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 .
DETAILED ACTION
1. Applicant’s amendment and response filed 11/30/25 is acknowledged and has been entered. Claims 1-6 filed 8/21/23 are pending. Claims 1 and 4 are independent claims.
2. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
3. The drawings are objected to because Figure 8 is labeled Figure 8 (comprises two graphs) and Figure 8 C and Figure 8 D. It appears that Applicant has not labeled the two graphs as Figure 8 A and Figure 8 B as they are disclosed in the brief description of the drawings in the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
4. 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.
5. Claims 1-6 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim interpretation: The specification discloses at [0038] that the term “TCR” includes heterodimers as well as single chain constructs. The composition recited in claim 2 and administered in claim 5 is being interpreted as encompassing a vector comprising the nucleic acid by itself (not in a host cell) or administration of a vector alone comprising the nucleic acid (i.e., gene therapy). With regard to the limitation “therapeutic”, the specification discloses that the term “treatment” includes therapeutic or prophylactic treatment of a subject in need thereof, and that a therapeutic or prophylactic treatment comprises prophylactic treatment aimed at the complete prevention of clinical and/or pathological manifestations and thus also includes amelioration or prevention of diseases ([00147]). The specification discloses that the term “subject” is used interchangeably with individual or animal or patient to refer to any subject for whom therapy is desired ([00148]). The specification discloses that a “diagnostic” composition is for use in detecting, diagnosing and/or prognosing cancer in a subject in vivo or in vitro, typically comprising administering the diagnostic agent (i.e., the nucleic acid, vector and/or host cell) to the subject and detecting binding of said diagnostic agent to its antigenic target ([00156], [00157]). The claims that recite a diagnostic method encompass administration to any subject in need encompassing any condition that presumably comprises expression of PRAME antigen and only recite an administering step.
The instant claims recite a pharmaceutical or diagnostic composition comprising a nucleic acid encoding a TCR comprising the recited CDRs (as is recited in instant base claim 1), including wherein the nucleic acid is a component of an expression vector (dependent claim 2) and wherein the expression vector is a component of a host cell (dependent claim 3), or a therapeutic or diagnostic method comprising administering the pharmaceutical or diagnostic composition of claim 1 to a subject in need thereof (as is recited in instant base claim 4), including wherein the nucleic acid is administered as a component of an expression vector (dependent claim 5), or including wherein the expression vector is administered as a component of a host cell (dependent claim 6).
The specification does not disclose how to use the instant invention, a pharmaceutical or diagnostic composition comprising the nucleic acid encoding a TCR comprising the CDRs recited in instant base claim 1, including wherein the nucleic acid is a component of an expression vector, wherein the nucleic acid is operably liked to regulatory sequences configured for expression of the TCR (dependent claim 2), or wherein the expression vector is a component of a host cell (dependent claim 3), a therapeutic or diagnostic method comprising administering the pharmaceutical or diagnostic composition of claim 1 to a subject in need thereof (independent claim 4), including wherein the nucleic acid is administered as a component of an expression vector, wherein the nucleic acid is operably linked to regulatory sequences configured for expression of the TCR (dependent claim 5), or including wherein the expression vector is administered as a component of a host cell comprising the expression vector (dependent claim 6).
The specification has not enabled the breadth of the claimed invention because the claims encompass:
(1) a diagnostic composition comprising a nucleic acid/vector thereof/host cell thereof encoding the recited TCR wherein it is unpredictable that the product can be used to diagnose any condition;
(2) a diagnostic method comprising administering the nucleic acid, vector thereof, or host cell thereof wherein it is unpredictable that the product can be used to diagnose any condition; and
(3) (i) a therapeutic method comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof, wherein the nucleic acid encoding a TCR receptor is what is administered or wherein the vector comprising the nucleic acid is what is administered, wherein it is unpredictable what cells the nucleic acid will incorporate into in vivo and if such administration will produce a therapeutic effect, including in the absence of a fused effector functionality for killing tumor cells (claims 4 and 5), or
3 (ii) a therapeutic method comprising administering the pharmaceutical composition comprising a host cell comprising a nucleic acid encoding the recited TCR and comprised in an expression vector (i.e., a host cell that expresses the recited TCR), wherein the patient is not HLA-A*02 positive, wherein the host cell is not a T cell or an NK cell that has the requisite machinery to allow a TCR to signal and engage in target cell killing, and wherein it is unpredictable that even if the host cell is such a T cell or an NK cell transduced with a vector comprising the nucleic acid that encodes the recited TCR and the subject is HLAA*02 positive, that in all conditions, including a PRAME positive cancer, such administration will induce a therapeutic endpoint.
Note that as in the claim interpretation section above in this rejection, “therapeutic” encompasses complete prevention of clinical and/or pathological manifestations and also includes amelioration or prevention of diseases; subjects are any animal subject; and a “diagnostic” composition is for use in detecting, diagnosing and/or prognosing cancer in a subject in vivo or in vitro.
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed therapeutic or diagnostic compositions and therapeutic or diagnostic methods may be used for their disclosed uses without undue experimentation.
The specification does not disclose any working examples of using a composition comprising the recited nucleic acid/or vector comprising said nucleic acid as a pharmaceutical or a diagnostic. The specification does not disclose any species of conditions that may be treated (including prophylaxis according to the definition of therapeutic in the specification) except under the broad disclosure of cancer. There are no working examples of using a host cell comprising the said nucleic acid (i.e., a host cell expressing the recited TCR as an adoptively transferred cell) as a pharmaceutical or a diagnostic. One of skill in the art was aware that the presence of T cells specific for a tumor antigen that are capable of killing tumor-antigen-transfected cells in vitro does not correlate to treatment/prevention of cancers in vivo. This is due to such considerations as immunosuppressive factors and antigen expression (peptide/MHC) and distribution in the tumor microenvironment.
For example, evidentiary reference Kalos and June (Immunity, 2013, 39: 49-60) teach that although there are strategies for modifying T cells by genetic engineering for adoptive transfer, abTCR-based targeting approaches (such as the instant method of adoptive transfer of host cells expressing the recited TCR) remain susceptible to the common tumor escape mechanisms of MHC down modulation and altered peptide processing (especially page 50, column 2 at paragraph 2). Kalos and June discuss the potently immunosuppressive microenvironment present at the tumor site (page 50, column 1 at paragraph 1), and “A significant obstacle to overcome is the exhaustion of T cells in the immune-suppressive milieu within the tumor microenvironment (page 54 at the first full paragraph, column 1). Kalos and June teach “With regard to the tumor, essential questions related to the relevance of tumor burden remain to be addressed. Adoptively transferred T cells make complex “decisions”, sensing multiple inputs and responding to tumor with multiple effector functions including proliferation and functional differentiation. As a result, there is the theoretical consideration that the most effective T cell activation may require higher tumor burden and that therapies may paradoxically be less effective or require higher doses at earlier stages of disease. Corollary issue related to the impact of tumor-driven immunosuppressive mechanisms, involving both surface receptors and soluble mediators, will be important to unravel (paragraph spanning columns 1-2 on page 56). See entire reference.
Evidentiary reference Fuchs and Krackhardt (Cells 2022, 11(3), 410; https://doi.org/10.3390/cells11030410, pages 1-36) teaches engineering TCR-transgenic (against a tumor associated antigen) T cells to adoptively transfer to multiple myeloma (MM) subjects. Fuchs and Krackhardt teach that such an approach aims for targeting a specific antigen on the tumor cell surface in its native formation, potent T cell activation with subsequently efficient tumor cell killing, as well as the initiation of stable, long-term immune memory for tumor control (paragraph spanning pages 2-3). Fuchs and Krackhardt teach that while direct tumor killing is attributed to CD8+ T cells, CD4+ T cells hold important accessory functions for anti-tumor immunity (paragraph spanning pages 19-20). Fuchs and Krackhardt teach that stable expression of the antigen of interest on the cell surface, in this instance, as a peptide on an MHC complex, and its coverage of the tumor entirety before therapy initiation will influence therapeutic response. Fuchs and Krackhardt teach that generally a large degree of intratumoral heterogeneity is expected before the start of treatment already, and therapeutics targeting antigens with incomplete coverage specifically select for target-negative and thereby therapy-resistant tumor cell clones (section 4.2 at the first paragraph). Fuchs and Krackhardt teach that for TCR-based approaches, tumor cells become unrecognizable for the T cell compartment, for example, by downregulation, loss and./or mutation of the antigen processing and presentation machinery, like the b2m domain of the MHC-I complex (section 4.2 at the third paragraph). Fuchs and Krackhardt also describe the dysfunction of tumor reactive T cells after their infiltration into the highly immunosuppressive TME (tumor microenvironment) (section 4.2 at the first paragraph). Crosstalk between T cells and other tumor-promoting immune cells in the tumor niche can lead to dysfunction of T cells, including by Tregs in terms of competitive IL2 consumption, immunosuppressive cytokine secretion and/or suppression of APCs via CTLA-4 they can also reduce antitumor immunity (section 4.2 at the second paragraph). Fuchs and Krackhardt teach that apart from Treg cells MDSCs (myeloid derived suppressor cells), B regulatory cells, or in the case of MM, the MM cells themselves can express and secrete immunosuppressive factors that impair T cell functionality (section 4.2 at the second paragraph on page 22). Fuchs and Krackhardt conclude that “For both, CAR as well as TCR, there are many approaches assessed already to face resistance mechanisms. Despite conceptual attractiveness, they still must prove clinical superiority, more durable response rates, and prolonged survival in MM patients” (last sentence of reference). See entire reference.
The specification discloses that genetic transfer of tumor antigen-specific TCRs into primary T cells allows for rapid generation of tumor-reactive T cells with defined antigen specificity even in immunocompromised patients ([0005]). The specification further discloses that host cells comprising the TCR, the nucleic acid, or the vector of the invention includes lymphocytes such as CTLs, NK cells, NKT cells, or gamma/delta T cells ([0015]). The specification discloses that the TCR termed “T4.8-1-29” that comprises the CDRs recited in the instant claims (i.e., SEQ ID NOs:1-6) is from a T cell clone induced from CD8+- enriched T cells stimulated with mature DCs (mature antigen presenting cells) that were in vitro transcribed with RNA encoding the PRAME tumor antigen (Examples). This said TCR specifically recognized HLA-A2+ T2 cell loaded with saturating amounts of PRAME100-108 peptide (i.e., the VLDGLDVLL peptide). The T cell clone bearing this TCR demonstrated high IFN-gamma secretion in coculture with PRAME expressing, HLA-A*02+ tumor cell lines K562-A2 and Mel-624.38. The DNA encoding the TCR was sequenced and reconstructed ([00192]), and either in vitro transcribed into RNA encoding the full T4.8-1-29 TCR sequence for transient transfection of recipient effector T cells by electroporation, or used for stable transduction of T effector CD8+ cells by using retroviral vector constructs ([00193]-[00194]). The T4.8-1-29 expressing cells showed efficient lysis of relevant VLD peptide- loaded target cells ([00200]-[[00203]) and against human tumor cell line K562 transfected with encoding sequences for HLA-A*02:01 and PRAME tumor antigen ([00204]-[00211]), but not with PRAME+ K562 cells expressing a different HLA molecule ([00216]). The TCR was antigen specific on HLA-A2 positive tumor target cell lines ([00216]-[00220]) and induced lysis ([00221]), but did not activate upon coculture with unmodified healthy tissues from HLA-A2 positive donors ([00222]).
One of skill in the art is aware that TCRs on T cells directly bind to a peptide/MHC complex and that co-receptors such as CD4 and CD8 molecules aid in the stabilization of this interaction and the triggering of the signaling cascades and that genetic modification of T cells isolated from peripheral blood to target a chosen antigen using cell surface receptors that recognize tumor associated antigens can be accomplished by delivery of TCR genes that are targeting the tumor. One of skill in the art is also aware that NIK cells comprise cytolytic machinery that can recognize and react against transformed cells (tumor cells). The art further recognizes that NK cell activating receptors share similarities with TCR/CD3 signaling as they also utilize CD3 zeta for signaling cascade initiation. Both NK and T cells primarily act on their targets with the secretion of perforin and granzyme into the immunological synapse and trigger apoptosis in the target cell. Studies have shown that genetically modified NK-92 (a cell line that does not express KIRs or ‘killer inhibitory receptors’ that can suppress activation) can express functional TCRs on cell surfaces when provided with the co-expression of CD3 complex proteins (i.e., CD3 epsilon, gamma and delta chains plus or minus CD3 zeta, “DGE” or “DGEZ”) and can demonstrate antigen-specific cytotoxicity against specific antigens via the introduced TCR. Additionally, the art recognizes that primary NK cells can be genetically modified with TCR alpha and beta chains along with the CD8 alpha and beta co-receptor and the full CD3 complex. See evidentiary reference Karahan et al. (Turk. J. Hematol, 2023, 10: 1-10). Karahan et al. also teach that it is still unclear how the diverse range o KIRS (i.e., inhibitory receptors) in primary human NK cell populations may impact TCR-NK functions and whether or not certain KIR-ligand combinations would have a deleterious effect. Karahan et al. also teach that it has been observed that introducing a second TCR into T cells via genetic modification is problematic due to the heterodimeric nature of the TCR ligand binding domain which is composed of TCR alpha and beta chains, leading to mispairing of the new TCR chains with endogenously expressed ones, creating mixed TCR dimers (see entire reference).
Thus, the art evidences that T cells and NK cells have or can be engineered to express a TCR that can signal and trigger target cell killing. This is relevant to the issue of the pharmaceutical (or diagnostic) composition comprising the nucleic acid/vector thereof and administering it to produce a therapeutic effect or a diagnostic determination, as it is unpredictable that T cells (exclusively or at all) will be transduced in vivo and to acceptable levels of expression and in sufficient numbers and if so, to even bind to the relevant target and furthermore to effect a pharmaceutical or therapeutic effect.
Evidentiary reference Burdek et al. (Cancers, 2025, 17: 242, pages 1-19) teaches that the PRAME antigen was shown to be a T cell target for acute myeloid leukemia (AML) after stem cell transplantation without overt toxicity (summary). Burdek et al. teach that MDG1011 is an autologous TCR-T cell therapy specific for PRAME and developed as a treatment option for patients with myeloid malignancies, including AML, MDS (myelodysplastic syndrome), and MM (multiple myeloma). Burdek et al. further teach that the recombinant TCR used in MDG10011 (i.e., the TCR T4.8-1-29, which possesses the CDRs recited in the instant claims) recognized PRAME100-108 VLD-peptide presented by HLA-A*02:01 (abstract and paragraph spanning pages 2-3). Burdek et al. teach that two preclinical batches of MDG1011 were produced from enriched CD8+ T cells of healthy donors and that such T cells displayed strong VLD-TCR expression, cytokine secretion, and cytotoxicity after antigen-specific activation in vitro, while showing no signals of on-target/off-tumor or off-target recognition, and showing functionality after activation by multiple target cells. Burdek et al. teach that preclinical studies demonstrated that MDG1011 displayed key attributes of high specificity, sensitivity, and safety required for regulatory approval of a first-in-human clinical study of patients with myeloid malignancies. Burdek et al. teach that the IMPs (i.e., Investigational Medical Products) applied in nine patients displayed antigen-specific functionality, and elsewhere, clinical study results for MDG1011 showed no dose-limiting toxicity and signs of biological and/or clinical activity in several patients (e.g., abstract). Burdek et al. conclude “Based on the favorable safety profiles of PRAME as a target antigen and MDG1011 in vitro and in vivo, this TCR-T therapy approach merits further investigation as a potential adoptive cell transfer to fill the unmet medical need for patients suffering from myeloid malignancies” (last sentence of reference). See entire reference.
The clinical study referenced by Burdek et al. (i.e., CD-TCR-001: ClinicalTrials.gov Identifier:NCT03503968) is poised to investigate AML, MDS, and MM patients with no results yet reported (see printout of ClinicalTrails.gov ID NCT35803968, 2023, 13 pages, https://clinicaltrials.gov/study/NCT03503968?tab=researcher.
However, evidentiary reference Thomas et al. (Cancers, 2025, Sep 11, 17(18):2968, doi: 10.3390/cancers17182968) teaches that clinical activity of different duration was reported for two patients administered MDG1011, one patient with relapsed AML and extramedullary disease was reported to have a complete response and the second patient with multilineage MDS and myelofibrosis completed the 12 month study period without progression to secondary AML. A third patient with MM was a temporary stable disease until progression on day 84 after infusion (see section 3.5). All other patients did not respond to MDG1011 treatment and showed early progressive disease. All nine patients who received MDG1011 were homozygous for HLA-A*02:01 (section 3.1). The authors conclude that long-term persistence of TCR-T cells in the absence of supplemental IL-2 was seen in the patient with multilineage MDS who did not progress to secondary AML in the 12 month study period, supporting the contention that greater clinical benefit may be achieved in patients with lower disease burdens (section 5). See entire reference.
Thus, Thomas et al. teach that after administration of T cells transduced with nucleic acid encoding the recited TCR to the nine patients, such administration did not result in a therapeutic effect in a majority of the patients.
As pertains to the issue of a diagnostic composition or diagnostic method, evidentiary reference Kaczorowski et al. (Am J Surg Pathol, 2022, 46(11): 1467-1476) teaches that although PRAME is expressed in a wide variety of epithelial and nonepithelial tumors and that PRAME detection may be useful in selected diagnostic contexts, its routine application is greatly limited by low specificity. Kaczorowski et al. teach that PRAME [expression] always needs to be interpreted with other immunohistochemical results and placed in the clinicopathological context. Kaczorowski et al. teach that PRAME is a relatively unspecific immunohistochemical marker, which limits its use in diagnostic pathology, and that PRAME was variably expressed to different percentages in tumors, with some being negative for PRAME expression (see entire reference, especially abstract and last paragraph of reference). In addition, the nucleic acid itself is not a detection agent in the context of identifying a PRAME positive tumor.
There is insufficient guidance in the specification as to how to use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
With regard to the product claims, Applicant may potentially obviate this portion of the instant rejection pertaining to intended use by deleting recitation of “pharmaceutical or diagnostic” in the claim preamble (similar to the language in the allowed parent application). With regard to the composition comprising the host cell displaying the TCR on its surface, Applicant might further consider amending the claim to recite that the host cell is a T cell or a modified effector host cell that is an NK cell or an NKT cell that further comprises co-transfected CD4 or CD8 and signal transducing CD3 gamma, delta, epsilon, and zeta (see the instant specification at [00130]).
With regard to the method claims, Applicant might consider amending the therapeutic method claim to recite ‘A therapeutic method for amelioration of a cancer expressing a complex of HLA-A*02:01 and the peptide VLDGLDVLL (SEQ ID NO: 32) on its surface, the method comprising administering the host cell of claim 3 to a subject in need thereof.’ As is stated in the instant rejection, the definition in the instant specification of “treating” includes ‘preventing’. The Examiner has presently entered into the record in the instant rejection, evidence showing clinical effect in treating such a cancer in some patients.
Also as is stated in the instant rejection with regard to administration of the nucleic acid operably linked to regulatory sequences configured for expression of the TCR, it is unpredictable that T cells (exclusively or at all) will be transduced in vivo and to acceptable levels of expression and in sufficient numbers and if so, to even bind to the relevant target and furthermore to effect a pharmaceutical or therapeutic effect; it is unpredictable that the nucleic acid can be a treatment modality (or even a detection agent).
With regard to the diagnostic method claim, Applicant might consider amending the claim to recite ‘A method of detecting a tumor that expresses a complex of HLA-A*02:01 and the peptide VLDGLDVLL (SEQ ID NO: 32) on its surface, the method comprising administering the host cell of claim 3 to a subject, wherein the host cell is modified to comprise a dye or a contrast agent that is released upon antigen recognition of the said complex, and detecting said recognition’ (see the specification at [00154]). Note that as indicated in the instant rejection, a nucleic acid itself is not a detection agent in the context of a PRAME positive tumor.
6. No claim is allowed.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641