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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 2, 2026 has been entered. No claim amendments were submitted with this submission.
Claims 1, 7-8, 10, 14, 16, 20-22, 24, 27, 36-37, 44-46 and 51-55 are pending in the application. Claims 7-8, 36-37, 44-46 and 51 remain withdrawn from consideration, pursuant to the Restriction Requirement mailed June 27, 2022.
Claims 1, 10, 14, 16, 20-22, 24, 27, and 52-55 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated August 6, 2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 29, 2025 was filed after the mailing date of the first Office action on the merits on December 1, 2022. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claims 1, 10, 14, 16, 21, 24, 27, and 52-55 are rejected under 35 U.S.C. 103 as being unpatentable over Miller (Blood. 2005 Apr 15;105(8):3051-7), Chan (J Immunol. 2007 Jul 1;179(1):89-94), Cooper (Trends Immunol. 2001 Nov;22(11):633-40), Terunuma (US20160075996A1), and Anjos (US20180169147A1).
Miller teaches a method of treating cancer, comprising preconditioning patients with either intravenous cyclophosphamide at a dose of 750 mg/m2 or intravenous fludarabine at a dose of 25 mg/m2 for 5 days prior to administration of NK cells (page 3052, left column, third paragraph). Miller also teaches that patients receiving this treatment did not experience graft-versus-host disease (page 3052, right column, second paragraph).
Miller further teaches administration of IL-2 to the above patients (page 3052, right column, second paragraph). Miller also teaches that IL-2 is useful to activate NK cells (page 3051, right column, second paragraph).
Miller further teaches that NK cells may be KIR (i.e., HLA) mismatches and allogeneic to the patient (page 3052, left column, first paragraph, also see abstract), which is pertinent to claim 24.
Miller further teaches that the use of low-dose immunosuppression does not result in NK cell expansion in vivo, and that in patients receiving fludarabine, levels of IL-15, which correlates with in vivo haploidentical NK-cell expansion, had returned to baseline by day 7 (page 3056, left column, first paragraph, and Figure 6), which is pertinent to claim 55.
Miller further teaches that the above method is capable of improved treatment of acute myeloid leukemia (page 3056, right column, third paragraph), which is pertinent to claim 54.
However, Miller does not teach administration of activated gamma-delta T cells, or that the NK cells are contacted with a soluble fibroblast growth factor receptor 1 (SFGFR1).
Chan teaches that CD56 on natural killer (NK) cells is a ligand for fibroblast growth factor receptor (FGFR)1 that is constitutively expressed on fibroblasts in both membrane-bound and secreted (i.e. soluble) forms (page 89, left column). Chan further teaches that coculture of NK cells with synovial fibroblasts results in NK cells with a CD56dim phenotype with increased cytotoxicity against K562 cancer cells (Figure 2B and page 90, right column). Chan elaborates that it is the interaction between CD56 and FGFR1 which is responsible for this change in phenotype (page 93, left column, second paragraph).
Cooper teaches that NK cells can be activated by IL-2 (page 635, right column, third paragraph). Cooper further teaches that CD56bright NK cells proliferate in the presence of IL-2, whereas CD56dim cells do not (page 634, right column, last paragraph through page 635, left column, first paragraph).
Terunuma teaches that activated NK cells are useful in the treatment of cancer, viral infection, or bacterial infection, including HIV (para. 0146-0150), which is pertinent to claims 52 and 53. As HIV is a retrovirus according to Applicant's specification at paragraph 0137, Terunuma also inherently teaches the subject matter of claim 27.
Terunuma further teaches that activation of NK cells can be determined by examining cytotoxic activity against a leukemia cell line K562.
Anjos teaches a method of treating an infection comprising administering an effective amount of activated gamma-delta T cells (para. 0109). Anjos further teaches that the infection may be bacterial or viral, and may also include HIV (para. 0110).
Anjos also teaches that expanded gamma-delta T cells increase the expression of NK cell-associated activating/cytotoxicity receptors, such as NKp30, NKp44, NKG2D, DNAM-1 and 2B4 (para. 0217).
Anjos further teaches culturing gamma-delta T cells in a culture medium comprising cytokines such as IL-2 (para. 0009 and 0013).
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 Miller, Chan, Cooper, Terunuma, and Anjos to arrive at the claimed invention. The prior art teaches that cells may be activated by either IL-2 (Miller) or by FGFR1 (Chan), both of which will increase cytotoxic activity. Both IL-2 and FGFR1 were known to be useful for the same purpose.
Additionally, as Chan teaches that NK cells treated with soluble FGFR1 are pushed to a CD56dim phenotype, there would be fewer regulatory CD56bright cells in the combination. This would naturally solve the problem of presence of over-proliferation of CD56bright cells. The use of FGFR1 to produce a more cytotoxic CD56dim population, as taught by Chan, would solve this problem.
A person of ordinary skill in the art would be able to combine the teachings of Miller, Chan, Cooper, and Terunuma by known methods, resulting in a combination that would predictably activate NK cells, which each component in the combination performing its known, usual function.
Likewise, the prior art also teaches that both NK cells and gamma-delta T cells were known to be useful in the treatment of HIV, according to Terunuma and Anjos, respectively. It is therefore prima facie obvious to combine these therapies to arrive at a composition which would also predictably treat HIV.
Applicant argues that the cited references do not teach every aspect of the claims; specifically, the cited references do not use non-HLA matched cells, and the cited references do not teach temporary lymphosuppression, the killing off of NK cells after 4-15 days, and a vaccine effect from the NK cells. Applicant further argues that Miller focuses on depletion of CD3+ cells, which includes gamma-delta T cells that are required for the claimed invention to function, and would make it impossible to combine the teachings of Anjos, since Anjos requires the presence of CD3+ T cells to function. Applicant further argues that neither Miller nor Anjos recognizes the advantage of allogeneic cells having a short life span, yet are able to create a vaccine effect.
Applicant's arguments have been considered fully but are not found to be persuasive.
Miller teaches that the cells used are allogeneic to the patient (page 3052, left column, first paragraph). Applicant's experiments also rely on allogeneic cells.
Applicant's specification does not include a definition for cells that are "not HLA-matched with the patient" Under the broadest reasonable interpretation of this term, "not-HLA matched" is interpreted to mean any level of mismatch in HLA loci between donor and patient.
The haploidentical cells of Miller matches only one set of HLA markers, a 50% match and a 50% mismatch (see, for example, Sugita (Int J Hematol. 2019 Jul;110(1):30-38), cited previously). Therefore, the cells of Miller are not HLA-matched with the patient.
Miller also teaches that lower doses of immunosuppression prevent in vivo NK cell expansion (page 3056, left column, first paragraph). Miller also teaches that after 14 days post-transfusion, infused NK cells were not detected in patients with lower doses of immunosuppression (Figure 1 and abstract: "Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells."). This indicates that the lack of persistence of the NK cells post-transfusion was also known in the art.
With regards to Applicant's arguments that Miller does not teach that preconditioning temporarily suppresses the patient's immune system, the claimed method does not specify how this is to be accomplished. In the interview with the Examiner on October 7, 2024, Applicant stated that temporary lymphosuppression may be accomplished by any of the methods described in Tables 1-5 of the instant specification on page 45. This includes 25 mg/m²/day IV fludarabine, which is identical to the method of Miller. Miller therefore inherently teaches this claim limitation.
In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). Also see In re Spada, 911 F.2d 705, 709, 15 USPQ2d and MPEP 2112(V). The method of preconditioning taught by Miller is within the scope of those performed by Applicant's specification, and would result in identical functional properties when performed. The temporary lymphosuppression is a natural result of the prior art. Therefore, the method performed by Miller anticipates this claim limitation. If Applicant intends a specific method of temporary lymphosupression, such method steps must be specifically recited in the claims.
With regards to Applicant's arguments that the prior art does not teach a vaccine effect, this appears to be a latent property or advantage of performing the known method steps. Mere recognition of latent properties in the prior art docs not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). The fact that Applicant 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. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). MPEP 2145(II).
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). MPEP 2112(II).
With regards that the use of gamma delta T cells in contrast to Miller's use of depletion of CD3+ cells, the lower dose of lymphosuppression performed by Miller would result in only a transient suppression of T cells within the patient, as evidenced supra. While the NK product itself may be purified of T cells, the patient's own body was not completely lymphodepleted. Therefore, the teachings of Anjos are therefore combinable with Milller.
This rejection is therefore maintained.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Miller, Chan, Cooper, Terunuma, and Anjos as applied to claim 1 above, and further in view of Tavel (J Interferon Cytokine Res. 2010 Jul;30(7):46 1-4).
The teachings of Miller, Chan, Cooper, Terunuma, and Anjos as they pertain to claim 1 have been discussed supra. However, Miller, Chan, Cooper, Terunuma, and Anjos do not teach administration of interferon alpha.
Tavel teaches that interferon-alpha at dosages between 2.5 million IU and 35 million IU significantly decreases levels of HIV (page 464, left column, first paragraph and Figure 1). Given an average surface area of a patient of 1.8 m2, this would result in a dosage well within the limits recited in claim 20.
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 Miller, Chan, Cooper, Terunuma, Anjos, and Tavel to arrive at the claimed invention. As stated above, methods of treating HIV with combinations of NK cells activated by IL-2 and sFGFR1 and gamma-delta T cells were known in the art. Since Tavel teaches that interferon alpha is also useful in treating HIV, it is prima facie obvious to combine the two treatments which are known for the same purpose. MPEP 2144.06. A person of ordinary skill could readily envision combining the method of treatment according to Miller, Chan, Cooper, Terunuma, and Anjos with the interferon alpha of Tavel by known methods, which each component in the combination performing its known, usual function, and the combination would have yielded nothing more than predictable results.
Applicant argues that the teachings of Tavel does not remedy the alleged deficiencies of Miller, Chan, Cooper, Terunuma, and Anjos. This argument is not persuasive, for reasons described supra.
This rejection is therefore maintained.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Miller, Chan, Cooper, Terunuma, and Anjos as applied to claim 1 above, and further in view of O'Brien (J Acquir Immune Defic Syndr. 2013 July 1; 63(3): 280-288).
The teachings of Miller, Chan, Cooper, Terunuma, and Anjos as they pertain to claim 1 have been discussed supra. However, Miller, Chan, Cooper, Terunuma, and Anjos do not teach administration of a COX-2 inhibitor.
O'Brien teaches that aspirin is useful in treating HIV (abstract and page 8). According to Applicant's specification at paragraph 0088, aspirin is a COX-2 inhibitor.
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 Miller, Chan, Cooper, Terunuma, Anjos, and O'Brien to arrive at the claimed invention. As stated above, methods of treating HIV with combinations of NK cells activated by IL-2 and sFGFR1 and gamma-delta T cells were known in the art. Since O'Brien teaches that aspirin is also useful in treating HIV, it is prima facie obvious to combine the two treatments which are known for the same purpose. MPEP 2144.06. A person of ordinary skill could readily envision combining the method of treatment according to Miller, Chan, Cooper, Terunuma, and Anjos with the aspirin of O'Brien by known methods, which each component in the combination performing its known, usual function, and the combination would have yielded nothing more than predictable results.
Applicant argues that the teachings of O'Brien does not remedy the alleged deficiencies of Miller, Chan, Cooper, Terunuma, and Anjos. This argument is not persuasive, for reasons described supra.
This rejection is therefore maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. National Marrow Donor Program (Retrieved from the Internet at https://www.nmdp.org/patients/understanding-transplant/haploidentical-transplant on 9 February 2026) teaches that a haploidentical donor shares exactly half of their human leukocyte antigen (HLA) markers with the patient (page 1).
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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/PETER JOHANSEN/Examiner, Art Unit 1642