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 .
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.
Priority
The instant application, filed 03/09/2023, claims domestic benefit to US provisional application 63/318,484, filed 03/10/2022.
Status of Claims/Application
Applicant’s preliminary amendment of 06/26/2023 is acknowledged. Claims 3-5, 8, 11-12, 18, 27, 29, 37-38, 42-44, and 46 are amended and claims 9-10, 13-16, 19-26, 28, 30-36, 39-41, 45, and 47-54 are cancelled.
Claims 1-8, 11-12, 17-18, 27, 29, 37-38, 42-44, and 46 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/19/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings filed 03/09/2023 are objected to for containing colored drawings without an appropriate petition under 37 CFR 1.84(a)(2). Figures 3-4 comprise colored figures. Submission of black and white/greyscale drawings or an appropriate petition under 37 CFR 1.84(a)(2) is required.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 27 is objected to for the following informality: line 6 of the claim comprises a capital “A”. The claim is a single sentence and; therefore, the “A” should be lowercase.
Claim 42 is objected to for the following informality: part 2 of the claim comprises a capital “A”. The claim is a single sentence and; therefore, the “A” should be lowercase.
Claim Rejections - 35 USC § 112(b)
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 6, 11, 17, 27, 29, 37-38, 42, and 46 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 6 recites the limitation “wherein a plurality of allogeneic NK cells” is derived from the PBMCs, NK cell lines, cord blood stem cells and pluripotent stem cells and the combination thereof. The claim depends on claim 5 which recites that the composition of claim 1 further comprises a plurality of PBMCs, NK cell lines, cord blood stem cells, or pluripotent stem cells or a combination thereof. It is unclear if the intention of claim 6 is to further limit the composition to further comprising a plurality of allogenic NK cells or if the intention of claim 6 is to say that the cells of claim 5 must express allogeneic NK cells which would mean that they also must be allogeneic. As such, the metes and bounds of claim 6 are indefinite.
Claim 11 recites the limitation “wherein the anti-PD-L1 antibody is selected from the group consisting of an IgG Fc domain with high affinity to FcgRs, that is optionally avelumab or PDL-GEX”. The limitation recited is indefinite for the following reasons:
An IgG Fc domain with high affinity to FcgRs is not a type of anti-PD-L1 antibody. While an anti-PD-L1 antibody can comprise an IgG Fc domain with high affinity to FcgRs, the claim recites that the anti-PD-L1 antibody is selected from an IgG Fc, which, on its own, would not act as an anti-PD-L1 antibody.
Additionally, the recitation of “optionally avelumab or PDL-GEX” also renders the claim indefinite as the antibodies recited following the word “optionally” are narrower embodiments of the preceding limitations and it is unclear if they are a limiting feature of the claimed invention or exemplary embodiments. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation anti-PD-L1 antibody, and the claim also recites avelumab or PDL-GEX, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 17 line 1 recites “and and/or” rendering the scope of the claim indefinite as it is unclear if the conjugation is supposed to be “and” or “and/or”. Appropriate correction is required.
Claim 27 recites the limitation “optionally wherein the anti-PD-L1 antibody is a bispecific or multimeric antibody”. In this instance, the use of “optionally” renders the claim indefinite as it is unclear if the limitations which follow are limiting features of the claimed invention or if they are exemplary embodiments. Additionally, broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 27 recites the broad recitation anti-PD-L1 antibody, and the claim also recites bispecific or multispecific antibody, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 29, 37, and 38 are rejected by virtue of their dependency on claim 27.
Claims 29, 37, and 38 recite “the method of claim 27”. Claim 27 recites two methods, one starting on page 4, line 1 and the other starting on page 5, line 3. As such, it is unclear which of the two methods is being referenced by claims 29, 37, and 38, rendering the metes and bounds of the claims indefinite. MPEP 2173.05 (e) states “if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended. “
Claim 29 recites “and/or” twice in the list recited, once on line 10 and again on line 11 rendering the claim indefinite as it is unclear which groups are claimed.
Claim 37 recites “the natural killer cells after being administered to the subject”. There is insufficient antecedent basis for this limitation in the claim. Claim 37 depends on claim 27 and neither of the claims refer to natural killer cells or natural killer cells that are administered.
Claim 38 recites the limitation “optionally wherein the cancer is a semi-solid tumor, a solid tumor, acute myeloid leukemia (AML), or lymphoma”. In the instant claim, the use of optionally renders the claim indefinite as it is unclear if the limitations which follow are a limiting feature of the claimed method of exemplary embodiments. Additionally, broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 37 recites the broad recitation cancer, and the claim also recites semi-solid tumor, a solid tumor, acute myeloid leukemia (AML), or lymphoma, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 42 recites the limitation “optionally wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody. In this instance, the use of “optionally” renders the claim indefinite as it is unclear if the limitations which follow are limiting features of the claimed invention or if they are exemplary embodiments. Additionally, broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 27 recites the broad recitation anti-PD-L1 antibody, and the claim also recites bispecific or multispecific antibody, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 46 is rejected by virtue of its dependency on claim 42 as it does not resolve the ambiguity discussed above.
Claim 46 recites “the composition of claim 42”. It is unclear if the recitation is referencing the composition that is in the method of making a composition in claim 42 part 1) or the composition recited in claim 42 part 2), rendering the metes and bounds of the limitation indefinite. See MPEP 2173.05(e)
The claim further recites “the population of immune cells” on page 7, line 8. There is insufficient antecedent basis for this limitation in the claim. The claim depends on claim 42 which does not recite a population of immune cells.
The claim further recites “in natural killer cells after the co-culturing step” in the last two lines. There is insufficient antecedent basis in the claim for natural killer cells and the co-culturing step. The claim depends on claim 42 which does not recite natural killer cells or a culturing step.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 42 is rejected under 35 U.S.C. 101 because the claim recites both a method of making a composition and a composition, which are two separate statutory categories of invention (specifically a method and a product). The claim, as a whole, does not fall within one of the four statutory categories, and; therefore, does not pass step 1 of the subject matter eligibility test of 35 USC 101. See MPEP 2106.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7-8, 11-12, 27, 29, 37-38, 42, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0000945 A1 (Wetering, S.V. and A. Kruisbeek) 3 JAN 2019 in view of Versteven, M., et al (2018) Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer Frontiers in Immunology 9(394); 1-13 and WO 2021/108025 A1 (Irvine, D., et al) 03 June 2021.
US’945 teaches mature dendritic cells obtained from DCOne cells, which is a cell line derived from the peripheral blood of a patient with acute myeloid leukemia (AML) (page 2, [0023]; page 3, [0035]). Mature DCOne cells are characterized by the appearance of expression of CD83+, while the other cell surface receptors such as CD34 and CD1a remain present as well. The expression of other relevant markers are also shown in Figure 1, which shows that the cells have low to no expression of CD14 and, in the mature state, express CD34, CD1a, DC-SIGN, langerin, CD80, CD86, CD40, and CD83 (page 3, [0034]). US’945 further teaches that the mature DCOne cells endogenously express at least one tumor antigen, selected from the group consisting of WT-1, RHAMM and PRAME, p53, and Survivin (page 4, [0044]). US’945 further teaches that the cells express high levels of MHC Class I and MHC Class II (page 3, [0031]).
US’945 teaches that the mature DCs may be loaded with at least one antigen. Such loading may be accomplished using methods known in the art, for example, by loading with tumor antigens. The mature DCs will process the antigens and present them to corresponding immune cells of the immune system via particular molecules, e.g. via MHCI or MHCII molecules, thereby correspondingly activating the humoral and/or cellular immune response which combats the disease or builds up an immunological memory preventing diseases in a prophylactic fashion (pages 4-5, [0050]).
US’945 teaches that the cells are particularly suitable for use in a vaccine, such as a therapeutic cancer vaccine (page 3, [0031]). Therapeutic vaccines are medicines that belong to a class of substances known as biological response modifiers which work by stimulating or restoring the immune system’s ability to fight infections and disease. Therapeutic vaccines are intended to treat an existing cancer by strengthening the body’s natural defenses against the cancer (page 3, [0032]). US’945 teaches that the cells are particularly suited for use as a medicament, particularly for the treatment of cancers, more in particular AML (page 4, [0043]). US’945 also teaches that the mDCOne cells are particularly suited for the treatment of cancers including lung cancer, breast cancer, head and neck cancer, chronic myeloid leukemia, ovarian cancer, colon cancer, multiple myeloma, prostate cancer, skin cancer, myelodysplastic syndrome, brain cancer, and bladder cancer (page 4, [0044]).
US’945 teaches an immunogenic composition comprising the mDCOne cells in combination with a pharmaceutically acceptable carrier (page 9, claim 17) as well as a method for treating cancer comprising administering to a subject suffering from cancer the mature dendritic cells (page 8, claim 6).
US’945 differs from the instantly claimed invention in that US’945 does not teach that the DC vaccine composition comprises an anti-PD-L1 antibody. US’945 also does not disclose that, in the method of treating cancer, the composition is administered intratumorally as recited in instant claim 27.
Versteven teaches that dendritic cells (DCs) are key antigen-presenting cells capable of presenting tumor antigens to T lymphocytes and promoting innate immunity via, for example, natural killer cells and γδ T cells. To obtain and engineer DCs for therapeutic approaches, they can be generated ex vivo from multiple sources such as monocytes and CD34+ hematopoietic progenitor cells, or they can be enriched from peripheral and cord blood (page 1, paragraph 1).
Versteven teaches that two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient’s antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the PD-1 pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunotherapy tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. Versteven provides a review on the role of PD-1 signaling in DC-mediated antitumor immunotherapy (abstract).
Versteven teaches that it is generally agreed that the therapeutic potential of DC-based immunotherapy could be improved by tackling the immunosuppressive tumor microenvironment that contributes to ineffective or suboptimal responses. Employing intrinsic and adaptive immune resistance mechanisms, PD-1 is a top-ranked checkpoint contributor to blunting immune responses. Based on the expression pattern of PD-1 and PD-L1 on immune cells and cellular contacts between DC and a myriad of immune effector and regulatory cells, blocking PD-1 and PD-L interactions will likely impede tumor cell-mediated immune suppression, enhance T cell and NK cell activation and effector functions and inhibit conversion or activation of Treg cells (page 3, right column, paragraph 4).
In combination with DC vaccination, systemic blockade with anti-PD-1 mABs, or anti-PD-L mABs, resulted in increased activation of cytotoxic CD8+ T cells and decreased Treg cell numbers and showed better therapeutic efficacy compared with either monotherapy by preventing tumor growth and prolonging survival in tumor-bearing mice in cancers including glioblastoma, breast cancer, and melanoma (page 4, right column, paragraph 2).
Versteven further teaches that, over the past 8 years, a select number of phase I/II clinical trials combining DC vaccination with anti-PD-1 or anti-PD-L1 antibodies in a range of malignancies have been initiated and were ongoing. The trials are presented in Versteven, table 1 (page 5, left column, paragraph 2; page 6, Table 1). Versteven discloses two clinical trials in which anti-PD-L1 antibodies were being combined with DC vaccines for the treatment of cancer. These trials include a combination of avelumab with an autologous DC vaccine for the treatment of metastatic colorectal cancer and the combination of durvalumab with a DC/AML fusion vaccine for the treatment of AML (rows 11-12). The trials also include a study in which autologous DCs loaded with autologous tumor antigens is administered intratumorally (Table 1, row 4).
Versteven teaches that the majority of mABs bear a mutation in their Fc-portion making target cells insensitive to ADCC mediated through FcγRIIIa. By keeping the Fc part not mutated, avelumab results in ADCC-mediated clearance of PD-L1+ tumor cells (paragraph bridging columns, page 4).
WO’025 teaches cell-based vaccines combined with anti-cancer immunotherapies and teaches that the vaccines are typically administered into the patient’s tumor to provide an intratumoral immune activation. Immune checkpoint inhibitors (ICI) may be administered before, during, or after vaccine administration. ICI may also be a component of the vaccine (abstract). WO’025 further teaches that the ICI includes small molecules, antibodies, or antibody fragments against PD-1, PD-L1 or CTLA-4 (page 32, lines 1-6). Activation of T cells normally depends on an antigen-specific signal following contact of the T cell receptor (TCR) with an antigenic peptide presented via the MHC while the extent of this reaction is controlled by positive and negative antigen-independent signals emanating from a variety of co-stimulatory molecules. PD-1 delivers a negative immune response when induced on T cells. Contact between PD-1 and one of its ligands induces an inhibitory response that decreases T cell multiplication and/or the strength and/or the duration of a T cell response. Suitable PD-1 antagonists include compounds that either block a ligand of PD-1 to interfere with or inhibit the binding of the ligand to the PD-1 receptor, or bind directly to and block the PD-1 receptor (page 32, line 25 – page 33, line 7). WO’025 further teaches that the antibody can be avelumab (page 91, claim 22).
WO’025 teaches that the composition comprises a vaccine and the ICI and is formulated in a dosage suitable for intratumoral injection (page 91, claims 20-24).
WO’025 teaches that the vaccines may include additional cancer antigens not derived from the isolated activated cells including p53, MUC family, and PRAME (page 36, line 13-page 37, line 8).
WO’025 further teaches that the vaccine composition may further include dendritic cells and/or cytotoxic T cells that are autologous or allogeneic (page 30, lines 24-25; page 29, line 32-page 30, line 14; page 91, lines 17-18).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the composition of US’945 to further include an anti-PD-L1 antibody, such as avelumab, based on the teachings of Versteven, and to include the anti-PD-L1 antibody in the same composition as the vaccine as taught by WO’025. It would have further been obvious to administer the combination intratumorally based on the teachings of WO’025. An ordinarily skilled artisan would have been motivated to further include an anti-PD-L1 antibody in order to impede tumor cell-mediated immune suppression and enhance T cell and NK cell activation and effector functions and inhibit conversion or activation of Treg cells. An ordinarily skilled artisan would have had a reasonable expectation of success because US’945 teaches antigen presenting mature dendritic cells for use as a vaccine in the treatment of cancer and Versteven teaches methods of enhancing the function of dendritic cell-based vaccination in cancer therapy comprising the use of PD-L1 antibodies. Furthermore, Versteven teaches that combination of DC vaccination with anti-PD-1 mAbs or anti-PD-L1 mAbs resulted in increased activation of cytotoxic CD8+ T cells and decreased Treg numbers with better therapeutic efficacy compared with either monotherapy thereby preventing tumor growth and prolonging survival in cancers in including glioblastoma, breast cancer, and melanoma; which overlap with the cancers disclosed by US’945 for treatment with the mature DCOne vaccine, which include brain cancer, breast cancer, and skin cancer.
It would have been obvious to include the PD-L1 antibody in the same composition as the mature DCOne vaccine as WO’025 teaches that, in combinations of vaccines and ICI for the treatment of cancer, the ICI may be a component of the vaccine. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’095, WO’025 teaches cell-based vaccines for the treatment of cancer and also teaches overlapping tumor antigens for expression with the vaccine including p53, PRAME, and the MUC family. WO’025 also teaches that the ICI is a PD-L1 antibody, including avelumab, which overlaps with the teachings of Versteven.
Regarding claims 5 and 7, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to further include autologous or allogenic dendritic cells and/or T cells, which are both types of peripheral blood mononuclear cells, in the composition taught by the combination of US’095, Versteven, and WO’025 based on the teachings of WO’025. It would have been obvious to include these cells as WO’025 teaches their further inclusion in vaccine compositions that also comprise immune checkpoint inhibitors. An ordinarily skilled artisan would have had a reasonable expectation of success as like US’095, WO’025 teaches cell-based vaccines for the treatment of cancer.
Regarding claim 8, an ordinarily skilled artisan would have reasonably expected that the mature DCOne vaccine in combination with the anti-PD-L1 antibody would result in synergistic activation of FCgR expressing NK cells and that the activation of NK cells would result in increased NK-mediated lysis of tumor cells based on the teachings of Versteven. Specifically, Versteven teaches that based on the expression pattern of PD-1 and PD-L on immune cells and cellular contacts between DC and a myriad of immune effector and regulatory cells, blocking PD-1/PD-L interactions will likely impede tumor cell-mediated immune suppression enhancing T cell and NK cell activation and effector functions (page 3, right column, paragraph 3). Versteven also teaches that combinations of DC vaccination and systemic blockade with anti-PD-1/PD-L1 antibodies resulted in better therapeutic efficacy compared with either monotherapy by preventing tumor growth and prolonging survival in tumor-bearing mice compared with either monotherapy (page 4, right column, paragraph 2), results which suggest synergistic tumor treatment with the combination.
Furthermore, the activation of NK cells and myeloid mononuclear cells and the increased secretion of chemokines and proinflammatory cytokines would flow naturally from the administration of the combination therapy to a patient with cancer. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Regarding claim 37, while the combination of US’945, Versteven, and WO’025 do not explicitly disclose that the surface expression of both CD25 and CD137 increases on NK cells after administration to the subject, the claimed increased surface expression is a mechanistic outcome that would flow naturally from administration of the mature DCOne vaccine in combination with an anti-PD-L1 antibody as suggested by the combination of applied references. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Furthermore, one of ordinary skill in the art would expect these markers to increase as they are known activation markers of NK cells and Versteven teaches that the combination of DC and PD-1/PD-L blockade will enhance T cell and NK cell activation and effector functions.
Claims 5-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0000945 A1 (Wetering, S.V. and A. Kruisbeek) 3 JAN 2019 in view of Versteven, M., et al (2018) Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer Frontiers in Immunology 9(394); 1-13 and WO 2021/108025 A1 (Irvine, D., et al) 03 June 2021 as applied to claim 1 above, and in further view of Van Elssen, C.H.M.J., et al (2014) Natural Killer Cells: The secret weapon in dendritic cell vaccination strategies Clin. Cancer Res. 20(5); 1095-1103.
The combination of US’945, Versteven, and WO’025 teach the composition of claim 1 as discussed above.
The combination of applied references, however, does not disclose that the composition further comprises allogeneic NK cells.
Van Elssen teaches that dendritic cells, the most efficient antigen presenting cells of the immune system, have been used in clinical vaccination strategies for cancer (page 1095, left column, paragraph 1). In mice, DC-induced natural killer cell activation was proven to be an absolute prerequisite for induction of Th1 polarization. Human in vitro data demonstrate that NK cells and DCs cooperate in pathologic conditions. This triggered the evaluation of NK cell responses in clinical DC vaccination studies (Table 1). The immunostimulatory effect of NK-DC interaction is based on bidirectional cross-talk by which both cell types become activated (page 1097, right column, paragraph 1). NK cells hold the capacity to control and enhance DC mediated antitumor immune responses by inducing maturation of Th1 polarizing DCs, providing DCs with antigenic material for presentation and killing of inappropriately matured DCs (page 1097, right column, paragraph 2).
Not only are NK cells capable of DC activation, but also, reciprocally, DCs stimulate NK cells by soluble, as well as contact-dependent, activators, thereby enhancing their cytokine production, proliferation, survival, and cytotoxicity (page 1098, right column, paragraph 1).
The reciprocal effects of NK-DC interaction provide a strong rationale for the combined use of NK cells and DCs in immunotherapy and the use of allogeneic NK cells has shown promising results in cancer immunotherapy (page 1099, right column, paragraph 2).
Van Elssen further teaches simultaneous injection of NK and DCs via intratumoral injection. NK cells lyse tumor cells tumor cells, thereby making antigenic material available for DCs to take up and present. In addition, NK cells induce maturation of bystander DCs and lyse inappropriately mature iDCs. Reciprocally, mature DCs can activate NK cells to proliferate, secrete cytokines, and augment NK cell cytotoxicity (page 1100, left column, paragraph 2). Van Elssen further teaches blood-derived NK cells (page 1100, Fig. 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the composition taught by the combination of US’945, Versteven, and WO’025 to further comprise allogeneic natural killer cells derived from PMBC based on the teachings of Van Elssen. An ordinarily skilled artisan would have been motivated to further include allogeneic NK cells as Van Elssen teaches that the reciprocal effects of NK-DC interaction provide a strong rational for combining the use of NK cells and DCs in immunotherapy. Specifically, NK cells induce maturation of bystander DCs and lyse inappropriately matured iDCs while mature DCs can activate NK cells to proliferate, secrete cytokines, and augment NK cell cytotoxicity. Van Elssen also teaches that the use of allogeneic NK cells has shown promising results in cancer immunotherapy. An ordinarily skilled artisan would have had a reasonable expectation of success as Van Elssen teaches that NK cells are the secret weapons in DC vaccination and the combination of US’945, Versteven, and WO’025 teach vaccination with mature DCOne vaccines which have a mature DC phenotype.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0000945 A1 (Wetering, S.V. and A. Kruisbeek) 3 JAN 2019 in view of Versteven, M., et al (2018) Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer Frontiers in Immunology 9(394); 1-13 and WO 2021/108025 A1 (Irvine, D., et al) 03 June 2021 as applied to claim 1 above, and in further view of US 2019/0256602 A1 (Campbell, J., et al) 22 Aug 2019.
The combination of US’945, Versteven, and WO’025 teach the composition of claim 1 as discussed above.
Versteven further teaches that, in addition to the pioneering CTLA-4 and PD-1 inhibitors, other immune checkpoints have been attributed to hamper DC-mediated immunity, including LAG-3 and TIM-3. The LAG-3 mAb IMP321 was demonstrated to induce DC maturation and is now further tested in clinical trials. Versteven teaches that, overall, targeting multiple checkpoints simultaneously with DC therapy is likely to result in synergistic efficacy (page 8, right column, paragraph 1). Versteven further teaches that, combined with anti-PD-1, other emerging immune checkpoint inhibitors such as TIM3, LAG-3, CTLA-4, and BTLA were able to further increase the IFN-gamma producing and proliferative capacity of T cells (paragraph bridging pages 4-5).
The combination of applied references, however, does not disclose that the anti-PD-L1 antibody is bispecific or multi-specific.
US’602 teaches bispecific antibody molecules which bind to PD-L1 and LAG-3 and their application in cancer therapy (abstract; page 3, [0027]). US’602 teaches that anti-PD-1/PD-L1 antibodies are predominantly involved in breaking immune tolerance and activating an anti-tumor immune response. LAG-3, expressed on T cells following activation, and constitutively expressed on exhausted T cells, further maintains these cells in a suppressive state. Blockade of LAG-3, when employed in combination with other established immune suppressive molecules, for instance PD-1/PD-L1, has also been shown to provide a synergistic improvement in immune response in murine tumor models. US’602 postulates that therapies targeting both of these pathways simultaneously will directly address mechanisms which promote and maintain T cell exhaustion. It is postulated that bispecific antibodies that bind both LAG-3 and PD-L1 confer a number advantages over the combination of monoclonal antibodies against these antigens including: directed therapy, bridging, and localization (pages 2-3, [0025]-[0033]).
US’602 teaches the antibody molecule for use in a method of treating cancer in a patient where the method comprises administering a therapeutically effective amount of the antibody. US’602 teaches that the cancer includes melanoma, breast cancer, or glioblastoma multiform. The method further comprises administering an anti-tumor vaccine to the patient (page 159, claims 35-38).
US’602 teaches a composition comprising the bispecific antibody molecule and teaches that the composition can be administered alone or in combination with other treatments, concurrently or sequentially, or as a combined preparation with another therapeutic agent or agents. US’602 teaches that the therapeutic agent can be an anti-cancer therapy, such as an anti-tumor/cancer vaccine (page 13, [0163]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the anti-PD-L1 antibody in the composition taught by the combination of US’945, Versteven, and WO’025 with the LAG-3/PD-L1 bispecific antibody of US’602. An ordinarily skilled artisan would have been motivated to make this substitution as Versteven teaches that targeting multiple immune checkpoints, including PD-L1 and LAG-3, simultaneously with DC therapy is likely to result in a synergistic effect and US’602 teaches that the use of LAG-3 and PD-L1 antibodies has been shown to provide synergistically improved immune responses in murine tumor models. Additionally, US’602 teaches that the use of bispecific antibodies targeting LAG-3 and PD-L1 convers a number of advantages over the combination of monoclonal antibodies against the targets. An ordinarily skilled artisan would have had a reasonable expectation of success as US’602 teaches that the bispecific antibody can be in a combined preparation with an anti-cancer therapy, such as an anti-tumor/cancer vaccine.
Claims 17-18 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Santegoets, S.J.A.M., et al (2006) In vitro priming of tumor-specific cytotoxic T lymphocytes using allogeneic dendritic cells derived from the human MUTZ-3 cell line Cancer Immunol Immunother 55; 1480-1490 in view of Grenga, I., et al (2016) A fully human IgG1 anti-PD-L1 Mab in an in vitro assay enhances antigen-specific T-cell responses Clinical & Translational Immunology 5 (e83); 1-12.
Santegoets teaches that adoptive transfer of in vitro-induced and expanded tumor specific cytotoxic T lymphocytes (CTL) presents a promising immunotherapeutic approach for the treatment of cancer. The in vitro induction of tumor reactive CTL requires repeated stimulation of CTL precursors with dendritic cells (DC). To circumvent problems like scarcity of blood DC precursors and donor variability, it would be attractive to use DC from a non-autologous, unlimited source. DCs derived from the human acute myeloid leukemia (AML) cell line MUTZ-3 are attractive candidates since these DCs closely resemble monocyte-derived DC (MoDC) in terms of phenotype and T cell stimulatory capacity. Santegoets demonstrates that functional CTL clones can be generated against multiple tumor-associated antigens by stimulating CD8β+ CTL precursors with peptide-loaded allogeneic, HLA-A2-matched MUTZ-3 derived DC. A consistent induction capacity, as determined by MHC tetramer-binding, was found in multiple donors and comparable to autologous peptide loaded MoMDC. The data presented indicates that MUTZ-3-derived DC can be used as stimulator cells for in vitro priming and expansion of functional TAA-specific effector CTL. MUTZ-3 derived DCs thus represent a ready and standardized source of allogeneic DC to generate CTL for therapeutic adoptive transfer strategies (abstract).
Santegoets teaches that it was recently shown that DC could be cultured from the MUTZ-3 cell line, a CD34+ human AML cell line and that, upon stimulation with GM-CSF, IL-4, and TNF-α, MUTZ-3 precursor cells acquire a DC like morphology and phenotype consistent with conventional myeloid DC, expressing high levels of MHC, costimulatory and adhesion molecules. Furthermore, they are capable of antigen processing and presentation via MHC class I and II, resulting in stimulation of specific CD8+ and CD4+ T cells. Santegoets teaches that DC generated from the cell line might serve as universal stimulators for the generation of effector CTL in vitro (page 1481, left column, paragraph 3). Santegoets further teaches the selection and activation of highly reactive anti-tumor T cell populations ex vivo (page 1481, left column, paragraph 1).
Santegoets teaches a method in which CD8β+ CTL precursors were isolated from PBMC of HLA-A2+ healthy donors and a prostate cancer patient by positive selection. Mature MoDC and MUTZ-3 DCs, prepared as described above, were loaded with 25 μg/ml peptide for 2-4 h at room temperature and irradiated. 1x105 peptide loaded DCs were cultured for 10 days with 1x106 CD8β+ CTL precursor cells and 1x106 autologous PBMC in Ysssel’s medium supplemented with hAB serum, IL-6 and IL-12. At day 1, IL-10 was added. From day 10, CTL cultures were stimulated every week for 5 weeks with 1x105 fresh peptide-loaded DCs in the presence of IL-7. Two days after each restimulation IL-2 was added. One day prior to each restimulation a sample was taken and analyzed by flow cytometry (paragraph bridging columns, page 1482). Santegoets reports the applicability of MUTZ-3 DC as stimulators for cells for the generation and expansion of TAA-specific CTL for adoptive transfer in a clinical setting.
Santegoets further characterized mature MoDCs and MUTZ-3 DCs and teaches that, like DCs cultured from monocytes (MoDCs), or CD34- bone marrow derived precursors (CD34-derived DC), DCs cultured form the human cytokine-dependent myeloid cell line MUTZ-3 (MUTZ-3 DC) exhibit true DC morphology and characteristics. After differentiation in the presence of GM-CSF, IL-4, and TNF-α, and maturation with a cytokine cocktail containing TNF-α, IL-6, IL-1β, and PGE2, MUTZ-3 DC expressed intermediate to high levels of the costimulatory molecules CD80, CD86, and CD40, and of DC-specific molecules CD1a, DC-SIGN, and CD83. Thus, MUTZ-3 DCs phenotypically resemble MoDCs and CD34-derived DCs (page 1483, paragraph bridging columns; Figure 1). Based on figure 1, which clarifies that the MoDCs were mature MoDCs, the results of Santegoets indicate that the MUTZ-3 DCs exhibited a mature dendritic cell phenotype. Additionally, the instant specification states that “having a mature dendritic cell phenotype means that the modified cell of leukemic origin is capable of performing similar functions to those of a mature dendritic cell. The term includes both immature dendritic cells (“imDC”) and mature dendritic cells (“mDC”), depending on maturity” (instant specification, page 16, First paragraph under “B.”). A definition which further indicates that the MUTZ-3 DC of Santegoets meets the limitation of the cells having a “mature dendritic cell phenotype”.
The teachings of Santegoets differ from the instantly claimed method in that Santegoets does not teach the addition of an anti-PD-L1 antibody.
Grenga teaches that MSB0010718C, also known as avelumab, is a fully human IgG1 antibody targeting PD-L1 that is capable of mediating ADCC of tumor cells (page 1, right column, paragraph 3). Grenga teaches that recent studies had shown that blockade of the PD-1/PD-L1 pathway, using commercially available blocking antibodies in PBMCs of patients with chronic infections can restore functionality of impaired T-cell immune responses. The current study examined the ability of blockade of the PD-1/PD-L1 pathway to enhance immune activation in a normally functioning immune system, using PBMC from apparently healthy individuals, as well as investigated the potential lytic effects of avelumab on activated immune cells. It is shown that the addition of avelumab to antigen-specific in vitro stimulation (IVS) assay using normally functioning peripheral immune cells (a) increased the frequency of activated antigen-specific CD8+ T lymphocytes, and did so to a greater extent than that seen with commercially available PD-L1 blocking antibodies, (b) induced a switch in the production of Th2 to Th1 cytokines, (c) reduced total cell number as well as CD4+ T cell frequency, which was attributed to a reduction in cell proliferation, and (d) did not alter cell viability. In addition, the ability of avelumab to enhance antigen-specific immune activation in PBMCs from metastatic breast cancer patients was demonstrated. Overall, the findings indicate that avelumab does not induce lysis of activated human immune cells that express elevated levels of PD-L1, but instead, significantly increased antigen-specific immune activation (page 2, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of activating and expanding immune cells disclosed by Santegoets by adding an anti-PD-L1 antibody, such as avelumab, to the culture during expansion based on the teachings of Grenga. An ordinarily skilled artisan would have been motivated to further add avelumab as Grenga demonstrates that the addition of avelumab to antigen-specific in vitro stimulation increased the frequency of activated antigen specific CD8+ T lymphocytes, induced a switch from the production of Th2 to Th1 cytokines, and did not alter cell viability. An ordinarily skilled artisan would have had a reasonable expectation of success as Santegoets is teaching methods of expanding antigen-specific CD8 T cells and Grenga demonstrates the increase of antigen-specific CD8 T cells using avelumab in cultures.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Santegoets, S.J.A.M., et al (2006) In vitro priming of tumor-specific cytotoxic T lymphocytes using allogeneic dendritic cells derived from the human MUTZ-3 cell line Cancer Immunol Immunother 55; 1480-1490 in view of Grenga, I., et al (2016) A fully human IgG1 anti-PD-L1 Mab in an in vitro assay enhances antigen-specific T-cell responses Clinical & Translational Immunology 5 (e83); 1-12 as applied to claim 17 above, and in further view of
US 2019/0256602 A1 (Campbell, J., et al) 22 Aug 2019 and Versteven, M., et al (2018) Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer Frontiers in Immunology 9(394); 1-13.
The combination of Santegoets and Grenga teach the method of claim 17 as discussed in detail above.
The combination of applied references; however, does not teach that the anti-PD-L1 antibody is a bispecific or multispecific antibody.
The teachings of US’602 and Versteven are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the anti-PD-L1 antibody in the method taught by the combination of Santegoets and Grenga with the LAG-3/PD-L1 bispecific antibody of US’602 based on the teachings of Versteven. An ordinarily skilled artisan would have been motivated to make this substitution as Versteven teaches that targeting multiple immune checkpoints, including PD-L1 and LAG-3, simultaneously with DC therapy is likely to result in a synergistic effect and US’602 teaches that the use LAG-3 and PD-L1 antibodies has been shown to provide synergistically improved immune responses in murine tumour models. Additionally, US’602 teaches that the use of bispecific antibodies targeting LAG-3 and PD-L1 convers a number of advantages over the combination of monoclonal antibodies against the targets. An ordinarily skilled artisan would have had a reasonable expectation of success as Versteven and US’602 are also focused on T cell activation and expansion.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693