DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
This office action is in response to an amendment filed 6/8/2026.
Claims 1-3, 6-13 and 15-21 are pending in this application.
This application is a divisional application of U.S. Application No. 17/047,059, filed April 12, 2019, now U.S. Patent 11,390,659, which claims priority as a 371 filing of PCT/CN2019/082408 filed 4/12/2019 which claims priority to PCT/CN2018/082947 filed 4/13/2018. The certified copy of the priority document in English accompanies this filing.
Information Disclosure Statement
An IDS filed 6/8/2026 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action
Response to Amendments
Applicants amendments are sufficient to overcome the objections to the claims. New objections are noted below.
The rejections under 35 USC 112, second have bene overcome by amendment.
Several of the rejections under 35 USC 112, first have been overcome and new issues generated by the amendments. These stand below.
Claim Objections
Claim 9 is objected to because of the following informalities: Claim 9 should refer to just the abbreviated form of APC as the abbreviation was previously established in claim 1 and need not be spelled out a second time.
Grammatically, the last line in claim 9 should recite –of the sequence step--. Appropriate correction is required.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1-3, 6-13 and 15-21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is in part a new rejection but in part maintained as indicated below.
The following issues as regards the rejection under 35 USC 112a, lack of description stand or are newly noted.
First, part b) of claim 1 newly recites that the population of activated T cells are isolated “using a ligand that specifically recognizes a cytokine”. This recitation by requiring that a ligand be used to isolate the activated T cells presents a goal without steps by which the means to accomplish the goal are provided. Furthermore, the ligand that binds a cytokine does not have an explicit relationship to the cell in the claim by simply being a ligand to a cytokine. To the contrary, ligands are used to isolate by binding with specificity to the activated T cells and hence the ligand and the steps are more specific. To this end, the disclosure teaches that a ligand that recognizes IFNγ can be used. The process involves
Ligands that specifically recognize the cytokine, such as antibodies or receptors for the cytokine, can be used to isolate the enriched population of activated T cells. In some embodiments, the enrichment step comprises contacting the first co-culture with antigen-loaded PBMCs to obtain a stimulated co-culture, and isolating an enriched population of activated T cells from the stimulated co-culture using a ligand that specifically recognizes a cell surface molecule, such as 4-1BB (also known as CD137).
Secondly, part c) of claim 1 requires an end product of at least about 10% of the T cells specifically respond to the tumor antigen. A step of ensuring the level of specifically responding cells in a population is at least 10% is not generally known. The disclosure does not expound on the art.
Part d) requires sequencing to identify a paired genes encoding TCRa and TCRb. It appears that this is meant to be each corresponding to a TCR in the cell and not random combinations of TCRa and TCRb. However, the claims by reciting TCRs based on paired genes does not make this relationships clear. TO the contrary, the disclosure teaches these are cognate pairs
[0016] In some embodiments, the sequencing step comprises bulk sequencing of a first portion of the tumor antigen-specific T cells to provide a plurality of genes encoding TCRα and TCRβ, and single-cell sequencing of a second portion of the tumor antigen-specific T cells providing cognate pairing information of the plurality of genes encoding TCRα and TCRβ, thereby providing a plurality of TCRs based on paired genes encoding TCRα and TCRβ.
Furthermore, in claim 1, the individual has clinically benefitted from MASCT by administering a DC loaded with a plurality of tumor antigens comprising the target tumor antigen. It is not clear how thereafter the DC comprises the target tumor antigen away from the population. Without such a step, the method will not lead to an ability to isolate just TCR specifically recognizing the tumor target antigen. The remaining were co-cultured with T-cells for 7-9 days for maintenance of these cells. ELISPOT was used to assess T cell response measured by MHC restricted T cell response to allow creation of a precise MASCT (T cells comprising patient specific antigen peptide pools).
From here TCR specifically recognizing the tumor antigen were found by the 2m (optimized protocol) comprising,
1) PBMC cells from the individual were isolated and differentiated into immature DC with GM-CSF and IL-4. The DC were pulsed with a peptide pool including CEA, RGS5 and HPV18-E7 and differentiated into mature DC. These are “the DC from the individual loaded with a tumor antigen pool”.
2) The loaded DC cells were co-cultured with PBMC comprising T cells in a cytokine cocktail of IL-2, IL-7 and IL-15 with anti-PD1.
3) The co-culture was stimulated with PBMCs pulsed with the peptide pool.
3) The cells were enriched in a process comprising IFNg to form IFNg T cells which were then co-cultured with antigen loading mature DC with cytokine cocktail and anti-PD-1 and 1-2 days later anti-CD3 was added and the culture grown for an additional 16-17 days to from tumor antigen specific T cells.
The pooled versions were distilled to specific antigens wherein the tumor antigen specific T cells were stimulated by individual peptides -CEA, RGS5, HPV18-E7 as well as IFNgCD3+ T cells stimulated by CEA on beads. Single cell amplification coupled with NGS isolated cognate pairs of TCRa and b that are CDA specific, RGS5 and HPV18-E7. This is critical in identifying TCR specifically recognizing target tumor antigens.
Claim 18 refers to one or more substitutions that are provided for by phage display based affinity maturation. claim 19 refers to mutating one or more amino acids at position in the variable region to enhance pairing of the TCRa and TCRb. Both of these are methods provided to achieve a potential outcome. However, the disclosure does not provide the locations for substitutions or mutations.
Hence, the disclosure only teaches a method of obtaining a TCR receptor specifically recognizing a target tumor antigen peptide, the method comprising isolating PBMC cells from an individual with the target tumor wherein the individual has received clinical benefit from Multiple Antigen Specific Cell Therapy (MASCT) directed at the target tumor wherein the PBMC are differentiated into immature DC with GM-CSF and IL-4 then pulsed with the target antigen and differentiated into mature DC to form tumor antigen loaded DC cells which are co-cultured with PBMC comprising T cells in a cytokine cocktail of IL-2, IL-7 and IL-15 with anti-PD1 then enriched in a process comprising culturing in IFNg to form IFNg T cells which were then co-cultured with tumor antigen loaded mature DC with the cytokine cocktail and anti-PD-1 and 1-2 days later with anti-CD3 and then cultured for an additional 16-17 days to from tumor antigen specific T cells wherein single cells are subjected to next generation sequencing to identify TCR receptor gene cognate pairs of a and b chains that are then introduced into an immune response and those inducing an induce response in the presence of the tumor antigen are identified as the TCR specifically recognizing the target tumor antigen. To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
For written description, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
Response to arguments
Applicants argue that following bulk sequencing, single cell sequencing of a plurality of the tumor antigen specific to cells allows identification of cognate pairs of TCRa and TCRb. However, the claims are more broadly drawn. .Applicants argue that Elispot assay allows one to assess responses. However, the claim neither uses this step nor modifies the method such that a potential population with 10% of the population specifically response to the tumor antigen peptide is isolated. As to claim 19 (for the same reasons as newly added claim 18 to this, the issue is one from the disclosure does not know which amino acids to alter in either claim to achieve the desired outcome. What is missing to use known methods and functional assays is characterization of the TCR and what substitutions and mutations are necessary. The claims are distinctly drawn to a genus of known and unknown species of outcomes. Applicants do not provide the requisite identification parameters to know which of the numerous substitutions and mutations that can be used by claiming simply steps to achieve a goal. What is required is that the structural/functional nexus be known. Applicant’s arguments have not addressed this issue as set forth in the rejection. The predictability of identifying mutants is not a high art and requires as set forth above that the molecule be characterized. In the face of missing structural requirements, there exist large genus of sequences comprising any number of non-functionally as well as functionally active sequences that do not affect the instant invention.
State of the Art
The process of developing tumor specific TCR that specifically recognize target tumor antigen peptides at the time of filing had many different approaches. The most common at the time of filing was to isolate TCR and virally transfer the TCR genes into T cells (see Chandran and Klebanoff, Immunological Reviews, 2019, page 132, col 2). This review teaches that affinity enhancement and other modifications as claimed are empirically determined for each TCR and as stated on page 133, col 2 “It is important to note, how‐ ever, that development of off‐tumor/off‐target toxicities is by no means a universal property of all affinity‐enhanced TCRs”. Another approach is to genetically engineer TCR and TCR mimetics (see page 134, col 2)
Applicants have previously published a method which not claimed but disclosed teaches methods of preparing a cancer therapy (US 20180078624).
[0122] The present invention provides cell-based immunotherapy methods of treating cancer in an individual, collectively referred to as Multiple Antigen Specific Cell Therapy (MASCT). The methods make use of antigen presenting cells (APCs, such as dendritic cells) loaded with a plurality of tumor antigen peptides, and activated T cells induced by the multiple-antigen loaded APCs. Both the multiple-antigen loaded APCs and the activated T cells are capable of eliciting tumor antigen-specific T cell response in vivo and ex vivo, including response by cytotoxic T cells and helper T cells, as well as generating an immune memory through memory T cells. Therefore, in various embodiments of the MASCT method, multiple-antigen loaded APCs (such as dendritic cells), activated T cells, co-culture of APCs and T cells (including activated PBMCs), or any combination thereof can be administered to an individual to treat a cancer or neoplastic condition, or to prevent tumor relapse, progression or metastasis.
The two are related in that they process T cells by exposure to DC loaded with tumor antigens. The difference between the two is that the instant method uses the individual so treated above to isolate the cells to be used in a co-culture method to produce activated T cells and processes them further with an enhancement process and further subjects the cells to a second exposure of the population of DC loaded with the antigen in order to select for TCR that specifically recognize the tumor antigen.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached on 8 am - 5 pm.
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/MARIA MARVICH/Primary Examiner, Art Unit 1633
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