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 .
Priority
Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e).
Status of the Claims
Claims 1-13 are pending.
Claims 1-13 are examined herein.
Claim Rejections - 35 USC § 112
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 1-13 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 Federal Circuit has clarified the written description requirement. The court stated that a written description of an invention "requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials". University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). The court also concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not description of that material". Id. Further, the court held that to adequately describe a claimed genus, Patent Owner must describe a representative number of the species of the claimed genus, and that one of skill in the art should be able to "visualize or recognize the identity of the members of the genus". Id.
Claims 1-13 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 claims 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 applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Applicant claims a method of increasing the cytolytic and/or anti-tumor function of CD8 iTregs, comprising: transducing the CD8 iTregs with a construct, wherein the construct expresses a ligand, thereby producing ligand-expressing CD8 iTregs, thereby increasing the cytolytic and/or anti-tumor function of the ligand-expressing CD8 iTregs compared to CD8 iTregs not containing or expressing the ligand. The scope of the recited ligands is reasonably interpreted to encompass any polypeptide ligand, both naturally occurring and synthetic. The only claim that places meaningful limitations on the structure of said ligands is Claim 4, which recites several ligands selected from CD19, CD33, CD123, CD45, CD83, and VISTA.
Applicant describes in the specification suppression, 48Hr killing assays, Xeno GVHD, GVT assays (Detailed description, example 1, p. 9) to characterize CD8 induced iTregs (induced or activated T regulatory cells cultures in presence of IL-2, TGF-b, or rapamycin) (Summary, p. 2) cell surface markers where they found CD103+ surface marker exhibiting CD8 iTregs to be most potent and cytolytic while shown to be preserving suppressive activity (Detailed description, Example 2, p. 11). The CAR construct transduced iTregs were also characterized using similar cytolytic assays where they found anti-tumor activity against Nalm-6 tumor cells (Figure 9).
The T cells used in these assays were induced CAR Treg cells where the CD8+ iTregs express aCD19scFv (Car19) (Detailed description, p. 8) and demonstrates that CAR19 T-cell therapy offers remission in several acute B-cell malignancies (Detailed description, p. 7).
Applicant does not describe success using any other ligands including the others listed in Claim 4 – CD33, CD123, CD45, CD83, VISTA with respect to any cytolytic or suppression assays in similar fashion as CD19. Applicant also does not describe transduction of these ligands with CAR construct with CD8+ iTregs or characterization of such fusion protein induced T cells. Applicant also does not describe the immunotherapy including these ligands will be utilized against which specific type of cancer. For example, the CAR19 T-cell therapy is used against treatment for acute lymphocytic leukemia while Ehninger (Ehninger, A., et al. "Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia." Blood cancer journal 4.6 (2014): e218-e218) teaches that CD33 and CD123 are studied for therapy against acute myeloid leukemias. Harfmann (Harfmann, et al. "CD45-directed CAR-T cells with CD45 knockout efficiently kill myeloid leukemia and lymphoma cells in vitro even after extended culture." Cancers 16.2 (2024): 334) teaches that CD-45 directed CAR T cell therapies especially with CD45ko/CD45 – CAR engineered immune cells against blood cancer as CD45 receptors are abundantly present on all blood cells including some immune effector cells. However, the targeting of myeloid-lineage associated antigens such as CD33 and CD123 is shown to be impeded by their expression in other tissues for example in liver and endothelial cells raising tumor toxicity (Harfmann). In view of these teachings it is not unreasonable to conclude that these ligands would not function as required by the claims when expressed in a CD8+ Treg.
The group of ligands claimed in the present invention are also structurally different from each other. For example, CD33, Cd83 are members of the immunoglobulin superfamily where CD33 is expressed on myeloid lineage whereas CD83 is expressed on dendritic cells, activated B-cells, T cells, monocytes, microglia, and neutrophils (Harfmann, Ehninger). CD123 is a interleukin 3 receptor consisting of heterodimeric protein with alpha and beta subunits found on pluripotent progenitor cells (Ehninger). Thus, many of these cell surface markers are structurally also different from each other. As such, Applicant has not provided a sufficient description of the structure-function relationship with regard to the genus of ligands expressed by CD8+ iTreg cells and the recited effects of increasing the cytolytic and/or anti-tumor function of the ligand-expressing CD8 iTregs compared to CD8 iTregs not containing or expressing the ligand. The only species of the claimed recited genus of ligands described by Applicant as having the required effect is CD19 and this single example is insufficient to describe the vast genus of ligands as encompassed by the claims.
Thus, in view of the vast number of structural variants encompassed by the claims and the lack of adequate description of the structure-function relationship of the claimed genus in view of the teachings of the prior art one of ordinary skill in the art would not have recognized applicant as being in possession of the claimed genus.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 of this title, 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 1-8, 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Imura, Yuki, et al. "CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD." JCI insight 5.14 (2020): e136185 in view of Mahic, Milada, et al. "Generation of highly suppressive adaptive CD8+ CD25+ FOXP3+ regulatory T cells by continuous antigen stimulation." European journal of immunology 38.3 (2008): 640-646.
Applicant claims, a method of increasing the cytolytic and/or anti-tumor function of CD8+ iTregs by transducing the CD8+ iTregs with a construct expressing a ligand which induces the anti tumor function of the iTregs (Claim1); the transduction does not abrogate suppressor function of the CD8+ iTregs (Claim 2); the construct expressing a ligand is a CAR construct (Claim 3); the construct expresses a ligand selected from CD19, CD33, CD123, CD45, CD83, Vista (Claim 4); the ligand expressed by the construct recognizes a pathogenic, tumor, foreign, or self-antigen (Claim 5); the ligand-expressing iTregs exhibit cytotoxicity and suppressor function (Claim 6); the ligand-expressing iTregs are cytotoxic to tumor cells (Claim 7);
Applicant further claims a method of delivering therapy to a patient providing ligand-expressing CD8 iTregs (Claim 8); the method does not suppress graft-vs-tumor (GVT) activity in the patient (Claim 10); the method augments graft-vs-tumor (GVT) activity in the patient (Claim 11); the method reduces or eliminates tumor cells in the patient (Claim 12).
Regarding Claim 1, Imura teaches the induction of CD19-targeted CAR Tregs from human peripheral blood T cells. (p. 2 ¶ 2).
Regarding Claim 2, Imura teaches that CD19-CAR Tregs suppressed proliferation of B cells more efficiently than empty vector–transduced Tregs and suggests that CD19-CAR Tregs retain the suppressive activity of empty vector–treated Tregs. (p. 4 ¶ 3).
Regarding Claims 3-5, Imura teaches that the cells were transduced with CAR constructs to express the CD19 ligand, which can function as both a foreign and self antigen depending on context. (p. 2 ¶ 2).
Regarding Claim 8, Imura teaches that CD19-targeted CAR Tregs from human peripheral blood T cells were delivered to mice along with PBMCs. Imura teaches that delivery of PBMCs alone resulted in severe GvHD, leading to weight loss and death. Imura teaches that the co-delivery of CD19-targeted CAR Tregs suppressed GvHD resulting from PBMCs. (p. 6 ¶ 1-3).
Imura otherwise teaches that CD19-targeted CAR (CD19-CAR) CD8+ T cells were conventional in the art. (p. 2 ¶ 2).
Imura does not teach that the Treg cells are CD8+ Treg cells, or that the cells produce effects such as anti-tumor functions or cytotoxicity.
Mahic teaches the generation (reasonably reading on induction) of highly suppressive CD8+ Treg cells by continuous antigen stimulation. (p. 642 left col. ¶ 1). Mahic teaches that CD8+ Treg cells may have some characteristics that are attributed to cytotoxic T cells, due to the cells’ production of cytotoxic factors granzyme A, granzyme B and perforin. (p. 664 left col. ¶ 1). Mahic teaches that the CD8+ Treg cells suppress T cell immune responses by a contact dependent mechanism. (p. 642 left col. ¶ 1, p. 664 left col. ¶ 2).
It would have been prima facie obvious at the time of filing to substitute the CD8+ Treg cells as taught by Mahic for the Tregs as taught by Imura. One having ordinary skill in the art would have been motivated to do so because Mahic teaches that the CD8+ Treg cells have the advantages of being highly suppressive and adaptive, exhibiting some cytotoxic (cytolytic) activity. Imura acknowledges that CD19-targeted CAR (CD19-CAR) CD8+ T cells were conventional in the art, and the conventional cells appear to share at least some properties with the CD8+ Treg as taught by Mahic. The Treg and CD8+ Treg cells of Imura and Mahic present obvious application in therapeutic methods for treating autoimmune diseases and as such would have been obvious substitutions for one another.
Applicant provides evidence in the specification that CD8+ Tregs expressing CD19 to be potent and cytolytic while shown to be preserving suppressive activity (Detailed description, Example 2, p. 11). Applicant provides evidence that the CAR construct transduced iTregs were found to exhibit anti-tumor activity against Nalm-6 tumor cells (Figure 9). Applicant provides evidence that the CAR construct transduced iTregs maintained and augment graft-vs-tumor (GVT) activity in a treated patient. (Example 2, Figure 4).
In view of the forgoing and without evidence to the contrary, it is reasonable to conclude that the induced CD19-expressing, CD8+ Tregs that are rendered obvious by the combined teachings of Imura and Mahic would inherently exhibit and maintain cytotoxicity and suppressor function, be cytotoxic to tumor cells, maintain and augment graft-vs-tumor (GVT) activity and reduce tumor cells.
Claims 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Imura, Yuki, et al. "CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD." JCI insight 5.14 (2020): e136185 in view of Mahic, Milada, et al. "Generation of highly suppressive adaptive CD8+ CD25+ FOXP3+ regulatory T cells by continuous antigen stimulation." European journal of immunology 38.3 (2008): 640-646 and further in view of Romano, Marco, et al. "Treg therapy in transplantation: a general overview." Transplant International 30.8 (2017): 745-753.
Applicant claims a method of delivering therapy to a patient providing ligand-expressing CD8 iTregs (Claim 8); wherein the CD8+ iTregs used to produce the ligand- expressing CD8 iTregs are obtained from the patient (Claim 9) and wherein the patient has undergone a hematopoietic stem cell transplantation (HSCT) (Claim 13).
The teachings of Imura and Mahic as they are applied to claims 1-8, 10-12 are set forth previously herein and are incorporated by reference. The combined teachings of Imura and Mahic do not render obvious an autologous source of the CD8+ iTregs nor and wherein the patient has undergone a hematopoietic stem cell transplantation.
Romano teaches that hematopoietic stem cell transplantation (HSCT) is an established procedure concerning the infusion of autologous, syngeneic or allogeneic stem cells for several high-risk hematologic malignancies. Romano teaches that the main side effect of HSCT is graft-versus-host disease (GvHD) (p. 746 left col. ¶ 1). Romano teaches that one identified approach involves the use of regulatory T cells (Tregs) as a cellular therapy for the treatment of GvHD (p. 746 left col. ¶ 2). Romano teaches that in some studies in humans, the Tregs were obtained from the patients and then expanded before treatment. (p. 750 left col. ¶ 3).
It would have been prima facie obvious at the time of filing to modify the invention rendered obvious by the combines teachings of Imura and Mahic to obtain the Tregs from the patient as taught by Romano. One having ordinary skill in the art would have been motivated to do so because Romano teaches that the studies treating GvHD can use Tregs obtained from the patient, and as such provide a reasonable expectation of success.
It would have been prima facie obvious at the time of filing to modify the invention rendered obvious by the combines teachings of Imura and Mahic to use the treatment on patients that have undergone hematopoietic stem cell transplantation (HSCT). One having ordinary skill in the art would have been motivated to do so because Romano teaches that patients that have undergone hematopoietic stem cell transplantation (HSCT) can exhibit GvHD that in turn can be treated effectively with Tregs, and as such provides a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHARLES A LOGSDON whose telephone number is (571)270-0282. The examiner can normally be reached M-F 8:30 - 5:00 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, Bratislav Stankovic can be reached at (571) 270-0305. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHARLES LOGSDON/Primary Examiner, Art Unit 1662
Prosecution Insights