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 Status
Claims 1-10 are pending.
Claims 9-10 are new claims.
Claims 1-10 have been examined.
Priority
This application is a 371 of PCT/EP2021/085062 filed on 12/09/2021 and claims foreign priority of EP 20306528.9 filed on 12/10/2020.
Withdrawn Objection
The objection of claims 1-7 are withdrawn because the amendment to claims 1-7 overcomes the objection.
Maintained Rejection
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.
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.
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Magnani et al. (WO 2017/079,215 A1, cited 1/16/2026) in view of Gao et al. (Blood. (2019) 134 (Supplement 1): 2001, cited 1/16/2026) and Varelias et al. (J Clin Invest. 2018;128(5):1919-1936, cited in IDS 6/9/2023).
Claim 1 is drawn to a method of controlling Graft Versus Host Disease (GVHD) in a patient after transplantation comprising administering to the patient a therapeutically effective amount of a population of MAIT cells.
Magnani et al. teach hematopoietic cell transplantation is a promising therapeutic approach in the treatment of hematologic diseases, disorders, or conditions (e.g., thalassemias, sickle cell disease, leukemias, lymphomas, myelomas) as well as in rescue from chemotherapy and high-dose radiation such as cancer therapy [p2, 004; p38, 0114]. Magnani et al. teach, a patient may avoid reintroducing diseased cells from his own autologous donation into his system by using allogenic cells (reading allogeneic hematopoietic cell transplantation), but risks such complications as graft-versus-host disease (GVHD) [p2, 004]. Magnani et al. teach, in bone marrow transplants, it is known that the higher the number or percentage of HSCs implanted into a recipient, the greater percentage of engraftment of the donor HSCs in the recipient [0121]. Consistently, the specification disclosed the term "bone marrow transplantation" or "hematopoietic stem cell transplantation" used herein should be considered as interchangeable, referring to the transplantation of hematopoietic stem cells in some form to a recipient (p4, 23-25). Thus, Magnani’s hematopoietic cell transplantation also reads on bone marrow transplantation according to applicant’s disclosure.
Magnani et al. do not teach administering a therapeutically effective amount of a population of MAIT cells to control Graft Versus Host Disease (GVHD) in the patient after transplantation.
Gao et al. teach gut graft-versus-host disease (GVHD) is a serious complication after hematopoietic stem cell transplantation (HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAIT) are a group of innate-like T cells enriched in the intestine, which may alter the composition of the intestinal microflora or exert a certain immunomodulatory effect to protect the intestinal mucosa from further damage for the inflammatory response known in the art (p1, Background & Purpose). Gao et al. teach the total number of infused MAITs in the graft of gut GVHD patients was significantly lower than that of no GVHD patients (p1, Results to p2, para 2). Gao et al. further show gut GVHD was more likely to occur in patients who were infused with a smaller number of MAIT cells in grafts (p2, Fig. 1), suggesting the potential functional effects of MAIT cells on gut GVHD. Gao et al. further suggest MAIT cells may function through direct immunosuppression or regulation of intestinal microflora (p2, Conclusion).
Similarly, Varelias et al. teach MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT) in the Abstract. Varelias teaches acute graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplantation (BMT) and results in considerable morbidity and mortality. Major target organs include the gastrointestinal (GI) tract, liver, and skin, all of which represent tissues with extensive environmental interfaces (p1919, col 1, Introduction). Varelias et al. teach recipient MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B). Varelias et al. further teach in order to regulate disease during GVHD, recipient MAIT cells must survive conditioning (reading on maintaining an effective amount of MAIT cells) and the incoming alloreactive donor graft in the early transplant period (p1924, col 2, para 1).
Because (a) Gao et al. teach infused MAIT cells in the graft of gut GVHD patients significantly lower than that of no GVHD patients (p1, Results to p2, para 2) and (b) Varelias et al. teach MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B), one of ordinary skill in the art would have found it obvious to administer an effective amount of MAIT cells taught by Gao et al. in view of Varelias et al. to reduce the risk of developing complications of graft-versus-host disease GVHD for Magnani’s patients after allogeneic hematopoietic cell transplantation , reading on controlling Graft Versus Host Disease (GVHD) in a patient after transplantation comprising administering to the patient.
One of ordinary skill in the art before the effective fining date of this invention would have found it obvious to combine (i) Magnani et al. and (ii) Gao et al. in view of Varelias et al. because (a) Magnani et al. teach allogeneic hematopoietic cell transplantation is a promising therapeutic approach in the treatment of hematologic diseases with risks of developing graft-versus-host disease (GVHD) [p2, 004], (b) Gao et al. teach the total number of infused MAITs in the graft of gut GVHD patients was significantly lower than that of no GVHD patients and suggest the potential functional effects of infused MAIT cells on gut GVHD(p1, Results to p2, para 2; p2, Fig 1), and (c) Varelias et al. teach MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B). The combination would have reasonable expectation of success because all references teach graft-versus-host disease (GVHD) as a complication resulting from allogeneic hematopoietic cell transplantation.
With respect to claim 2, Magnani et al. teach, a patient may avoid reintroducing diseased cells from his own autologous donation into his system by using allogenic cells, reading allogeneic hematopoietic cell transplantation [p2, 004].
With respect to claims 3-4 and 8, Magnani et al. teach hematopoietic cell transplantation is a promising therapeutic approach in the treatment of hematologic diseases, disorders, or conditions (e.g., thalassemias, sickle cell disease, leukemias, lymphomas, myelomas) as well as in rescue from chemotherapy and high-dose radiation such as cancer therapy [p2, 004].
With respect to claim 5, Magnani et al. teach the transplanted patients under chemotherapy or high-dose radiation [p12, 037; p57, claim 37], reading on undergone a cytoablative therapy.
With respect to claim 6, Varelias et al. teach MAIT cells found in relatively high frequencies in the blood, liver, and GI tract (p1921, col 1, last para to col 2, line 1-2); thus one of ordinary skill in the art would have found it obvious to isolate MAIT cells from blood samples. Furthermore, Varelias et al. teach MAIT cell expansion ex vivo (p1934, col 1, para 5), reading on prepared from cell culture.
With respect to claim 7, Varelias et al. teach functional MAIT cells are activated and expressing IL-17 (p1928, col 1, last para to col 2, para 1). Varelias et al. teach MAIT cell activation requires presentation of riboflavin-based precursors captured by the MHC class I–related molecule MR1. In addition, MAIT cells can also be activated in an antigen-independent manner by IL-12 and IL-18. The end result of MAIT cell activation is to limit microbial colonization and disease by potential pathogens (p1931, col 2, para 2). Varelias et al. further teach IL-17 is required to maintain epithelial cell barrier function, and perturbation of IL-17 in this context can lead to enhanced inflammation and GI damage. It is thus likely that the protection from GVHD in the GI tract by MAIT cells reflects their role in maintaining mucosal integrity and that the enhanced donor T cell responses (p1932, col 1, para 1). Because (i) Varelias et al. teach MAIT cell expansion ex vivo (p1934, col 1, para 5) and (ii0 functional MAIT cells are beneficially activated to express IL-17 (p1928, col 1, last para to col 2, para 1) to maintain epithelial cell barrier function (p1932, col 1, para 1), one of ordinary skill in the art would have found it obvious to beneficially administer activated and expanded MAIT cells to reduce the risk of developing complications of graft-versus-host disease GVHD for Magnani’s patients after allogeneic hematopoietic cell transplantation.
With respect to claim 9, Magnani et al. teach, in bone marrow transplants, it is known that the higher the number or percentage of hematopoietic stem cell (HSC) implanted into a recipient, the greater percentage of engraftment of the donor HSCs in the recipient [0121]. Varelias teaches acute graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplantation (BMT) and results in considerable morbidity and mortality. Consistently, the specification disclosed the term "bone marrow transplantation" or "hematopoietic stem cell transplantation" used herein should be considered as interchangeable, referring to the transplantation of hematopoietic stem cells in some form to a recipient (p4, 23-25). Thus, Magnani’s hematopoietic cell transplantation further reads on bone marrow transplantation according to applicant’s disclosure.
With respect to claim 10, Varelias teaches acute graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplantation (BMT) and results in considerable morbidity and mortality. Major target organs include the gastrointestinal (GI) tract, liver, and skin, all of which represent tissues with extensive environmental interfaces (p1919, col 1, Introduction).
Applicant’s Arguments
Magnani does not teach administration of MAIT cells (Remarks, p4, Claim Rejections - 35 USC§ 103, para 2).
Gao does not suggest administration of MAIT cells for treating GVHD. Several different cell types may be lower in GVHD patients as compared to no GVHD patients, however, one of ordinary skill in the art would recognize that administration of any one of the lowered cell types would not necessarily be an effective treatment (Remarks, p4, 2nd last para).
Varelias does not teach or suggest administration of MAIT cells. As this teaching is completely missing from the cited references, no combination of the cited references would make the claimed invention obvious (Remarks, p4, last line to p5, para 1).
New claim 9 requires that the transplantation is a bone marrow transplantation. Gao teaches that there was no difference in MAIT cell levels in patients receiving a bone marrow stem cell graft (page 1, last paragraph) in Remarks, (p4, para 2).
New claim 10 requires that the GVHD is skin or liver GVHD (see page 3, lines 8-10). In contrast, Gao and Varelias only observe differences in MAIT cells in gut GVHD. Gao actually teaches that the number of MAIT cells was not different between no GVHD and skin GVHD patients (Remarks, p4, para 2).
Response to Arguments
Applicant's arguments filed 4/15/2026 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s argument (i) is not persuasive because applicant argues a single reference of Magnani alone whereas the rejection is based on Magnani et al. in view of Gao et al. and Varelias et al. In particular, Varelias et al. teach MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT) in the Abstract. Major target organs include the gastrointestinal (GI) tract, liver, and skin, all of which represent tissues with extensive environmental interfaces (p1919, col 1, Introduction). Varelias et al. teach recipient MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B). Varelias et al. further teach in order to regulate disease during GVHD, recipient MAIT cells must survive conditioning (reading on maintaining an effective amount of MAIT cells) and the incoming alloreactive donor graft in the early transplant period (p1924, col 2, para 1). Thus, one of ordinary skill in the art would have found it obvious to administer exogenous MAIT cells to control (prevent or treat) GVHD in a patient receiving bone marrow transplantation (BMT) by maintaining an effective amount MAIT cells in the target organs of GVHD such as gastrointestinal (GI) tract, liver, and skin. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144(I).
Applicant’s argument (ii) is not persuasive because applicant argues a single reference of Gao alone whereas the rejection is based on Magnani et al. in view of Gao et al. and Varelias et al. Varelias et al. teach recipient MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B). Varelias et al. further teach in order to regulate disease during GVHD, recipient MAIT cells must survive conditioning (reading on maintaining an effective amount of MAIT cells) and the incoming alloreactive donor graft in the early transplant period (p1924, col 2, para 1). Thus, one of ordinary skill in the art would have found it obvious to administer exogenous MAIT cells to control (prevent or treat) GVHD in a patient receiving bone marrow transplantation (BMT) by maintaining an effective amount MAIT cells in the target organs of GVHD such as gastrointestinal (GI) tract, liver, and skin. See response to argument (i) above.
Applicant’s argument (iii) is not persuasive because applicant narrowly interprets Varelias’s teachings. Varelias et al. teach recipient MAIT cells abrogate GVHD induced by allogeneic stem cell transplantation and further suggest any effect on survival was due to the absence of MAIT cells alone (p1923, col 1, last para to col 2, last line 4-5; Fig 1 A and B). Varelias et al. further teach in order to regulate disease during GVHD, recipient MAIT cells must survive conditioning (reading on maintaining an effective amount of MAIT cells) and the incoming alloreactive donor graft in the early transplant period (p1924, col 2, para 1). Thus, one of ordinary skill in the art would have found it obvious to administer exogenous MAIT cells to control (prevent or treat) GVHD in a patient receiving bone marrow transplantation (BMT) by maintaining an effective amount MAIT cells in the target organs of GVHD such as gastrointestinal (GI) tract, liver, and skin. See MPEP 2144.01 "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). A person of ordinary skill in the art is well defined as a person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at ___, 82 USPQ2d at 1396. See MPEP 2141.03 (I).
Applicant’s argument (iv) is not persuasive because Varelias et al. teach in order to regulate disease during GVHD, recipient MAIT cells must survive conditioning (reading on maintaining an effective amount of MAIT cells) and the incoming alloreactive donor graft in the early transplant period (p1924, col 2, para 1). The insufficient amount of survived MAIT cells in patients after bone marrow transplant would not be able to control or prevent GVHD development and each recipients may need different effective amount of MAIT cells to control or prevent GVHD. Thus, one of ordinary skill in the art would have found it obvious to administer an “effective amount” exogenous MAIT cells to a patient with GVHD due to insufficient amount MAIT cells in the GVHD patient even though the patient with GVHD has similar amount MAIT cells compared to other patients without GVHD after bone marrow transplant.
Applicant’s argument (v) is not persuasive because The insufficient amount of survived MAIT cells in patients after bone marrow transplant would not be able to control or prevent GVHD development and each recipients may need different effective amount of MAIT cells to control or prevent GVHD as described in response to argument (iv). Thus, one of ordinary skill in the art would have found it obvious to administer an “effective amount” exogenous MAIT cells to a patient with GVHD due to insufficient amount MAIT cells in the GVHD patient even though the patient with GVHD has similar amount MAIT cells compared to other patients without GVHD after bone marrow transplant.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 17/414,689 (the ‘689 application, 1/29/2026) in view of Magnani et al. (WO 2017/079,215 A1, cited 1/16/2026) in view of Gao et al. (Blood. (2019) 134 (Supplement 1): 2001, cited 1/16/2026) and Varelias et al. (J Clin Invest. 2018;128(5):1919-1936, cited in IDS 6/9/2023).
Claim 1 of the ‘689 application disclosed a method of administering mucosa
associated invariant T (MAIT) cells to a subject with cancer in need.
Claim 2 of the ‘689 application disclosed the cancer is a hematologic malignancy.
Claims 1-2 of the ‘689 application do not teach administering a therapeutically effective amount of a population of MAIT cells to control Graft Versus Host Disease (GVHD) for hematologic malignancy therapy in the patient after transplantation.
The relevancy of Magnani et al. in view of Gao et al. and Varelias et al. as applied to claims 1-10 above not repeated here.
Because Magnani et al. in view of Gao et al. and Varelias et al. teach beneficial administration of an effective amount of MAIT cells to control Graft Versus Host Disease (GVHD) in the patient after transplantation for hematologic malignancy therapy, one of ordinary skill in the art would have found it obvious to combine an effective amount of mucosa associated invariant T (MAIT) cells taught by claims 1-2 of the ‘689 application for hematologic malignancy therapy with Magnani et al. in view of Gao et al. and Varelias et al. for the same purpose of hematologic malignancy therapy.
Thus, claims 1-2 of the ‘689 application in view of Magnani et al., Gao et al. and Varelias et al. are obvious to the instant claims 1-10.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 4/15/2026 have been fully considered but they are not persuasive. See response to arguments above.
Conclusion
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.
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/J.L/Examiner, Art Unit 1658
07-June-2026
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
Prosecution Insights