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 .
Applicant's response to the previous Office action, dated April 27, 2026, has been received. By way of this submission, Applicant has cancelled claim 56.
Claims 1, 6-9, 12, 18, 35, 40-42 and 54-55 are pending in the application. Claims 9, 12 and 18 remain withdrawn from consideration, pursuant to the Restriction Requirement mailed November 26, 2021.
Claims 1, 6-8, 35, 40-42 and 54-55 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated January 28, 2026.
Claim Rejections - 35 USC § 112
Claim 56 was previously 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.
Applicant's cancellation of claim 56 has rendered this rejection moot, and it is withdrawn.
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 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Mariani (Leukemia (2005) 19, 664-670) in view of Fournie
(US20090304688A1, cited in IDS) and Jakobovits (US20160175358A1, cited in IDS as WO2016081518A2).
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.
Applicant argues that there was no reasonable expectation of success in making the claimed product, as Oberg (Cancer Res. 74:1349-1360, 2014, cited in IDS) allegedly teaches inconsistent or negligible enhancement of γ9δ2 T cell cytotoxicity by a [(Her2) x CD3] bispecific T cell engager across different pancreatic tumor cell lines, and Bluemel (Cancer Immunol Immunother. 59:1197-1209, 2010, cited in IDS) allegedly teaches that T cell-mediated cytotoxicity via bispecific T cell engagers depends on factors such as epitope distance from the membrane and antigen size, and since the epitopes targeted by the [(Her2) x CD3] bispecific T cell engager described in Oberg and those targeted by blinatumomab differ, and because the respective targeted antigens (HER2 vs CD19) are structurally distinct in size, the results reported in Oberg cannot reasonably be extrapolated to blinatumomab.
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, and that Fournie shows that neither Rituximab nor Campath (two therapeutic antibodies) produced a statistically significant improvement in the specific lysis of Daudi cells when combined with gamma-delta T cells, in contrast to Applicant's data.
Applicant further argues that further publications by Oberg (Cellular Immunology 296:41-49, 2015, cited in IDS) teaches away from the claimed combination, as a Her2xCD3 bispecific antibody engages alpha-beta T cells better than gamma-delta T cells, and that the Her2xCD3 bispecific antibody does not enhance gamma-delta T cell activity across all pancreatic tumor cell lines, and Oberg discourages the use of gamma-delta T cells in combination with CD3 targeting bispecific T cell engagers such as blinatumomab.
Applicant further argues that the cited references do not teach every aspect of the claims as amended, as Mariani does not teach CD45RA- cells, and that Jakobovits does not offer supporting data in the assertion that PD-1 deficient gamma-delta T cells retain cytotoxicity. Applicant cites references to Odorizzi and Wei (cited previously) that PD-1 silencing reduces antitumor activity. Applicant further asserts that the statements from Leek and Koh do not support that PD-1 expression can be removed by culture, as Iwasaki and Zumwalde (cited in IDS) show that significant percentages of gamma-delta T cells continue to express PD-1 following in vitro culture.
Applicant's arguments have been considered fully but are not found to be persuasive.
The claims are not drawn to methods of making gamma-delta T cells that do not express PD-1, nor are the claims drawn to methods of treatment of cancer. They are drawn to a product comprising said cells and blinatumomab. There are no culture steps recited in the claims, nor do the claims assert any specific utility of treatment. 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.
With regards to Applicant's arguments concerning Oberg, Oberg does not teach blinatumomab. Blinatumomab is a bispecific T cell engager that targets CD19 and CD3 (see paragraph 3 of Applicant's specification). Applicant's own argument clearly states that "the results reported in Oberg cannot reasonably be extrapolated to blinatumomab." One therefore cannot make an assumption on the predictability of the field by the teachings of Oberg.
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).
Applicant’s assertion that the previous Office action contains acknowledgements that the cells of Mariani are CD45RA positive and therefore distinct from the claimed CD45RA negative cells is merely a restatement of Applicant’s position, and not an concession of this statement.
Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) (“To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’”); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) (“This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness.” (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that “the expectation of success need only be reasonable, not absolute”)). MPEP 2143.02(I).
The instant claims also recite no mechanism of action to distinguish them from Fournie.
With regards to Applicant's arguments concerning Oberg's later publications (Cellular Immunology 296:41-49, 2015, cited in IDS), Oberg encourages combinations of gamma-delta T cells and blinatumomab, stating on page 48, left column, first paragraph: "While bispecific antibodies such as blinatumomab or catumaxomab have shown impressive potential in clinical trials, the adoptive transfer of gamma-delta T cells together with bispecific antibodies with specificity for gamma-delta T cells and tumor antigens could be envisioned since this protocol induced less cell death induction in activated gamma-delta T cells compared to re-stimulation with PAg.".
With regards to Applicant's arguments concerning expression of PD-1, as stated previously, 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.
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). This is the same method used in the specification at page 19. For this reason, the cells of Mariani must exhibit the same properties as the claimed cells with regards to expression of CD45RA.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Applicant has not met this burden.
"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. MPEP 2112.01.
Jakobovits is explicit in teaching: "[a]ccordingly, an engineered γδ T-cell that lacks PD-1 can retain its cytotoxic activity regardless of expression of PD-L1 and PD-L2 by tumor cells. In some cases, an engineered γδ T-cell of the disclosure lacks the gene locus for the PD-1 gene. In some cases, expression of the PD-1 gene in an engineered γδ T-cell is disrupted by gene editing technologies." (para. 0074). This is a clear motivation to make a γδ T-cell that lacks PD-1. In such a case, culture conditions become irrelevant, as a cell that lacks the PD-1 gene due to genetic manipulation as suggested by Jakobovits cannot express PD-1 at all.
The burden of proof is on the Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his or her claimed product. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980). MPEP 2112(V). Applicant has not met this standard.
This rejection is therefore maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Lameris (Crit Rev Oncol Hematol. 2014 Dec;92(3):153-65) teaches that treatment with zoledronic acid and IL-2 promotes the differentiation of peripheral blood gamma-delta T-cells toward an effector/memory-like phenotype, and combinations of gamma-delta T cells and anti-CD3 bispecific T cell engagers (page 160, left column, fourth paragraph).
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER JOHANSEN whose telephone number is (571)272-0280. The examiner can normally be reached Monday-Friday, 7:00 to 3:00.
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/PETER JOHANSEN/Examiner, Art Unit 1644
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