claim does not limit the genetic modification to a particular nucleotide sequence, mutation, deletion, insertion, target site, regulatory element, or other structural alteration. Thus, each recited result defines a genus encompassing any genetic modification capable of producing the specified biological effect.
The specification does disclose particular examples of genetic modifications directed to TCR, B2M, PD1, and TGFBR2, including identified gene-editing targets and sequence-specific reagents. However, those disclosed examples constitute particular species within the claimed genera. However, claim 79 is not limited to those disclosed target sites, mutations, or editing reagents, but instead encompasses structurally distinct modifications at other coding sequences, regulatory sequences, interacting genes, or other genomic locations, so long as the modification ultimately produces the recited reduction or inactivation of TCR or B2M expression, or reduction of the TGFβ/TGFβR2 or PD1/PDL1 interaction.
The specification does not establish that the particular disclosed modifications are representative of the full structural diversity encompassed by these functionally defined genera, nor does it disclose a structure-function correlation that would permit one skilled in the art to identify, based on structure, the broader universe of genomic modifications capable of producing each claimed result. The disclosure of particular gene targets and particular editing sequences therefore does not reasonably convey possession of all genetic modifications having the recited functions.
Claim 81 further limits the genetic modifications to those obtained using sequence-specific gene-editing reagents. This limitation identifies a category of tools for producing genetic modifications but does not restrict the underlying modifications to the particular structures disclosed in the specification or otherwise cure the lack of representative species or structure-function correlation discussed above. Claim 81 therefore remains deficient for the same reasons.
Accordingly, while the specification demonstrates possession of certain specific genetic modifications capable of producing the recited effects, it does not reasonably convey possession of the substantially broader genera encompassing any genomic modification that produces those effects. The present claims therefore fail to comply with the written description requirement of 35 U.S.C. 112(a).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 78, 79, and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Posey et al. (WO 2020/198413 A1) in view of Sachdeva et al. (Nature Communications 10, 5100 (2019)).
Regarding claim 78, Posey teaches a method for manufacturing a population of engineered therapeutic immune cells comprising providing immune cells originating from a donor, expressing an anti-MUC1 chimeric antigen receptor (CAR) in said cells, and expanding the cells to form a population of therapeutic immune cells.
Specifically, Posey teaches modified immune cells comprising a CAR that specifically binds MUC1 (see, e.g., claims 1–3). Posey further provides an express manufacturing protocol in Example 10, “Transduction and T Cell Expansion Protocol.” Example 10 teaches generating CART-TnMUC1 cells using T cells from normal donors ND473, ND474, ND502, and ND525. On Day 0, bulk CD4 and CD8 T cells were stimulated with CD3/CD28 beads, followed on Day 1 by transduction with packaged lentiviral vectors encoding the TnMUC1 CAR, after which the cells were allowed to expand. See Posey, Example 10, “Transduction,” particularly the disclosure corresponding to normal donor cells and lentiviral TnMUC1 CAR transduction.
Posey further teaches the claimed expansion step. Under Example 10, “T Cell Expansion,” the transduced cells were fed and split every two days and maintained in culture through an expansion phase. Posey subsequently reports experiments involving five different normal donors in which primary human T cells were transduced with TnMUC1 CAR lentivirus and diluted with fresh culture medium every other day during expansion. See Posey, Example 10, “T Cell Expansion,” and Figs. 31–33.
Posey reports that the TnMUC1 CAR-transduced cells achieved total fold expansions ranging from 8.7-fold to 169.6-fold, depending upon the donor and culture duration, and further confirms expression of the TnMUC1 CAR transgene by flow cytometry. See Posey, Example 10, Figs. 31–34.
Thus, Posey teaches providing donor-derived immune cells, expressing an anti-MUC1 CAR in the cells, and expanding those cells to form a population of engineered therapeutic immune cells.
Posey does not expressly teach introducing a further genetic modification in the genome of the cell that leads to enhanced expression of IL-2, IL-12, IL-15, or IL-18.
Sachdeva, however, teaches precisely such further genomic engineering of CAR-T cells. Sachdeva teaches repurposing endogenous T-cell loci to express IL-12P70 by inserting an IL-12P70 expression cassette into either the IL2Rα or PDCD1 genomic locus. Specifically, Sachdeva states that TALEN technology together with recombinant AAV6 repair vectors was used to place CAR and IL-12P70 expression under the control of the TRAC locus and either IL2Rα or PDCD1 regulatory elements, respectively. See Sachdeva, Results, introductory section describing repurposing of TCR, CD25 and PD1; Fig. 1a.
Sachdeva further teaches that this genomic modification results in conditional secretion of IL-12P70, with secretion being dependent upon tumor engagement, and that IL-12P70 promotes accumulation of the engineered CAR-T cells and markedly improves their antitumor activity in vitro and in vivo. See Sachdeva, Results; Figs. 2 and 4. Thus, Sachdeva teaches introducing a genetic modification into the genome of a CAR-T cell that leads to enhanced IL-12 expression as required by claim 78.
It would have been obvious to one of ordinary skill in the art at the time of the invention to further genetically modify the anti-MUC1 CAR-T cells of Posey according to Sachdeva by inserting an IL-12P70 expression cassette into an endogenous genomic locus, thereby obtaining anti-MUC1 CAR-T cells having a genomic modification leading to enhanced IL-12 expression.
One of ordinary skill in the art would have been motivated to make such a modification because Sachdeva teaches that repurposing endogenous T-cell pathways to provide controlled IL-12P70 expression improves CAR-T-cell functionality and antitumor activity. Sachdeva specifically reports that IL-12P70 expression increases CAR-T-cell accumulation and improves antitumor activity. See Sachdeva, Results and Figs. 2 and 4.
Applying this demonstrated CAR-T engineering strategy to Posey’s anti-MUC1 CAR-T cells would therefore have constituted the predictable use of a known genomic engineering technique to improve the antitumor functionality of a known CAR-T-cell product.
One of ordinary skill would have had a reasonable expectation of success because Sachdeva demonstrates the genomic engineering technique in primary human CAR-T cells, while Posey likewise employs primary human T cells to generate its anti-MUC1 CAR-T-cell population. Accordingly, claim 78 would have been obvious over Posey in view of Sachdeva.
Regarding claim 79, Posey in view of Sachdeva teaches the method of claim 78 for the reasons discussed above. Sachdeva additionally teaches further genetic modifications leading to reduced or inactivated TCR expression and/or reduced interaction between PD1 and PDL1.
Specifically, Sachdeva teaches targeted insertion of the CAR expression cassette into the TRAC locus. The insertion location was selected to inactivate TCR, resulting in engineered TCRαβ-negative, CAR-positive T cells. See Sachdeva, Fig. 1a–d and accompanying Results discussion, “Repurposing the TCR pathway via TALEN and adeno-associated virus (AAV6) treatments.” Fig. 1 expressly describes the TRAC CAR matrix and states that the insertion locations were chosen to inactivate TCR and PD1.
Sachdeva further teaches inserting IL-12P70 into the PDCD1 locus. Targeted integration at PDCD1 concomitantly inactivates PD1, which Sachdeva identifies as a major checkpoint of T-cell function. See Sachdeva, Results; Fig. 1a; Fig. 3. Because inactivation of PD1 prevents or reduces PD1-mediated interaction with its ligand PDL1, Sachdeva teaches the alternative limitation of claim 79 requiring a genetic modification leading to reduced interaction between PD1 and PDL1. Importantly, the PDCD1-targeted IL-12 embodiment provides both the limitation relied upon for claim 78 and the additional limitation of claim 79: the same targeted integration of IL-12P70 into PDCD1 provides IL-12P70 expression while concomitantly inactivating PD1. See Sachdeva, Results, PDCD1/IL-12P70 embodiment; Figs. 1 and 3.
It therefore would have been obvious to employ Sachdeva’s PDCD1-targeted IL-12P70 modification in Posey’s anti-MUC1 CAR-T cells because Sachdeva teaches that this modification provides the combined advantages of regulated IL-12 secretion and elimination of an inhibitory T-cell checkpoint. One of ordinary skill seeking to improve the antitumor functionality of Posey’s anti-MUC1 CAR-T cells would have had reason to employ the demonstrated modification for the same purpose taught by Sachdeva, with a reasonable expectation of success based upon Sachdeva’s experimental results. Accordingly, claim 79 would have been obvious over Posey in view of Sachdeva.
Regarding claim 81, Posey in view of Sachdeva teaches the method of claim 78 for the reasons discussed above. Sachdeva further teaches that the genetic modifications are obtained using sequence-specific gene-editing reagents. Specifically, Sachdeva uses TALEN-mediated genome editing together with AAV6 repair vectors to accomplish targeted genomic integration at the TRAC, IL2Rα, and PDCD1 loci. See Sachdeva, Methods, “Targeted integration of CAR and IL-12P70 constructs”; Table 2, “TALEN targets used in the study.” Table 2 expressly identifies the nucleotide sequences targeted by the TALEN reagents for each of the TRAC, IL2Rα, and PDCD1 loci and identifies the left and right TALEN binding sites. See Sachdeva, Table 2.
It would have been obvious to use the sequence-specific TALEN reagents taught by Sachdeva when introducing Sachdeva’s IL-12P70 genomic modification into Posey’s anti-MUC1 CAR-T cells because Sachdeva expressly employs those reagents to accomplish the targeted genomic insertion responsible for the IL-12P70 expression relied upon above. The use of such reagents therefore represents use of Sachdeva’s disclosed genome-editing technique for its known and intended purpose. Accordingly, claim 81 would have been obvious over Posey in view of Sachdeva.
Therefore, Posey in view of Sachdeva renders the present claims obvious. Posey teaches the core claimed manufacturing method—providing normal-donor T cells, expressing an anti-MUC1 CAR therein by lentiviral transduction, and expanding the resulting CAR-T-cell population (Posey, Example 10, “Transduction and T Cell Expansion Protocol,” Figs. 31–34). Sachdeva teaches further engineering CAR-T cells by sequence-specific targeted genomic insertion of IL-12P70 into IL2Rα or PDCD1, resulting in enhanced IL-12P70 expression and, when PDCD1 is targeted, concomitant PD1 inactivation (Sachdeva, Figs. 1–4; Table 2; Methods, “Targeted integration of CAR and IL-12P70 constructs”).
One of ordinary skill in the art would have been motivated to apply Sachdeva’s demonstrated genomic engineering strategy to Posey’s anti-MUC1 CAR-T cells to enhance CAR-T antitumor functionality while reducing inhibitory PD1 signaling and would have had a reasonable expectation of success because Sachdeva demonstrates the relevant targeted genomic modifications and resulting functional effects in CAR-T cells.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention as evidenced by the reference, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SHARON X WEN/Primary Examiner, Art Unit 1641
Prosecution Insights