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 .
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 8-10, 16-25, and 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over Xiang et al. (Cancer Cell. 26: 565-576; Published: October 13, 2014) and Zhu et al. (Theranostics. 7(10): 2732-2745; Published: July 7, 2017) and in view of Djaoud et al. (The Journal of Experimental Medicine. 214(6): 1827-1841; Published: May 3, 2017), Glassberg Csete et al. (US 2020/0384034 A1; Effectively Filed: June 6, 2019), Wang et al. (Molecular Medicine Reports. 19: 1471-1480; Published Online: January 8, 2019), and Handgretinger et al. (Blood. 131(10): 1063-1072; Published: March 8, 2018).
Regarding claims 8-10, 22-25, 27, and 29-31, Xiang et al. teaches that activated Vδ2 T cells can kill Epstein-Barr virus (EBV)-transformed autologous lymphoblastoid B cell suggesting the use of Vδ2 T cells for the treatment of EBV-induced lymphoproliferative diseases associated with EBV infection; see Abstract. Regarding claims 27 and 28, Xiang et al. teaches that Vδ2 T cells are specifically activated in an HLA-unrestricted manner which suggests that they could be used in both and autologous and allogeneic manner; see page 566 left column.
Regarding claims 16-18 and 21, Xiang et al. teaches expanding Vδ2 T cells comprising culturing human PMBCs with the phosphoantigen, pamidronate, and IL-2 for 14 days; see Expansion and Purification of Vγ9Vδ2-T Cells In Vitro. Supplement Figure S1D of Xiang et al. teaches that this expansion treatment of pamidronate and IL-2 results in increased expression of CD69, NKG2D, TRAIL, FasL, perforin and granzyme B.
Xiang et al. does not teach harvesting exosomes from Vδ2 T cells.
Regarding claims 16, 19, and 20, Zhu et al. teaches harvesting exosomes from NK cells comprising growing NK cells in media for 3 days or 72 hours, collecting the supernatant, and isolating the exosomes by centrifugation, filtration, and ultracentrifugation; see Exosome Isolation.
Regarding claims 8, 22, and 27-29, Zhu et al. teaches treating cancer with exosomes derived from autologous or allogeneic NK cells; see Abstract and page 2743 right column. Interestingly, Figure 2 of Zhu et al. teaches that the NK cell derived exosomes express FasL and perforin more abundantly than the NK cells from which they were derived.
It would have been obvious to one of ordinary skill in the art to try treating EBV-infected cells or EBV-induced cancer with exosomes derived from expanded Vδ2 T cells. Furthermore, it would have been obvious to one of ordinary skill in the art to obtain the exosomes by expanding Vδ2 T cells as taught by Xiang et al. followed by collecting and isolating exosomes as taught by Zhu et al. One would have had a reasonable expectation of success because Xiang et al. teaches that expanded Vδ2 T cells demonstrated increased expression of cytotoxic factors such as perforin and FasL. Xiang et al. teaches that γδ T cells are considered innate-like T cells with NK cells characteristic and, indeed, Xiang et al. demonstrated increased expression of the NK cell receptor, NKG2D, on the Vδ2 T cells following phosphoantigen and IL-2 activation; see page 2 left column and Figure S1D. Moreover, Glassberg Csete et al. teaches that T cells do secrete exosomes or extracellular vesicles that can be used therapeutically; see paragraph 304. Thus, one would have had a reasonable expectation that Vδ2 T cells would behave similarly to the NK cells of Zhu et al. in their capability to generate therapeutic exosomes.
Regarding the limitation “to expand Vδ2+ T cells for a first period of time” in step b) of claim 16, Wang et al. demonstrates that when IL-2 and a phosphoantigen is applied to a culture of PBMCs, the expansion, or increase in proportion, of Vδ2+ T cells naturally flows with an increase demonstrated as early as 4 days. Thus, it would have been obvious to one of ordinary skill in the art that after 4 days, the PBMCs have expanded to Vδ2+ T cells. Because Wang et al. teaches that there is further expansion of PBMCs from day 4 to day 16, Zhu et al. teaches collecting exosomes by culturing in stem cell media, or exosome-free media, and Glassberg Csete et al. teaches the therapeutic potential of exosomes, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method of Xiang et al. to change to exosome-free media after 4 days in order to collect supernatant containing exosomes from the expanded Vδ2+ T cells as taught by Zhu et al. One of ordinary skill in the art would have been motivated to grow the expanded Vδ2+ T cells in exosome-free or exosome-depleted stem cell media, as taught by Zhu et al., in order to obtain exosomes from the expanded Vδ2+ T cells and not from serum media supplement, such as FBS.
Further, one of ordinary skill in the art may reason that exosomes would comprise the same proteins found on the cell membrane, but, interestingly, Zhu et al. demonstrated that exosomes expressed these cytotoxic factors more abundantly than the cells from which they were derived. One would have been motivated to treat with Vδ2 T cell-derived exosomes because Vδ2 T cells are not HLA-restricted making them desirable for both allogeneic and autologous use, Vδ2 T cells are known to exert antiviral effects on EBV (see Djaoud et al.), and exosomes are more stable, less immunogenic, and can be further engineered for additional drug delivery. Further, regarding autologous or allogeneic Vδ2 T cells as the source of exosomes in claim 8, Handgretinger et al. teaches that Vδ T cells are not alloreactive; see Abstract. Thus, it would have been obvious to try treating EBV-infected cells and EBV-induced cancers with Vδ2 T cell-derived exosomes, from either autologous or allogeneic Vδ2 T cells, and it would have been obvious to optimize the therapeutically effective dose of exosomes for the treatment of EBV infection and EBV-induced cancer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 11, 26, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Xiang et al. (Cancer Cell. 26: 565-576; Published: October 13, 2014) and Zhu et al. (Theranostics. 7(10): 2732-2745; Published: July 7, 2017) and in view of Djaoud et al. (The Journal of Experimental Medicine. 214(6): 1827-1841; Published: May 3, 2017), Glassberg Csete et al. (US 2020/0384034 A1; Effectively Filed: June 6, 2019), Wang et al. (Molecular Medicine Reports. 19: 1471-1480; Published Online: January 8, 2019), and Handgretinger et al. (Blood. 131(10): 1063-1072; Published: March 8, 2018) as applied to claim(s) 8-10, 16-25, and 27-31 above, and further in view of Young et al. (Chinese Journal of Cancer. 33(12): 581-590; Published: December 2014) and Correia et al. (OncoImmunology. 2(1): e22892; Published: January 2013).
The teachings of Xiang et al. and Zhu et al. and in view of Djaoud et al., Glassberg Csete et al., Wang et al., and Handgretinger et al. as related to claim(s) 8-10, 16-25, and 27-31, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Zhu et al. teaches exosomes from NK cells to teach an epithelial malignancy, the references do not teach treating an EBV-induced epithelial cancer with Vδ2 T cell-derived exosomes.
Young et al. teaches that epithelial sites in the oropharynx and salivary glands appear to be the major sites for viral replication in latent EBV infection; see page 581 right column. Young et al. teaches that non-keratinizing squamous cell carcinoma is one main histological type of nasopharyngeal carcinoma (NPC) which can be further divided into differentiated non-keratinizing carcinoma (type II) and undifferentiated carcinoma (type III), and these type II and type III tumors are predominantly EBV-positive; see page 582 paragraph bridging columns. Carcinomas with similar features to undifferentiated nasopharyngeal carcinoma, also referred to as undifferentiated carcinomas of nasopharyngeal type (UCNT) or lymphoepitheliomas, have been described at other sites including the thymus, tonsils lungs, stomach, skin, or uterine cervix; see page 582 right column. The undifferentiated form of nasopharyngeal carcinoma (NPC) shows the most consistent worldwide association with EBV and UCNTs of the stomach are consistently EBV-positive; see page 581 right column and page 582 right column.
Young et al. does not teach treating an EBV-induced epithelial cancer with Vδ2 T cell-derived exosomes.
Correia et al. teaches that phosphoantigen-activated Vγ9Vδ2 T cells can recognize and kill a large variety of tumor cell lines in vitro and in vivo (in xenograft models), including nasopharyngeal carcinoma; see page 2 leftmost column.
Given that EBV has been demonstrated to infect epithelial cells and is associated with some epithelial cancers, such as NPC, and that phosphoantigen-activated Vγ9Vδ2 T cells can recognize and kill malignant epithelial cells, including NPC, it would have been obvious to one of ordinary skill in the art to treat epithelial cancer associated with EBV, including NPC, with exosomes derived from Vδ2 T cells as taught by Xiang et al. and Zhu et al. One of ordinary skill in the art would have had a reasonable expectation of success treating EBV-induced epithelial cancer with exosomes derived from Vδ2 T cells expanded by phosphoantigen as taught by Djaoud et al. because Correia et al. teaches that phosphoantigen-activated Vγ9Vδ2 T cells are capable of killing NPC – a type of epithelial cancer commonly associated with EBV infection.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 15 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Xiang et al. (Cancer Cell. 26: 565-576; Published: October 13, 2014) and Zhu et al. (Theranostics. 7(10): 2732-2745; Published: July 7, 2017) and in view of Djaoud et al. (The Journal of Experimental Medicine. 214(6): 1827-1841; Published: May 3, 2017), Glassberg Csete et al. (US 2020/0384034 A1; Effectively Filed: June 6, 2019), Wang et al. (Molecular Medicine Reports. 19: 1471-1480; Published Online: January 8, 2019), and Handgretinger et al. (Blood. 131(10): 1063-1072; Published: March 8, 2018) as applied to claim(s) 8-10, 16-25, and 27-31 above, and further in view of Morse et al. (Journal of Translational Medicine. 3: 9; Published: February 21, 2005).
The teachings of Xiang et al. and Zhu et al. and in view of Djaoud et al., Glassberg Csete et al., Wang et al., and Handgretinger et al. as related to claim(s) 8-10, 16-25, and 27-31, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Xiang et al., Zhu et al., Djaoud et al., nor Wang et al. teach a pharmaceutical composition comprising Vδ2 T cell-derived exosomes and a pharmaceutically acceptable carrier and routes of administration.
Morse et al. teaches a pharmaceutical composition comprising dendritic cell-derived exosomes, called DEX or dexosomes, diluted in 0.9% normal saline administered by both subcutaneous and intradermal injections; see pages 3-4.
Given that Morse et al. teaches a pharmaceutical composition comprising immune cell-derived exosomes and suitable routes of administration for treating cancer, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success treating an EBV-infected cell or EBV-induced cancer with the Vδ2 T cell-derived exosomes taught by Xiang et al., Zhu et al., and Djaoud et al. as a pharmaceutical composition diluted in saline and administered by subcutaneous and intradermal injections as demonstrated by Morse et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed September 29, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant's arguments filed September 29, 2025 have been fully considered but they are not persuasive.
Applicant argues that the claimed protocol for the expansion of Vδ2+ T cells is distinct from that taught by Xiang et al. because the method of claim 16, from which all other claims depend, recites a two-step stimulation – referring to steps b) and c).
The Office disagrees. Steps b) and c) recite culturing the cells for a first and second period of time which is open to any period of time. Step b) now recites the functional language “to expand to Vδ2+ T cells” which confers a minimal time requirement to the first period of time, although that time period is not definitively defined in the instant disclosure nor the art.
Applicant’s argument regarding the alleged distinction of a two-step stimulation suggests that Applicant may consider Xiang et al. as fulfilling steps a), b), and d) of claim 16 with the “first period of time” being the 14 days of expansion procedure in Xiang et al. Wang et al. (Molecular Medicine Reports. 19: 1471-1480; Published Online: January 8, 2019), added to the rejection to address the amended functional language “to expand Vδ2+ T cells”, demonstrates that the art understood that when IL-2 and a phosphoantigen is applied to a culture of PBMCs, the expansion, or increase in proportion, of Vδ2+ T cells naturally flows with an increase demonstrated as early as 4 days. Thus, the “first period of time” necessary “to expand Vδ2+ T cells” may be interpreted, in line with the art, as little as 4 days. More specifically, “expanded Vδ2+ T cells” in step c) does not confer a critical threshold or proportion of Vδ2+ T cells be reached and “first period of time” and “second period of time” are broad.
Step c) requires, after the first time period, culturing the expanded Vδ2+ T cells in exosome-free media with the phosphoantigen and IL-2 for a second period of time; however, there is no functional language in the claim to limit the “second period of time”. There is no required step separating steps b) and c). Thus, the method of Xiang et al. modified to change the media to exosome-free media after 4 days meets the two-step stimulation as currently claimed.
The rejections have been updated to include Wang et al. as necessitated by amendment.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Long et al. (Frontiers in Immunology. 10: 2193; Published: September 18, 2019) teaches γδ T cells play an important role in controlling EBV infection and transformation. Hsiao et al. (Chemistry & Biology. 21: 945-954: Published: August 14, 2014) teaches several phosphoantigens to activate Vδ2 T cells. Wada et al. (Cancer Medicine. 3(2): 362-375; Published: February 7, 2014) teaches the treatment of gastric cancer with Vγ9Vδ2 T cells. Masters et al. (Nature Protocols. 2(9): 2276-2284; Published: September 13, 2007) teaches that refreshing media in cell culture is necessary every 1-2 days or twice a week depending on the cell line or type and type of medium.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 7:30am - 5:00pm.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682