Patent Application 17286334 - METHOD FOR ACTIVATIONPROLIFERATION OF T CELLS

Title: METHOD FOR ACTIVATION/PROLIFERATION OF T CELLS

Application Information

Invention Title: METHOD FOR ACTIVATION/PROLIFERATION OF T CELLS
Application Number: 17286334
Submission Date: 2025-05-15T00:00:00.000Z
Effective Filing Date: 2021-04-16T00:00:00.000Z
Filing Date: 2021-04-16T00:00:00.000Z
National Class: 435
National Sub-Class: 458000
Examiner Employee Number: 98153
Art Unit: 1632
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 1

Cited Patents

No patents were cited in this rejection.

Office Action Text

DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .

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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 16th, January, 2025 has been entered.

Claim Status
Claims 1-32 are pending.
Claims 1-13 and 21-32 are withdrawn.
Claims 14-20 are under examination.

New Claim Objections
Claim 20 is objected to because of the following informalities:
“ex vivo” should be italicized as “ex vivo.”
Appropriate correction is required.

Withdrawn Claim Rejections - 35 USC § 112(a)
New Matter
The rejection of claims 14-20 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the written description requirement due to the presence of new matter as set forth in the previous office action is withdrawn in view of Applicant’s amendments.

New Claim Rejections - 35 USC § 112(a)
Scope of 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.

Claims 14-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
An in vitro method for delivering a nucleic acid into T cells, comprising a step of contacting a cell population containing T cells simultaneously with at least one kind of T cell activating ligand and a nucleic acid delivery carrier containing a nucleic acid inside and free of a T cell activating ligand added to its surface,
wherein activation/proliferation of T cells by the T cell activating ligand and introduction of the nucleic acid into T cells by the nucleic acid delivery carrier are simultaneously performed in one pod

does not reasonably provide enablement for:
in vivo methods of delivering a nucleic acid into T cells.

The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.

Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” 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 weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.

Breadth of the Claims

Instant claims encompass:
“contacting” a cell population containing T cells
This encompasses all ways of contacting the cell population, including in vitro methods as well as in vivo methods that may use all possible routes of administration.

“nucleic acid delivery carrier containing a nucleic acid inside”
This encompasses all possible nucleic acid carriers including viral vectors of all possible types and serotypes as well as non-viral vectors.

Direction or Guidance Presented
While contemplating methods for delivering a nucleic acid into T cells in vitro (para. [0002-0003, 0010, 0191, 0202, 0206, 0208, 0211-0214]) and in vivo (para. [0003, 0166, 0169, 0191, 0195, 0202, 0214, 0216, 0218-0219]), Applicant provides limited guidance on method conditions (Examples 15-16 pg. 89-91).

Present Working Examples
in vitro
The following examples include in vitro embodiments and do not include in vivo embodiments.

Example 15 – Highly efficient mRNA transfection into human peripheral blood CD3 positive pan T cells by co-addition of activation stimulant and lipid nanoparticles (para. [0242])
Cell Type: Human peripheral blood CD3 positive pan T cells
Human T-Activator CD3/CD28 was added to the medium.
Subsequently, lipid nanoparticle compound 35-luc mRNA encapsulating luciferase mRNA (TriLink) were added to the medium such that the concentration of luciferase mRNA in the medium was 0.1, 0.3 or 1 pg/ml, and the mixture was stood in a 5% CO2 incubator at 37°C for 72 hr.
It was shown that addition of lipid nanoparticles encapsulating Luc mRNA to T cells under activation stimulation dramatically improves transfection activity (Fig. 4). In addition, the survival and proliferation rate of T cells was maintained at a high level (Fig. 5).

Example 16 – Highly efficient luc mRNA transfection into human CD4/CD8 positive T cells by co-addition of activation stimulant and lipid nanoparticles (para. [0243])
Cell Type: CD4 and CD8 positive cells from human peripheral blood leukocyte fraction
T cell activation stimulant, TransAct (Milteny 90 Biotech) was added.
Subsequently, lipid nanoparticle compound 35-luc mRNA encapsulating luciferase mRNA (TriLink) were added to the medium such that the concentration of luciferase mRNA in the medium was 1, 3 or 10 pg/ml, and the mixture was stood in a 5% CO2 incubator at 37*C for 72 hr.
It was shown that addition of lipid nanoparticles encapsulating Luc mRNA to T cells under activation stimulation dramatically improves transfection activity. In addition, the survival and proliferation rate of T cells was maintained at a high level.

Absent Working Examples
No working examples are provided in in vivo embodiments.

State of the Prior Art and Unpredictability of the Art
In Vivo Methods
Regarding methods of delivering nucleic acid delivery carriers into cells in vivo, Applicant is directed to the art of Paunovska et al. (Nano Lett. 2018 Mar 5;18(3):2148–2157.; henceforth “Paunovska”). Paunovska evidences in vivo delivery of nucleic acid delivery carriers (lipid nanoparticles), is not predicable from in vitro data. Specifically, Paunovska recites “in vitro delivery did not predict in vivo delivery” (abstract). Paunovska evidences to successfully deliver nucleic acids after systemic administration, nanoparticles must overcome complex obstacles that are difficult to model in vitro and a significant fraction of the drug can be lost at each point (pg. 2 2nd para.).
Regarding methods of delivering nucleic acid delivery carriers into cells in vivo, Applicant is further directed to the post-filing art of Ghosh et al. (Appl Biosaf. 2020 Mar 1;25(1):7–18.; henceforth “Ghosh”). Ghosh evidences viral vectors as nucleic acid delivery carriers may not predictably express in different cell types depending on the serotype of the vector (“various AAV serotypes have exhibited remarkably different expression patterns due to differences in cell entry and intracellular activities” pg. 8 col. 2 3rd para.). Ghosh evidences limitations of effective use of viral vectors in vivo including packaging capacity, inflammatory response, cell type limitations, oncogeneis, and transient expression (Table 1 pg. 9).
Furthermore, regarding delivery in vivo, it is well known in the art that the route of administration of an agent effects the ability of the agent to transfect a specific cell type. For example, topical administration of a vector would not allow for expression in in the spleen due to physiological barriers. As evidenced by Paunovska, even systematic administration via mouse tail vein injection did not result in predictable expression of the nucleic acid (“Animal Experiments” pg. 8).
Therefore, because the delivery of nucleic acid carriers and ligands in vivo cannot predictably target and express the nucleic acid in specific cell types, Applicant is not enabled for methods of delivering a nucleic acid into T cells in vivo.

Unpredictability of the Art and the Quantity of Experimentation Necessary
As the arts of Paunovska and Ghosh demonstrate, the obstacles that hinder the use of the claimed method in in vivo embodiments are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant broadly claimed invention.

Conclusion
In conclusion, the breadth of the claims lack enablement because the specification provides limited working examples in in vitro and insufficient guidance for methods in vivo. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot predictably be performed. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.

New 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 14-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 14 recites “activation/proliferation of T cells by the T cell activating ligand” is performed in a wherein clause. However, claim 14 does not previously recite “proliferation.” Therefore, the is improper antecedent basis for the term “proliferation” within the claim.
The dependent claims are included in the basis of this rejection because they do not clarify the issue.

New Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin et al. (WO-2016/180778-A1; henceforth “Sahin”).
Regarding claim 14, Sahin discloses a method for delivering a nucleic acid into T cells, comprising a step of contacting a cell population containing T cells (splenocytes) with at least one kind of T cell activating ligand (anti-CD3 and anti-CD28; pg. 67-68), and subsequently contacting the cell population with a nucleic acid delivery carrier containing a nucleic acid inside in one pod (well) (MLV-E retroviral vector with CLDN6-CAR; pg. 67-68) (see also Figure 5; Example 1).
Regarding the negative proviso of claim 14, the nucleic acid delivery carrier disclosed by Sahin is a virus and is free of a T cell activating ligand added to its surface.
However, Sahin does not disclose activation/proliferation of T cells by the T cell activating ligand and introduction of the nucleic acid into T cells by the nucleic acid delivery carrier are simultaneously performed.
Nevertheless, regarding claim 14, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Sahin, and choose simultaneous activation from the finite number of two solutions of simultaneous activation and subsequence activation (pre-activation of Sahin). Regarding the reasonable expectation of success, instant claims only require introducing the nucleic acid in to the T cell. Since viruses can transfect cells in the absence of T cell activation, one of ordinary skill would have had a reasonable expectation of success in introducing the nucleic acid into at least one cell.
Furthermore, regarding claim 14, simultaneous activation is a timing of a step. Therefore, one of ordinary skill would not consider optimization of the timing of the activation step to be inventive.
Applicant is reminded that generally, differences in timings will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such timing is critical (MPEP 2144.05 II).

Regarding claim 15, further to the discussion of claim 14 above, Sahin discloses the T cell activating ligand includes an antibody to CD3 and/or an antibody to CD28 (anti-CD3 and anti-CD28; pg. 67-68).
Regarding claim 16, further to the discussion of claim 14 above, Sahin discloses two or more kinds of T cell activating ligands are contacted (anti-CD3 and anti-CD28; pg. 67-68).
Regarding claim 17, further to the discussion of claim 14 above, Sahin teaches the nucleic acid deliver carrier can be a liposome (“the nucleic acid encoding the antigen or variant thereof is formulated in liposomes” pg. 7 3rd para. ; see also pg. 38, 40-41, 68, 70; Claim 25).
Regarding claims 18 and 19, further to the discussion of claim 14 above, Sahin discloses the nucleic acid nucleic acid encodes a T cell activation promoting factor (claim 18), which is a CAR (claim 19) (CLDN6-CAR; Figures 4-8; pg. 64-68, 70-71; Example 1).
Regarding claim 20, further to the discussion of claim 14 above, Sahin discloses the method is performed ex vivo (isolated splenocytes in culture; Example 1; pg. 67-68).
Hence, the claimed invention as a whole was prima facie obvious.

Conclusion
No claims are allowable.

Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632

/MARCIA S NOBLE/Primary Examiner, Art Unit 1632