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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 9, 2026 has been entered.
Claim Status
Claims 17-22, 25-30 and 32-39 are currently pending in this application.
Election/Restrictions
Election was made with traverse of Group I, claims 17-28 and 32, in the reply filed on Oct. 15, 2025 and of the additional genetic modification species with defective FAS and gene editing agent species, and claims 18-19, 25-28 and 34-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 17, 20-22, 29-30, 32-33, and 39 have been considered on the merits.
Claim Objections
Claims 29-30 are objected to because of the following informalities: Claim 29 improperly uses a hyphen to break a sentence when grammatically a hyphen is only for joining or splitting words. Claim 30 appears to have a typographical error resulting in a superfluous “respectively” term. Appropriate correction is required.
Status of Rejections
Status of the rejections: the previous claim rejections under 35 USC §§ 112(d) and 102 are withdrawn in view of the claim amendments and arguments.
Claim Rejections - 35 USC § 112(a), Written Description
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.
Claim 30 is 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventors had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.” Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In the instant case, the species elected is for wherein the engineering is via gene editing agents. When claim 30 is analyzed in light of the specification, the instant invention is broadly directed to a method of making “engineered” immune cells inhibited for SOCS1 and FAS expression and/or activity using gene editing agents targeting any gene.
It must be emphasized that the scope of the claimed invention encompasses a broad genus of gene editing agents (see instant pg. 42-50), typically having a nuclease domain, such as a DNA-targeting molecule, such as a DNA-binding protein or DNA-binding nucleic acid, or complex, compound, or composition, containing the same, which specifically binds to or hybridizes to the gene being edited. In some embodiments, the DNA-targeting molecule comprises a DNA-binding domain, e.g., a zinc finger protein (ZFP) DNA-binding domain, a transcription activator-like protein (TAL) or TAL effector (TALE) DNA-binding domain, a clustered regularly interspaced short palindromic repeats (CRISPR) DNA-binding domain, or a DNA-binding domain from a meganuclease to induce targeted double-stranded breaks or single-stranded breaks, stimulating the cellular DNA-repair mechanisms, including error-prone nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Typical targeted gene regions include exons, regions encoding N-terminal regions, first exon, second exon, and promoter or enhancer regions.
There is insufficient written description in the specification to reasonably convey to one skilled in the relevant art at the time the application was filed that the inventors had possession of the claimed genus of agents defined merely functionally as “gene editing” to accomplish inhibition of expression or activity of SOCS1 and FAS as recited in the preamble. Instead, written description is provided in view of the prior art for where the gene editing agents target SOCS1 and FAS and eliminate or reduce their expression.
There is a lack of evidence in the instant specification as filed that the inventors were in possession of gene editing agents that binds to and disrupt any target gene to accomplish inhibition of expression or activity specifically of SOCS1 and FAS other than wherein the targets are the SOCS1 and FAS genes. The instant application is silent as to any structural description of such target genes indirectly reducing SOCS1 or FAS expression or activity.
From the prior art, the skilled artisan cannot envision all the gene editing targets that decrease the expression level or activity of SOCS and FAS without written description guidance in the instant application, and therefore conception is not achieved across the breadth of the genus of agents until a representative number of species has been sufficiently described for wherein a gene other than SOCS or FAS is targeted, e.g., Suv39h1. However applicant is invited to furnish evidence to the contrary.
The written description requirement may be satisfied through actual reduction to practice or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of this broad genus of gene editing agents to specifically accomplish SOCS1 and FAS inhibition. In the instant case, the specification fails to provide sufficient descriptive information. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
35 USC § 112(a) – Scope of Enablement
Claims 32-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the claims are enabled for wherein the engineered immune cells are cancer cell reactive lymphocytes (e.g., comprises a naturally occurring antigen receptor specific for a cancer antigen in the recipient or engineered to express a TCR or CAR specific to a cancer antigen in the recipient) and the recipient has the cancer cell which so targeted; the specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected to perform the claimed method wherein the immune cell is any type of immune cell and the cancer is any type of cancer.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue or unreasonable experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” or unreasonable include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Immune Cell
It must be emphasized that the scope of the claimed invention encompasses a broad genus of engineered immune cells, such as B cells (pg. 8, lines 5-6 and 22-32). In view of claims 20-21 and 39 (pg. 5, lines 1-5), the immune cell genus of claim 17 encompasses both T cells and non-T cells. The instant specification explains various subtypes of T cells are encompassed, including mucosal-associated invariant T cells (MAIT) and Th3 or Th22 helper T cells (pg. 8, line 22, to pg. 9, line 18; pg. 30). The genus encompasses cells engineered to express recombinant receptors as well as having naturally occurring antigen receptors (pg. 30).
While the prior art teaches methods of treating various cancers using adoptive cellular therapy by administration of engineered immune cells (typically tumor reactive T cells but also natural killer cells, dendritic cells and helper T cells) (see e.g., Borst et al., Nat Rev Immunol 18: 635-47 (2018) at Fig. 5)., the prior art does not teach this for all types of immune cells, such as B cells, Th3 helper T cells, Th22 helper T cells, or MAIT cells. However, applicant is invited to furnish evidence to the contrary.
The application describes one actual working embodiment of the claimed immune cell which is a CAR-T cell engineered to express a cancer cell targeting CAR receptor (pg. 87-89, FIG. 7-8). Thus, in view of the prior art, there is insufficient description in the specification that the inventors had enabled the claimed genus of immune cells. Nothing in dependent claim 33 remedies this deficiency.
Treatment of Cancer
It must also be emphasized that the scope of the claimed invention encompasses a broad genus of cancers to be treated by these engineered immune cells, as the claims are unlimited as to the cancer type. The prior art teaches that certain solid cancers, like glioblastoma, pancreatic, prostate cancers among others, were not treatable by any adoptive cell therapy as of the earliest effective filing date (Rizkallah et al., Front Immunol 17: 1800292 (2026) at pg. 2).
Furthermore, even allowing for a reasonable degree of experimentation, the instant application failed to enable all cancer antigen targeted immune cells via engineering (see Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023)).
In Amgen, the Supreme Court, held that claims drawn to a genus of monoclonal antibodies were invalid due to lack of enablement wherein the genus was merely functionally claimed by their ability to bind to a specific protein as opposed to reciting a specific structure. MPEP 2164.01 explains "it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that the patent owner sought to monopolize an entire class by their function, even though that class was much broader than the exemplary antibodies disclosed by their amino acid structure.
In the instant case, there is insufficient description in the specification that the inventors had enabled the claimed genus of TCR-T, CAR-T, CAR-NK or CAR-macrophage targeting any cancer. As discussed above, the skilled artisan cannot envision the full scope of targeting receptors.
In summary, claims 32-33 are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement, to a person skilled in the art to which it pertains or with which it is most nearly connected to, to perform the claimed method over the scope of any immune cell and any cancer. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to the immune cell genus and the cancer genus; undue and unreasonable experimentation would have been required for one skilled in the art to make the claimed composition to produce the recited result of treatment of cancer, which may never be achieved across the entire scope of the claims.
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 22 and 29-30 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 pre-AIA the applicant regards as the invention.
Claim 22 recites the term “autologous,” which is incoherent and unclear. For a cell to be autologous, the nature of cells must be considered in relation to a recipient and claim 22 lacks any recipient of said cells. Thus, whether autologous or not to any intended recipient is considered and disregarded as an irrelevant limitation to the claimed isolated cell.
Claim 29 recites the limitation of “usable for allogenic adoptive cellular therapy,” which is ambiguous and unclear. This phrase could mean (1) simply not toxic and thus safely administrable to a recipient subject (i.e., a generic type of universal immune cell) or (2) therapeutically effective in at least one type of cellular therapy (such as requiring an engineered immune receptor like a CAR or TCR). Thus, a person of ordinary skill in the art would not understand the metes and bounds of “usable” in this phrase in claim 29. Claim 30 is included in this rejection for depending from indefinite claim 29.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 17, 20-22, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Shifrut (Shifrut et al., Cell 175: 1958-71 (2018)) and Ren (Ren et al., Oncotarget 8: 17002-11 (2017)).
Regarding claims 17 and 20-21, Shifrut teaches isolated immune cells (e.g., T cells) genetically modified using the CRISPR/Cas9 gene editing system to ablate SOCS1 gene expression, rendering the cells SOCS1 defective (pg. 1966, col. 1, “CRISPR-ablation of…SOCS1”; pg. 1968, left col., last para.). Shifrut is silent as to the status of FAS expression/activity in these cells. On the other hand, Ren teaches isolated immune cells (e.g., T cells) rendered FAS defective via genetic modification using the CRISPR/Cas9 gene editing system to ablate FAS (Fas) expression (pg. 17004-17005) but is silent as to the status of SOCS1 expression/activity. Thus, the prior art of record does not disclose wherein the same immune cell is made defective for both SOCS1 and FAS.
However, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to combine into a single immune cell the aforementioned features disclosed by Shifrut (defective SOCS1) and Ren (defective FAS). Firstly, Shifrut teaches SOCS1 ablation in CD8+ T cells enhanced proliferation (Fig. 2, 5, pg. 1968, left col., last para.; pg. 1966, col. 1), while Ren teaches Fas ablation (conferring Fas signaling resistance) increased T cell expansion (pg. 17004, right col., Fig. 4, pg. 17007, left col., 2nd para.). Thus, it would have been prima facie obvious to combine into the same isolated CD8+ T cell both SOCS1 defectiveness taught by Shifrut and Fas defectiveness taught by Ren to achieve with a reasonable expectation of success a T cell with increased proliferative/expansion capability in vitro for use in generating large amounts of T cells in culture.
Regarding claim 22, both Shifrut and Ren teach wherein the immune cell is isolated as noted above and, as noted in a previous section, the term “autologous” is not limiting in this context.
Regarding claim 29, as detailed above Shifrut and Ren each teaches methods of genetically engineering T cells to be defective in respectively SOCS1 and FAS expression and activity. Further, both Shifrut (abstract, pg. 1966, right col.) and Ren (Fig. 4E-G) teach wherein such T cells are used for cancer immunotherapy in a subject and thus these T cells are considered suitable for adoptive cellular therapy. In particular, Ren teaches wherein the T cell is a Fas-resistant allogeneic “universal” CAR-T cell usable in allogenic settings (abstract).
Regarding claim 30, both Shifrut (pg. 1966, left col.) and Ren (Fig. 4) teach wherein the genetic engineering method comprises ablation of the target gene (SOCS1 or Fas) via introduction of (contacting the immune cell with) gene editing agents (CRISPR/Cas9 and gRNA).
Claims 17, 20-22, 29-30, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Shifrut and Ren as applied above, and further in view of Busch (Busch et al., Semin Immunol 28: 28-34 (2016)) and Abdelsamed (Abdelsamed et al., J Exp Med 214: 1593-1606 (2017)).
Regarding claim 39, Ren teaches methods wherein naïve T cells are genetically engineered via gene editing agents (Fig. 1), such as using a one-shot CRISPR system for double gene ablation (pg. 17003). Ren does not expressly teach wherein the immune cell is a naïve T cell (TN cell) defective for FAS. However Busch teaches using naïve T cells allows for researchers to control their differentiation in vitro by choice of cytokine/agent exposure (e.g., IL-7, IL15, IL21, Wnt-beta-catenin signaling) (pg. 6, last para.). Abdelsamed provides a research example of this studying differences between naïve, stem memory T cell (Tscm), memory T cell (Tcm) and effector memory T cell (Tem) by differentiating naïve T cells in vitro via cytokine-driven proliferation (abstract).
Thus, it would have been prima facie obvious to combine into the same naive T cell both SOCS1 defectiveness taught by Shifrut and Fas defectiveness taught by Ren to achieve with a reasonable expectation of success a naïve T cell with increased proliferative/expansion capability in vitro as a source of naïve T cells (or their descendants) for studying cell fate specification, phenotypic differentiation, and responses to antigens. One would be motivated to increase proliferative/expansion of the naïve T cells to obtain as many as possible for such research purposes, e.g., as taught by Abdelsamed, including differentiating such naive T cells into stem memory, memory T and effector memory T cells defective for both SOCS1 and FAS.
Response to arguments
Applicant traverses by arguing a lack of motivation to combine and reasonable expectation of success (pg. 7-8). Applicant also argues even if a prima facie obviousness exists, this is overcome by the unexpected synergistic results providing superior T cells in adoptive cell therapies. These arguments were not found persuasive.
As provided above, there is a motivation from just Shifrut and Ren to combine the two defective genes into a single immune cell to increase expansion ability in vitro. The therapeutic properties of the engineered immune cell are not relevant when it has other utilities and the prior art teaches it is obvious for such. The reasonable expectation of success required in the rejection above is to make an engineered immune cell defective for SOCS1 and FAS, which Applicant admits would be routinely accomplished given the motivation for such at the time (response pg. 7). The rejection does not rely on any reasonable expectation of success at achieving any synergistic effect in therapeutic activity in the treatment of cancer nor any complementary interaction between the two defective genes. The rejection merely relies on the expectation for an improvement in T cell proliferative ability in culture for applications desiring acquiring large numbers of T cells, or at least more efficiently and/or to save costs.
Regarding the purported unexpected properties of the immune cell defective for both SOCS1 and FAS. Applicant has failed to establish this for any such “engineered” immune cell. Rather the arguments are limited to T cells and their in vivo properties upon a therapeutic administration to a mammalian subject (see instant FIG. 7-8). Thus, claims 17 and 29 are not commensurate in scope to the unexpected property. Firstly, most claims do not involve a method of adoptive cellular therapy for cancer as in claims 32-33, which is required to manifest the purported unexpected result. Additionally, claim 17 encompasses any mechanism of rendering either SOCS1 or FAS defective (see e.g., claim 30 mentioning antibody derivatives). For dependent claims 20-21 and 39, although the immune cell may be limited to a T cell, or subtype thereof, this is also not commensurate in scope to an in vivo effect during an adoptive cellular therapy (e.g., for treating a cancer). Moreover, both Shifrut and Ren expected improvements in therapeutic applications as Shifrut teaches SOCS1 knockout in CD8+ T cells enhanced their anti-cancer function (cancer cell clearance) (Fig. 2, 5, pg. 1968, left col., last para.; pg. 1966, col. 1) while Ren teaches Fas knockout in T cells prolonged survival upon administration to a subject (xenograft mouse cancer model), which was predicted to enhance tumor control efficacy as part of a CAR T cell system (pg. 17004, right col., Fig. 4, pg. 17007, left col., 2nd para.). The scope of commensurability doctrine guards against rendering patentable over the prior art broad claims covering other predictable or routine utilities.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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