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 view of the Notice of Appeal filed on December 30, 2025, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
Claims 1, 6-9, 12, 18, 35, 40-42 and 54-56 are currently pending in the application. Claims 9, 12 and 18 remain withdrawn from consideration, pursuant to the restriction requirement dated November 26, 2021.
Claims 1, 6-8, 35, 40-42 and 54-56 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated July 30, 2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 56 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new grounds of rejection.
Claim 56 recites the limitation of Blinatumomab lacking an Fc region. However, Blinatumomab naturally lacks an Fc domain (see Tapia‑Galisteo (J Hematol Oncol. 2023 Jul 27;16(1):83) at page 8, left column, second paragraph: "Probably the main drawback of blinatumomab is its relatively small size (55 kDa), which added to the lack of a Fc domain results in a short half-life of approximately 2 h in humans..."). Claim 56 therefore does not meaningfully apply any limitations to the invention.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 6-8, 35, 40-42 and 54-56 were previously rejected under 35 U.S.C. 103 as being unpatentable over Mariani (Leukemia (2005) 19, 664-670, cited previously) in view of Fournie (US20090304688A1, cited in IDS).
Applicant argues that genetically silencing PD-1 expression impairs the anti-tumor function of T cells, citing references to Odorizzi (J Exp Med. 2015 Jun 29;212(7):1125-37, cited in IDS) and Wei (J Immunother Cancer. 2019 Aug 7;7(1):209, cited in IDS), and that such a modification would render the cells unsuitable and unsatisfactory for their intended therapeutic purpose, and for this reason, a reference that relies upon genetic silencing of PD-1 is not applicable. Applicant further argues that the cells of the invention and the cells of Mariani are distinct, as the claimed cells are CD45RA-negative, whereas the cells of Mariani are CD45RA- positive. Applicant asserts that the culture conditions described in the specification differ from those of Mariani, and therefore would result in cells with different characteristics than those of the claimed invention. Applicant further argues that Fournie does not provide evidence of a synergistic benefit between gamma-delta T cells and blinatumomab, and the mechanism of Fournie relies upon a different mechanism of action than that of the claimed invention.
Applicant's arguments are persuasive, and this rejection is hereby withdrawn.
Claims 1, 6-8, 35, 40-42 and 54-56 are rejected under 35 U.S.C. 103 as being unpatentable over Mariani (Leukemia (2005) 19, 664-670, cited previously) in view of Fournie (US20090304688A1, cited in IDS) and Jakobovits (US20160175358A1 (cited in IDS as WO2016081518A2). This is a new grounds of rejection.
Mariani teaches a method of ex vivo expansion of gamma-delta T cells, comprising culturing the cells in 1 micromolar zoledronic acid (zol) and IL-2 (page 666, left column, third paragraph and Figure 1).
Mariani further teaches that said cells may be CD27- and CD45RA- (Figure 2).
Mariani further teaches that said cells have antitumor properties, and such properties are dependent upon direct cell-to-cell contact (page 669, "Conclusions").
Mariani also teaches that gamma-9-delta-2 cells are CD3+ (page 664, left column, second paragraph).
Mariani further teaches that the gamma-delta T cells are expanded from peripheral blood (page 664, right column, "Culture conditions"), which is pertinent to claim 55.
Mariani also teaches that gamma-9-delta-2 cells are useful for treating cancer (abstract).
However, Mariani does not teach blinatumomab or cells that do not express PD-1.
Fournie teaches that expanded autologous gamma-delta T cells can improve the efficiency of therapeutic antibodies (para. 0008). Fournie also teaches pharmaceutical compositions comprising a therapeutic antibody and activated gamma-delta T cells, as well as kits for such (para. 0064, also see claim 33), which is pertinent to claims 6-8, 35, and 40-42.
Fournie also teaches methods of eliminating cancer cells by bringing said cell into contact with an activated gamma-delta T cell (para. 0014). Fournie also teaches that said activated gamma-delta T cell has been brought into contact with a gamma-delta T cell activator prior to administration (para. 0014), and that the gamma-delta T cell activator may be zoledronate (i.e. zoledronic acid) (para. 0028).
Fournie further teaches that the antibodies used may be bispecific antibodies or bispecific T cell engagers (BiTE) (para. 0106). Fournie also teaches MT103 (blinatumomab), a bispecific antibody which binds CD19 and CD3, as an exemplary antibody to be used in the above combination (para. 0109 and Table 1).
Jakobovits teaches the administration of gamma-delta T cells for the treatment of cancer (para. 0011, 0016, 0032).
Jakobovits further teaches that immune checkpoint proteins, such as PD-1, can influence T cell activity, and that tumors can dysregulate checkpoint protein function as an immune-resistance mechanism, particularly against T cells (para. 0072). Jakobovits further teaches that gamma-delta T cells can be engineered to lack PD-1 in order to address this problem, and that an engineered gamma-delta T cell that lacks PD-1 can retain its cytotoxic activity regardless of expression of PD-L1 and PD-L2 by tumor cells. (para. 0072-0074).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Mariani, Fournie, and Jakobovits to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since all of Mariani, Fournie, and Jakobovits are both concerned with the use of gamma-delta T cells for cancer immunotherapy. Since Mariani teaches that these cells are CD3+, a skilled artisan would be motivated to use a CD3/CD19 bispecific antibody such as blinatumomab, to bring the CD3+ T cells into contact with CD19+ cancer cells to affect a strong immune response, especially since Fournie teaches that combinations of expanded autologous gamma-delta T cells and bispecific T cell engagers have a predictable synergy. Likewise, Jakobovits teaches advantages of gamma-delta T cells that lack PD-1, and methods of generating such cells. A skilled artisan could readily envision and assemble a combination of the cells of Mariani and blinatumomab as taught by Fournie, which each component of the combination performing its known, regular function, leading to a predictable result of efficient cancer immunotherapy.
In response to Applicant's arguments, Jakobovits teaches gamma-delta T cells that lack PD-1 due to genetic manipulation. The limitation of the cells not being genetically modified is no longer present.
The references to Odorizzi and Wei do not refer to gamma-delta T cells, they refer to CD8+ effector cells and CD4+ CAR-T cells, respectively. The properties of these distinct cell populations cannot necessarily be inferred to the claimed population of cells.
Koh (Pediatric Blood and Cancer, (November 2016) Vol. 63, Supp. Supplement 3, pp. S210, cited previously) teaches that ex vivo expanded gamma-delta T cells showed no significantly increased inhibitory receptors (i.e., PD-1) on their surface after two weeks of culture with IL-2 and zoledronic acid (page 210, Abstract P-0570). Furthermore, Leek (WO2016166544A1, cited previously) teaches that gamma delta T cells may be cultured to remove PD-1 from the cell surface (pages 24-25).
As stated previously, the claims are not drawn to methods of making gamma-delta T cells that do not express PD-1. They are drawn to a product comprising said cells and blinatumomab. There are no culture steps recited in the claims. If Applicant has invented a novel method of making gamma-delta T cells that do not express PD-1, Applicant is invited to pursue that invention in a distinct, independent claim.
Applicant's arguments also raise questions of enablement, as the recited method of producing the claimed cells relies upon 1 micromolar zoledronic acid and 1,000 IU/ml IL-2 (see specification at page 19), while Applicant's remarks on page 8 of the reply submitted May 15, 2025 states that these culture conditions induce PD-1 expression on T cells. Clarification as to the exact culture conditions used in making the claimed cells with their asserted properties is requested.
With regards to Fournie, Fournie is explicit in teaching that "the therapeutic antibody can be an antibody selected from the antibodies in Table 1" (para. 0109), and MT 103 (i.e., blinatumomab) is included in this table. Also at para. 0108 of Fournie: "Other examples of therapeutic antibodies are listed in the following table, any of which (and others) can be used in the present methods.”
The experiments recited in Fournie are intended to be illustrative and not limiting the scope of this application (para. 0196). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123 II).
With regards to Applicant's assertion of unexpected results, once again, the claims are not drawn to a method of treating acute lymphocytic leukemia. They are drawn to a product.
Fournie is explicit in teaching combinations of expanded autologous gamma-delta T cells can enhance the properties of therapeutic antibodies (para. 0008). Fournie also explicitly teaches that bispecific antibodies may be used in such a combination (para. 0106). Fournie also teaches MT103 (Blinatumomab), a bispecific antibody which binds CD19 and CD3, as an exemplary antibody to be used in the above combination (para. 0109 and Table 1). This is a clear motivation to combine gamma-delta T cells with blinatumomab, along with a reasonable expectation of synergy between the two treatments.
Conclusion
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644