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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 04/10/2026 is acknowledged. Applicant has further elected a species of proliferative disease of breast cancer. However, in view of the prior art, the species of breast and lymphoma cancer have been rejoined.
Claims 1-19 are pending.
Claims 10-13, 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/10/2026.
Claims 1-9, and 14-16 are pending and are currently under consideration.
Claim Objections
Claim 14 is objected to for reciting “wherein the binding molecule comprises is at least” for unclear grammatical syntax. Appropriate correction is requested.
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 2-4, 6, 8-9, and 15-16 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.
Regarding claims 2, 4, and 9 the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 3-4, 6, 8-9, and 15, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 4, 6, 9, and 15-16, the term "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 16 is further vague and indefinite for reciting “increased expression of NKG2D”. Claim 16 refers back to Claim 14 where there is already expression of NKG2D. So, it’s unclear what contributes to the increased expression in Claim 16. For example, what genetic engineering components enable the increased expression?
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 6, 8, 14-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (US20190300594, published 10-3-2019).
As to claims 1-2, and 14, Kim et al. teach [0034, 0064] a method of treating a disease in a subject (e.g, cancer and viral infections) comprising administering a bispecific molecule where the first binding domain is capable of binding to NKG2-D type II integral membrane protein [0028] and the second binding domain is capable of binding to an antigenic target protein expressed on or in a cell associated with the disease in the subject. Kim et al. further teach administering [0028] an immune cell comprising a chimeric antigen receptor (CAR) comprising an extracellular NKG2D sequence (or NKAR). Specifically, Kim et al. teach “The bispecific molecules can bind Chimeric Antigen Receptors (CARs) wherein the receptor of the CAR is comprised of the non-natural NKG2D receptor ectodomain that binds its cognate modified α1-α2 domains with greater affinity (encompasses competitively binds compared to a NKG2D-ligand) than it does natural α1-α2 domains.”. Further, Kim et al. teach [0030-0031] that the NKG2D-ligand can be an MHC class I polypeptide-related sequence A (MICA) or soluble MICA (sMICA). It is assumed for examination purposes that SEQ ID NO:1 which is NKG2D as claimed is equivalent to NKG2D in the prior art.
As to claims 3-4, Kim et al. teach [0050] the generation of non-natural MicA variants fused to human IgG1, the DNA polynucleotides encoding the α1-α2 domains of, for example, MICwed (SEQ ID NO: 79) and MIC25 (SEQ ID NO: 81), were PCR amplified using primers that also introduced the polynucleotide encoding either an APTSSSGGGGS linker for fusion to C-terminal kappa light chain (SEQ ID NO: 84) or for a GGGS linker for fusion to C-terminal heavy chain of human IgG1 (SEQ ID NO: 82). Kim et al. further [0043] teach that the antibody constructs can include single-chain antibody molecules.
As to claims 6 and 15, Kim et al. teach [0029, 0042] that the immune cell is a T-cell or natural kill (NK) cell.
As to claim 8, Kim et al. teach [0021] CAR constructs comprising the CD8a hinge/transmembrane domain and intracellular 4-1BB and CD3zeta signaling domains. Kim et al. also taught [0037] a CAR construct with only the ectodomain of NKG2D fused to a second-generation CAR scaffold composed of transmembrane and intracellular domains from CD28 and the signaling domain of CD3ζ.
Claim(s) 1-4, 6, 8-9, 14-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Landgraf et al. (Communications Biology, 3: 296, published June 9, 2020).
Similar to the above inventorship in Kim et al, Landgraf et al. teach (Figure 5) a method of treating a subject with lymphoma (Raji tumors) comprising administering convertible CAR-Ts and Ritux-S3. The Ritux-S3 is the bispecific molecule which is rituximab conjugated to the MicAbody. Under the Methods section (1st column, page 10) MIC ligands and orthogonal variants were cloned by ligation-independent assembly as fusions to the C-terminus of either the kappa light-chain or the heavy-chain of human IgG1 antibodies via either an APTSSSGGGGS or GGGS linker. For any monoclonal antibody fusion generated, the appropriate VL or VH domains were swapped into either the kappa light-chain or ADCC-deficient IgG1 heavy chain. The CAR-T cells (page 10, 2nd column) comprised the CD8α-chain signal sequence, NKG2D variant, CD8α hinge, and transmembrane domains, 4-1BB, CD3ζ. It is assumed for examination purposes that SEQ ID NO:1 which is NKG2D as claimed is equivalent to NKG2D in the prior art.
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.
Claim(s) 9 is further rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US20190300594, published 10-3-2019) and/or Landgraf et al. (Communications Biology, 3: 296, published June 9, 2020).
Kim et al. and Landgraf et al. teach as set forth above. In particular, note that Landgraf taught treating a subject with a lymphoma.
Regarding Claim 9, the species of breast cancer was elected. Neither Kim et al. or Landgraf et al. specifically teach treating a subject with breast cancer.
However, both Kim et al. and Landgraf et al. provide the bispecific molecule for which to treat breast cancer. Both references teach convertible-Car-T cells expressing NKG2D and a bispecific antibody where one binding domain is capable of binding to NKG2D and the second binding domain is capable of binding to antigenic target protein expressed on or in a cell associated with the disease. In this case, the binding to the disease-associated target is facilitated by trastuzumab-MicAbody (targets Her2) or rituximab-based MicAbodies. (see para 0066 in Kim et al.).
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have further used the methods of either Kim et al. or Landgraf et al. to include treating breast cancer. One would have been motivated to do so because Landgraf et al. taught (page 6, 2nd column) that administration of 7M convertible CAR-T cells along with Rit(Ritixumab)-S3 (7M+Rit-S3) resulted in reduced tumor size relative to convertibleCAR-T cells alone (Fig. 5b, c). Furthermore, in the 35M+Rit-S3 cohort, tumor growth was completely suppressed. Thus, given the success of targeting and treating a lymphoma cancer, it would have been prima facie obvious to conduct similar in vivo studies using the trastuzumab-MicAbody because trastuzumab targets the Her2 receptor which is a well-known therapeutic target to treat Her2 positive breast cancer.
Claim(s) 16 is further rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US20190300594, published 10-3-2019) and/or Landgraf et al. (Communications Biology, 3: 296, published June 9, 2020) in further view of Lamprecht et al. (“CAR T-Cell Therapy: Update on the State of the Science”, April 2019, CAR T-Cell, Vol. 23, No. 2) and/or Depil et al. “ ‘Off-the-shelf’ allogenic CAR T cells: development and challenges; Nature Reviews Drug Discovery, Vol. 19, March 2020).
Regarding Claim 16, wherein the immune cell is an autologous or allogenic immune cell, Kim et al. refer [0035] to the common usage of autologous T-cells in CAR-T therapy and Landgraf (page 10, 1st column) speaks to the aggressive pursuit of developing allogenic cells to bring down the time, complexity, and cost of manufacturing to provide a more consistent, readily accessible product. However, neither reference specifically includes or directs the use of autologous or allogenic cells in their methodologies.
However, it is well known in the art that autologous cells are the foundation of CAR-T therapies. For example, Lamprecht et al. (“CAR T-Cell Therapy: Update on the State of the Science”, April 2019, CAR T-Cell, Vol. 23, No. 2) review the state of the art of CAR-T therapy teaching (page 7, under manufacturing process, and Figure 1) that the manufacturing of autologous CAR T cells is a carefully defined and regulated process and that “the first step in the process is collecting T cells from the patient” to be treated via apheresis. “This process, from collection of the autologous product to return of the CAR T-cell product, takes at least two weeks and is dependent on the rate of cellular reproduction to produce the replication-defective viral vector.” Hence, the harvesting of autologous immune cells is a critical first step.
Further, Depil et al. recognize (introduction, page 186) the success of using patient derived (autologous) cells in CAR-T therapy but also teach some of the disadvantages, such as cost of the process, manufacturing failure in some patients and current manufacturing processes of approximately 3 weeks, which translate into a delay in the availability of the treatment. Hence, Depil et al. highlight (page 186) the advantages of using allogenic cells in CAR-T therapy. “The manufacture of allogeneic CAR T cells from PBMCs collected from healthy donors is associated with the ability to make multiple vials from a single apheresis product, and therefore with rapid access to previously manufactured products. In addition, there is the opportunity to generate a bank of cells that express the different subtypes of human leukocyte antigen (HLA) complex to potentially select batches that match the HLA type of the patient. Furthermore, because allogeneic CAR T cells are created from healthy donors, they are generated from immune cells that have not been impacted by the immune effects of cancer or by exposure to chemotherapeutic agents, in contrast to autologous T cells from patients.” Allogeneic CAR T cells offer the possibility of treating relapsed or refractory malignancies with a readily available product. This may be a major advantage in diseases that progress rapidly, such as AML and ALL. Trials have already begun in ALL and AML, and are planned in lymphomas and multiple myeloma (page 194, and Table 2). Additionally, Depil et al. teach (page 187) that several strategies can be employed to reduce the risk of graft v. host disease (GVHD). “Several approaches have been developed for administering allogeneic CAR T cells with reduced risk of GVHD: use of donor-derived allogeneic T cells in stem cell transplant recipients, use of virus-specific memory T cells, use of non-αβ T cells and gene editing with TCR deletion in αβ T cells.”
Thus, one of ordinary skill in the art at the time of filing would consider it prima facie obvious to have used autologous immune cells in the methods of either Kim et al. or Landgraf et al. in treating a human patient because it was already well established in the field of CAR-T therapy that the first clinical step is to collect and harvest a patient’s own T-cells. Further, Depil et al. recognized the clinical success of using patient derived (autologous) cells in CAR-T therapy which has resulted in the approval of Kymriah and Yescarta.
It would have also been obvious to a person of ordinary skill in the art to have used allogenic cells in the methods of either Kim et al. or Landgraf et al because it was known prior to the time of the filing date of the instant invention that allogenic cells could be used successfully in CAR-T therapy and have several advantages versus the use of autologous immune cells. One would have been motivated to do so because Depil et al. taught that allogeneic CAR T cells are created from healthy donors, that have not been impacted by the immune effects of cancer or by exposure to chemotherapeutic agents. Moreover, in contrast to autologous T cells from patients, one can make multiple vials of allogenic cells from a single apheresis product which would provide rapid access to previously manufactured products. Further, given that trials have already begun in ALL and AML, and are planned in lymphomas and multiple myeloma (Table 2), there would be a likelihood of success in using allogenic cells.
Claim(s) 5, 7, and 14 is/are further rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US20190300594, published 10-3-2019) and/or Landgraf et al. (Communications Biology, 3: 296, published June 9, 2020 in view of Schmohl et al, (“Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modifed IL-15 Cross-linker”, Molec.Therap., Vol. 24, No.7, July 2016, IDS) and Hoyos et al. (“Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety”; Leukemia, Vol. 24, 2010).
Claim 5 is directed to fusing an interleukin-15 domain (or optionally an interleukin agonist) to either the first or second binding domain of the bispecific molecule. Alternatively, Claim 7 is directed to further engineering the immune cell to include interlukin-15 or an interlukin-15 agonist.
Schmohl et al. engineered a fully humanized tri-specific NK-cell engager (TriKE) utilizing human IL-15 as a modified crosslinker between anti-CD16 scFv and the anti-EpCAM scFV. Schmohl et al. teaches (page 1318, 1st column) that the molecular addition of IL-15 mediated natural killer cell proliferation, sustained ADCC activity, and improved lytic degranulation and cytokine secretion compared to BiKe treatment alone.
Hoyos et al. teach (page 1160, 2nd column) that as of 2010, it was evident from both clinical trials and preclinical models that the expansion and persistence of CAR-modified T cells in vivo were hampered by the lack of costimulatory signals after engagement with target antigens, as many tumor cells downregulate their expression of the costimulatory molecules required for optimal and sustained T-cell function, proliferation and persistence. While 2nd and 3rd generation CARs have partially resolved these issues, Hoyos et al. describe an alternative strategy that engineered CAR-modified T cells to receive not only costimulation through the CD28 pathway but also to ectopically produce IL-15, a cytokine crucial for T-cell homeostasis and survival. Their data show that transgenic expression of IL-15 improves survival, expansion and antitumor effects of CD19-specific redirected T cells. See also Figure 5, enhanced control of tumor growth was observed in mice receiving iC9/CAR.19/IL-15+ T cells.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have modified the bispecific molecule or the engineered immune cells of Kim et al. and Landgraf et al. so as to include an interleukin-15 domain because it was well known prior to the time of filing that the addition of IL-15 can improve the efficacy of both bispecific cancer therapy and/or CAR-T therapy. One would have been motivated to do so because compared to BiKe treatment alone, the molecular addition of IL-15 (making a TriKE) promoted natural killer cell proliferation, sustained ADCC activity, and improved lytic degranulation and cytokine secretion. Similarly, the addition of IL-15 in CAR-T therapy improved survival, expansion and antitumor effects of CD19-specific redirected T cells. Thus, the addition of IL-15 was known to improve bispecific therapy and CAR-T therapy and the likelihood of success is reasonable. Further the addition of IL-15 to known anti-cancer therapies is similar to the rationale in In re Kerkhoven wherein it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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, Julie Wu can be reached at 571-272-5205. 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.
/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights