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 .
The rejections under section 112(b) are withdrawn in view of Applicant’s amendments and remarks in connection with this ground of rejection.
The rejection under section 103 is maintained:
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.
Claims 1, 2, 23, 25 and 29 remain rejected under 35 U.S.C. 103 as being unpatentable over Orlando et al., Cancer Res (2018) 78 (12): 3337–3349 (Orlando) in view of U.S. Publication No. 20220265801; or EP 3370065; or U.S. Publication No. 20200069786.
Orlando teaches PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma:
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See pages 3343+.
The required adjuvant is provided in the administered formulations. The specific adjuvants are optional (see claim 23).
Those of ordinary skill would reasonably expect that the formulation would also be effective if the cancer was residual, see claim 29.
The amount of T-cells needed in the disclosed composition is a result-effective parameter that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Therapeutic efficacy and toxicity, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population), can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED5o. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors which can be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered once or twice daily every 3 to 4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
Any observed pharmacological effect, such as eliciting an immune response, would have been an aspect of the methods of the disclosed methods, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”).
Orlando may not explicitly teach that the T cells recognize a FRAME epitope of a peptide having an amino acid sequence of the recited SEQ ID NO’s, e.g.: FRAME epitope of a peptide having an amino acid sequence of SEQ ID NO: 2.
However, the secondary references demonstrate the recited peptides (SEQ ID NO: 2) are known peptides spanning the entire consensus PRAME, and that these peptides comprise the tumor-associated antigen PRAME and cancer-testis antigen (CTA), meaning it can be recognized by the immune system, making it a target for PRAME T cell therapies.
See U.S. Publication No. 20220265801; Example 3; SEQ ID NO 15.
See EP 3370065; SEQ ID NO: 20.
See U.S. Publication No. 20200069786, which discloses a peptide or covalently modified peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1-26, wherein said PRAME epitope is selected to be SEQ ID NO:2. In some aspects the disclosure provides a peptide that comprises the amino acid sequence of any one of... SEQ ID NOs: 2787 to 5431 shown in Table 28, Para. [0137]; SEQ ID NO: 2935 comprises 100% sequence identity to instant SEQ ID NO: 2.
In this way, those of ordinary skill could have applied T cells that recognize a FRAME epitope of a peptide having an amino acid sequence of the recited peptides in the manner required and in a predictable fashion for the purposes of eliciting an immune response in a subject having cancer. As outlined above, Orlando teaches treating cancer using genetically modified T cells with a PRAME-specific TCR. The secondary references are added for the proposition that PRAME epitopes from the recited peptides are applicable to this process of PRAME-targeted T cell therapy. Specifically, the secondary references teach that the particular known technique of using the recited peptides as tumor-associated antigen PRAME was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to T cell therapies that target tumor-associated antigen PRAME would have yielded predictable results. Accordingly, using T cells that recognize a FRAME epitope of a peptide having an amino acid sequence of the recited peptides for the purposes of eliciting an immune response in a subject having cancer would have been prima facie obvious.
In the remarks, Applicant indicated that, in cancer cells, the abnormally expressed PRAME - as an internal antigen (as opposed to an external antigen derived from, e.g., a bacterium or a virus) - is cut to fragments by cytosolic proteasome, and the resulting fragments/peptides are then loaded on an MHC Class 1 molecules (encoded by HLA-A, -B, or -C gene alleles) in the endoplasmic reticulum, as all nucleated cells - including cancer cells - express such HLA class 1 molecules (see para. [0136] of the published specification).
Though cancer cells generally do not express MHC Class 2 molecules (encoded by HLA- DP, -DQ, and -DR gene alleles), abnormally expressed PRAME from dead cancer cells can be picked up by professional antigen-presenting cells (APCs) such as Dendritic Cells, which do express MHC Class 2 molecules, and can load PRAME fragments digested in endosomes onto such MHC Class 2 molecules, thus activating MHC Class 2-restricted CD4+ helper T cells.
In this regard, abnormally-expressed PRAME cut to fragments from dead cancer cells are naturally picked up by professional antigen-presenting cells (APCs) such as Dendritic Cells, which express MHC Class 2 molecules, and load PRAME fragments digested in endosomes onto such MHC Class 2 molecules, thus activating MHC Class 2-restricted CD4+ helper T cells.
Those of ordinary skill would expect that these PRAME fragments would also contain PRAME epitopes corresponding to the instant SEQ ID NO's, thus activating MHC Class 2-restricted CD4+ helper T cells, that recognize these fragments. Accordingly, those of ordinary skill would expect that these MHC Class 2-restricted CD4+ helper T cells would necessarily recognize the recited epitopes, and using these T cells, in the manner taught by the applied references to treat cancers that express PRAME would have been prima facie obvious. The observation that these T cells recognize the recited epitopes is an invariable characteristic of the T cells, prepared in the manner outlined above. Therefore, the rejection is maintained.
THIS ACTION IS MADE FINAL. 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.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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