DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-20 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 10/3/2022 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through.
Claim Objections
Claims 1, 13, 16, and 19 are objected to because of the following informalities: claim 1 defines TCR as T cell receptors in line 1 but does not use the abbreviated form in line 13. For simplicity and streamlined claims, it is suggested that once an abbreviation is established that that term be used. Claim 13 lacks an article prior to “specific response” which makes it grammatically incorrect. For consistency, claim 16 requires the articles “a” prior to “TCRa” and TCRb” in line 1-2 as well as prior to “response” in line 3. Thereafter, in claim 19, “the’ is required prior to TCRb. As well, in claim 19 “paring” appears to be –pairing--. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 13, 17, 18 and 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 1 recites the limitation “the tumor antigen specific T cells” in part d), line 12 which lacks clarity in the context of the entire claim. The claim is directed toward identifying TCR “specifically recognizing” a target tumor antigen peptide. Part c has two populations of tumor antigen specific T cells. The first is the entire population and the second “specifically responds” to the target tumor antigen peptide and constitutes at least about 10% of the total population. By reciting “subjecting the tumor antigen specific T cells”, the claim appears to refer to the general population but the claim also appears to require the sub-population of T cells that specifically responds to the target tumor antigen peptide. While recognition and response are not required to be linked, the “population of tumor antigen-specific T cells” are not characterized, only those that respond. Hence, it is not clear if simply being part of the population of alleged tumor antigen specific T cells is adequate to arrive at the required end product in the preamble.
Claim 13 recites the limitation "the population of APCs loaded with the target tumor antigen peptide" in claim 1. There is insufficient antecedent basis for this limitation in the claim. This claim is further confusing as the epitope is used to contact the APCs and yet the final product comprises the antigen peptide. It is really not clear the connection of this step to claim 1. If it is intended to depend from claim 9, the issue of epitope vs peptide still exists.
Claims 17 and 18 appear to refer to “the TCR” that is expressed in the host immune cell of claim 16. However, there are a plurality of TCR from which this claim depends. Hence, there is not sufficient antecedent basis for e this limitation in the claims. It would be proper to refer to that in claim 16 as the expressed TCR as opposed to the identified TCR of claim 1.
Claim 20 is vague and indefinite in that the metes and bounds of the term “derived from” are unclear. It is unclear the nature and number of steps required to obtained a “derivative” of the CEA. The term implies a number of different steps that may or may not result in a change in the functional characteristics of the peptide from the source that it is “derived from”.
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 1-20 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.
The instant claims are drawn to a method of engineering TCR to target tumor antigens associated with a tumor. In this case, the claims are generically recited in ways that lead to lack of description. This is a limited descriptive element wherein the claims broadly and incompletely claim the inventive elements.
Part a) co-cultures in non-descript media and use of Dendritic Cells (DC) from any source wherein the DC has any target tumor antigen peptide.
Part b) requires a step called an enrichment step with an enrichment process to lead to an enriched activated population of T cells. This is a descriptive term for a method wherein the steps cannot be performed relying on the terminology and this is not an art accepted limited definition.
Part c) requires a second co-culture event where again the media is any. The method 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 is at least 10% is not generally known.
Part d) requires sequencing to identify a pair of genes to provide a plurality of TCRs specifically recognizing the target tumor antigen.
Furthermore in claim 1, the individual has clinically benefitted from MASCT that is said to comprise administering to this individual an amount of activated T cells that are the result of a population of T cells with a population of DC that comprise a pool of tumor target antigens.
Claims 17-19 refer to steps that are descriptive in generic terminology wherein the exemplification demonstrates a single set or no set of conditions to describe the needed process. Claim 17 refers to “determining HLA restriction” it is not clear how this is performed or to what end. Claim 18 refers to adding “affinity maturation” which appears to be a mutational process by which the affinity of the TCR to the antigen is improved. However, no steps, no end points and no guidance accompanies this goal. Finally, claim 19 recites “enhancing the paring (pairing” of the TCR a and b chains. Like claim 18, this is a desire without steps.
These steps generically recite the method but the disclosure is much more limited. The specification teaches means of identifying target tumor antigens from subjects with the tumor thus there is correlation between the treatment. In Example 1, a patient with cervical cancer received MASCT treatment and following demonstrated enhanced T cell response to the cervical carcinoma antigen peptide pool and core tumor specific antigen peptides which were CEA, HPV18-E7 and RGS5. Similar tumor antigen specific T cells were identified from a patient with metastatic lung cancer using the protocol above with a pool including hTERT, p53, Survivin, NY-ESO-1, CEA, CDCA1, VEGFR1, VEGFR2, RGS5, CCND1, MUC1, Her2, MAGEA1, MAGEA3, WT-1 and neoantigen peptides-SMX-1, SMX-2 and SMX-3. Four antigens were identified as inducing a strong response and these were hTERT, CCND1, MAGE-A1 and WT-1 and subsequently hTGERT1 and 2.
The method of making the population of T cells were made as follows. The subjects have received MASCT treatment using autologous PBMCs. This practice was known in the art prior to the effective filing date (see Zhang et al, Annals of Oncology, 2017, page 1). DC obtained thereof are pulsed with a pool of potentially related tumor antigens associated with their tumor type. The DC comprising the pool of antigens were stimulated with TLR ligand to form mDC (mature dendritic cells). Half of the mDC were injected into the patient. 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.
As to HLA restriction assays, very little is provided except a table of donor and some indication of whether donors have those genotypes (table 4). HLA restriction is related to the HLA phenotype to which the TCR is restricted (Shafer et al, frontiers in Immunology, 2022, page 3, col 1).
While TCRs recognize antigens in the context of HLA presentation, CARs recognize natively folded proteins at the cell surface. Therefore, CARs overcome clinical limitations imposed by the HLA-restriction of TCRs. HLA encoding genes are the most polymorphic in the human genome, with over 20,000 HLA-class I alleles identified to date (10). Therefore, unlike CAR T therapy, patients selected for TCR T therapy must express not only the targeted antigen, but also the corresponding antigen-restricting HLA allele. For this reason, TCR T therapies typically utilize TCRs that are restricted to relatively common HLA alleles, such as HLA-A*02:01, which is present in about 47.8% and 16.8% of Caucasian and African American populations in the United States, respectively (11).
This publication teaches that affinity maturation is a nascent art that assesses the structure of the TCR and how it interacts with the target pMHC. Maturation was altered by utilizing mutations (see Shafer et al, page 11, col 2) As to affinity maturation, no demonstration of this method is provided in the disclosure.
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
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).
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.
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.
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, Maria Leavitt can be reached on 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARIA MARVICH/Primary Examiner, Art Unit 1633
.