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 .
Restriction/Election
Applicant’s election without traverse of the following:
Species A: MAIT cells and memory B cells,
Species B: nogapendekin alfa inbakicept (N-803) alone, and
Species C: a cytokine
in the reply filed on 20 July 2026 is acknowledged.
Status of the Claims
Claims 30-51 are currently under consideration.
Claim Objections
Claims 30, 34, 28, and 45 are objected to because of the following informalities:
Claims 30, 38, and 45 recite, “isolating from a patient derived peripheral” in line 3 and should recite, “isolating patient derived peripheral”.
Claim 30 recites “for into a composition for” in line 7 and should recite, “into a composition for”.
Claim 34 recites “further comprising a step of further stimulating” in line 1 and should recite, “further comprising a step of stimulating”.
Claims 30, 38, and 45 recite “administration to the patient” in the last line and should recite, “administration to the patient in need thereof” for consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34, 39-43, and 45-51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 34 is drawn to wherein the method further comprises “further stimulating” the cellular subsets; however, the independent claim 30 is drawn to isolating, treating and formulating. It is unclear how the method can “further stimulate” when no initial stimulation step is recited.
Claim 35 is drawn to wherein the “MAIT cells and/or the memory B cells” are exposed to the N-803. Given the independent claim 30 recites, “treating the combined MAIT cells and the memory B cells” it is unclear how the cellular subsets could be individually (i.e., “or”) treated. In addition, claim 35 is drawn to cells that are “exposed” to the N-803. It is unclear if “exposed” is meant to be synonymous with “treated” as recited in claim 30 or alternatively a broader scope.
Claim 39 is drawn to a minimum number of MAIT cells and memory B cells are isolated; however, independent claim 38 isolates only MAIT cells. Therefore, it is unclear if the composition further comprises (i.e., a second isolation step) isolating memory B cells, or alternatively, the memory B cells are isolated from a different source.
Claims 40-43 recite the limitation "the memory B cells" in lines 1-2. There is insufficient antecedent basis for this limitation in the claims.
Claim 42 is drawn to wherein the method further comprises “further stimulating” the cellular subsets; however, the independent claim 38 is drawn to isolating, treating and formulating. It is unclear how the method can “further stimulate” when no initial stimulation step is recited.
Claim 43 is drawn to cells that are “exposed” to the N-803. It is unclear if “exposed” is meant to be synonymous with “treated” as recited in claim 30 or alternatively a broader scope.
Claim 45 is drawn to “TxM”. It is unclear what structures are within the scope of “TxM”.
Claim 49 is drawn to wherein the method further comprises “further stimulating” the cellular subsets; however, the independent claim 45 is drawn to isolating, treating and formulating. It is unclear how the method can “further stimulate” when no initial stimulation step is recited.
Claim Rejections - 35 USC § 112(d)
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.
Claims 33 and 48 are 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.
Claim 33 is drawn to wherein the MAIT and memory B cells are combined before treatment with N-803. Independent claim 30 recites “treating the combined MAIT cells and memory B cells”; therefore, claim 33 does not further limit claim 30.
Claim 48 is drawn to wherein the MAIT cells are treated with N-803 or TxM. Independent claim 45 recites treating the MAIT cells with N-803 or TxM (see claim 45 lines 5-6); therefore, claim 48 does not further limit claim 45.
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.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 38, 40, 42, and 44 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102a)(2) as being anticipated by US2019/0300591 (referred to herein as Wong) as evidenced by Ussher (see Ussher et al. (2014) CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 44: 195–203), Millipore (see Millipore (2019) Human PBMC Isolation and Counting Using the Scepter™ 2.0 Handheld Automated Cell Counter. Lit. No. MS_AN3115EN Ver. 2.0), and Puckrin (see Puckrin (2022) What are PBMCs? Everything you need to know about peripheral blood mononuclear cells. REPROCELL).
Claim 38 is drawn to a method of preparing an immunotherapeutic composition for administration to a patient in need thereof, the method comprising: isolating from a patient-derived peripheral blood mononuclear cell fraction mucosal- associated invariant T (MAIT) cells; treating the MAIT cells with nogapendekin alfa inbakicept (N-803); and formulating the treated MAIT cells into a composition for administration to the patient. It is noted the recitation of “for administration to a patient in need thereof” in the preamble is an intended use.
Wong discloses an important therapeutic approach for treating cancer or infectious disease relies on augmenting immune cell activity against the disease cells. One such strategy includes stimulating immune cells ex vivo followed by adoptive transfer and/or directly increasing immune cell levels or activity in vivo in the patient (see Wong pg. 29 para [0287]). Specifically, Wong demonstrates that CD8+ T cells isolated from two healthy donors were cultured with “hIL7/IL21/TxM or the combination of individual recombinant IL-7, IL-21, and ALT-803 for 2-5 days” (see Wong pg. 32 para [0309]). Stimulation with hIL7/IL21/TxM, combination ALT-803, IL7, and IL-21, or ALT-803 alone resulted in 4.6, 3.9, and 2.5, respectively, fold increases in CD8+ T cells (see Wong pg. 33 para [0311]). It is noted ALT-803 is an alternative name for N-803 (see Wong pg. 15 para [0181]). Isolation of CD8+ T cells as disclosed by Wong encompasses MAIT cells given MAIT cells are CD8+ as evidenced by Ussher (see Ussher abstract, pg. 195, 1st para). In addition, the CD8+ T cells are cultured in tissue culture medium (i.e., physiologically compatible medium) (see Wong pg. 13 para [0169]) thereby arriving at the “formulating” step recited in claim 38. Therefore, Wong anticipates isolating MAIT cells from the PBMC samples of two healthy donors, incubating with either ALT-803 (i.e., N-803), and formulating the cells for adoptive transfer into a subject. This is pertinent to instant claim 38 and 44.
Regarding claim 40, T cells isolated from PBMC samples would inherently comprise “expanded MAIT and/or B cells” as these cells have been exposed to in vivo factors.
Regarding claim 42, Wong discloses the combination of ALT-803 with IL-7 and IL-21 thereby arriving at the instantly claimed “further stimulating” with “a cytokine”.
Claims 38, 40, 43, and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Connell (see Ellis-Connell as cited on the IDS received 02/24/2026 pg. 2 reference 9) as evidenced by Ussher (see Ussher et al. (2014) CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 44: 195–203), Millipore (see Millipore (2019) Human PBMC Isolation and Counting Using the Scepter™ 2.0 Handheld Automated Cell Counter. Lit. No. MS_AN3115EN Ver. 2.0), and Puckrin (see Puckrin (2022) What are PBMCs? Everything you need to know about peripheral blood mononuclear cells. REPROCELL).
Claim 38 is drawn to a method of preparing an immunotherapeutic composition for administration to a patient in need thereof, the method comprising: isolating from a patient-derived peripheral blood mononuclear cell fraction mucosal- associated invariant T (MAIT) cells; treating the MAIT cells with nogapendekin alfa inbakicept (N-803); and formulating the treated MAIT cells into a composition for administration to the patient. It is noted the recitation of “for administration to a patient in need thereof” in the preamble is an intended use.
Connell discloses N-803 activates MAIT cells in vitro and increases their ability to produce IFN-γ in response to bacterial stimulation (see Connell abstract). N-803 alters the phenotype and functions of MAIT cells which Connell suggest can be combined with other strategies to combat bacterial infections (see Connell abstract, sentence spanning pgs. 13-14). Specifically, Connell used both PBMC and isolated TCRVα7.2+ cells treated for 24 hours with increasing concentrations of N-803 which led to dose dependent increases in CD69+ MAIT cells (see Connell pg. 2, 4th para figure 1). Connell discloses, “future studies could investigate whether N-803 boosted MAIT cells could have a positive impact on the outcome of an Mtb challenge, most likely as an adjuvant in combination with other MAIT-directed vaccines” (see Connell pg. 14, 3rd para). In addition, Connell performs flow cytometry using cells supplemented with PBS- FBS (i.e., formulated for infusion or injection). Therefore, Connell anticipates isolating MAIT cells, treating with N-803 for 24 hours, and formulating the MAIT cells for administration to a subject in need thereof (i.e., as an adjuvant). This is pertinent to instant claims 38, 43, and 44.
Regarding claim 40, T cells isolated from PBMC samples would inherently comprise “expanded MAIT and/or B cells” as these cells have been exposed to in vivo factors.
Claim Rejections - 35 USC § 103
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.
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 should 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 38, 39, 40, and 42-51 are rejected under 35 U.S.C. 103 as obvious over US2019/0300591 (referred to herein as Wong) as evidenced by Ussher (see Ussher et al. (2014) CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 44: 195–203), Millipore (see Millipore (2019) Human PBMC Isolation and Counting Using the Scepter™ 2.0 Handheld Automated Cell Counter. Lit. No. MS_AN3115EN Ver. 2.0), and Puckrin (see Puckrin (2022) What are PBMCs? Everything you need to know about peripheral blood mononuclear cells. REPROCELL).
Claim 38 is drawn to a method comp of preparing an immunotherapeutic composition for administration to a patient in need thereof, the method comprising: isolating from a patient-derived peripheral blood mononuclear cell fraction mucosal- associated invariant T (MAIT) cells; treating the MAIT cells with nogapendekin alfa inbakicept (N-803); and formulating the treated MAIT cells into a composition for administration to the patient. Claim 45 is broader in the limitations of the treatment step (i.e., includes cytokines or alternatively TxM). It is noted the recitation of “for administration to a patient in need thereof” in the preamble is an intended use.
Wong discloses an important therapeutic approach for treating cancer or infectious disease relies on augmenting immune cell activity against the disease cells. One such strategy includes stimulating immune cells ex vivo followed by adoptive transfer and/or directly increasing immune cell levels or activity in vivo in the patient (see Wong pg. 29 para [0287]). Specifically, Wong demonstrates that CD8+ T cells isolated from two healthy donors were cultured with “hIL7/IL21/TxM or the combination of individual recombinant IL-7, IL-21, and ALT-803 for 2-5 days” (see Wong pg. 32 para [0309]). Stimulation with hIL7/IL21/TxM, combination ALT-803, IL7, and IL-21, or ALT-803 alone resulted in 4.6, 3.9, and 2.5, respectively, fold increases in CD8+ T cells (see Wong pg. 33 para [0311]). It is noted ALT-803 is an alternative name for N-803 (see Wong pg. 15 para [0181]). Isolation of CD8+ T cells as disclosed by Wong encompasses MAIT cells given MAIT cells are CD8+ as evidenced by Ussher (see Ussher abstract, pg. 195, 1st para). Therefore, Wong anticipates isolating MAIT cells from the PBMC samples of two healthy donors, incubating with either ALT-803 (i.e., N-803), and formulating the cells for adoptive transfer into a subject. This is pertinent to instant claim 38.
Regarding claim 42, Wong discloses the combination of ALT-803 with IL-7 and IL-21 thereby arriving at the instantly claimed “further stimulating” with “a cytokine”.
Alternatively, Wong also discloses exemplary methods for enhancing immune function include inducing proliferation and activation of NK and T cells via signaling of the IL-15R, IL-12R and IL-18R by the soluble fusion protein complex (see Wong pg. para [0022]). Wong demonstrates a hIL18/IL12/TxM fusion protein activates NK cells (see Wong pg. para [0144]). Taken together Wong teaches targeting IL-15R, IL-12R, and IL-18 is an exemplary method for enhancing immune function in T cells and subsequently achieves that enhancement using a hIL18/IL12/TxM fusion protein. Therefore, the ordinary artisan would have found it obvious to combine the N-803 (alone) for stimulating T cells as disclosed by Wong with the hIL18/IL12/TxM fusion protein as also disclosed by Wong to yield predictable results (i.e., teaches/demonstrates N-803 and the fusion protein enhance immune function). This is pertinent to claims 45 and 48.
Regarding claims 39 and 46, given 1mL of PBMC comprises 300-1200 x 103 T cells and 50-200 x 103 B cells as evidenced by Puckrin (see Puckrin pg. 2 Table 1), MAIT cells comprise up to 5% of T cells as evidenced by Ussher (see Ussher pg. 195, Introduction 1st para), and PBMC samples are typically 10mL as evidenced by Millipore (see Millipore pg. 2, 1st col. 1st para) isolating T cells and B cells from a PBMC sample would comprise at least 106 MAIT and B cells. In addition, Wong discloses cell therapies of the invention comprise administering activated T cells in the amount of 1x106 (see Wong pg. 3 para [0031]).
Regarding claims 40 and 47, T cells isolated from PBMC samples would inherently comprise “expanded MAIT and/or B cells” as these cells have been exposed to in vivo factors.
Regarding claim 49, Wong discloses the combination of ALT-803 with IL-7 and IL-21. Therefore, treating T cells with a combination of N-803, IL-7, and IL-21 (see Wong pg. 33 para [0311]) with IL-12/IL-18/TxM (see Wong pgs. 33-34 para [0316]) is with the scope of “further stimulating” with “a cytokine”.
Regarding claim 43, Wong incubates T cells with the individual cytokines and the hIL7/IL21/TxM “overnight” to demonstrate the hIL7/IL21/TxM had similar activity to the individual cytokines (see Wong pg. 32 para [0306-0307]). Therefore, the ordinary artisan would have incubated the T cells “overnight” with N-803 as this was an effective duration for activation.
Regarding claim 50, Wong incubates T cells with the individual cytokines and the hIL7/IL21/TxM “overnight” to demonstrate the hIL7/IL21/TxM had similar activity to the individual cytokines (see Wong pg. 32 para [0306-0307]).
Regarding claims 44 and 51, Wong discloses the pharmaceutical compositions can be formulated for injection (see Wong pg. 22 para [0224]).
Claims 30-44 are rejected under 35 U.S.C. 103 as obvious over Connell (see Ellis-Connell as cited on the IDS received 02/24/2026 pg. 2 reference 9) and Rezk (see Rezk (2020) B Cells selectively in duce CD8+ MAIT cell effector functions: Implications for multiple sclerosis. Multiple Sclerosis: Immunology and Basic Science 1, 94 (15 supplement) 5355) as evidenced by Ussher (see Ussher et al. (2014) CD161++CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 44: 195–203), Millipore (see Millipore (2019) Human PBMC Isolation and Counting Using the Scepter™ 2.0 Handheld Automated Cell Counter. Lit. No. MS_AN3115EN Ver. 2.0), and Puckrin (see Puckrin (2022) What are PBMCs? Everything you need to know about peripheral blood mononuclear cells. REPROCELL).
Claim 30 is drawn to treating a population of MAIT and B cells with N-803 and formulating the cells for administration to the patient.
Connell discloses N-803 activates MAIT cells in vitro and increases their ability to produce IFN-γ in response to bacterial stimulation (see Connell abstract). N-803 alters the phenotype and functions of MAIT cells which Connell suggest can be combined with other strategies to combat bacterial infections (see Connell abstract, sentence spanning pgs. 13-14). Specifically, Connell used both PBMC and isolated TCRVα7.2+ cells (i.e., MAIT cells) treated for 24 hours with increasing concentrations of N-803 which led to dose dependent increases in CD69+ MAIT cells (see Connell pg. 2, 4th para figure 1). Connell discloses, “Therefore, one possibility would be to use N-803 as an adjuvant during 5 OPRU mediated MAIT cell expansion to see if this could further reduce the bacterial burden. Another possibility would be to use N-803 in combination with BCG vaccination, which is already used to prevent TB disease globally. BCG vaccination can activate MAIT cells in vivo; therefore, BCG1N-803 treatment could further improve MAIT function against mycobacteria” (see Connell pg. 14, 3rd para). Connell also discloses the treated MAIT cells were suspended in RPMI media and FBS (see Connell pg. 16, 4th para), thereby arriving at the claimed “formulating” step recited in claim 30 and 38.
Rezk demonstrates B cells suppress proliferation of non-MAIT CD8+ T cells “yet significantly promote MAIT cell expansion in vitro” (see Rezk pg. 2, 1st para, emphasis added). Rezk cultures differentially activated B cells and CD8 T cell subsets in vitro using purified cell subsets from healthy controls (see Rezk pg. 1 last para). It is noted that whole B cell isolation from PBMC necessarily comprises memory B cells.
Therefore, the ordinary artisan would combine the N-803 activation and expansion of MAIT cells for use in the treatment of infection as taught by Connell with the B cell activation of MAIT cells as taught by Rezk given these are art recognized equivalents for the same purpose (i.e., methods of activating MAIT cells) to yield predictable results. There is a reasonable expectation of success given both N-803 and B cells (i.e., comprises memory B cells) are effective in activating and expanding MAIT cells. This is pertinent to instant claims 30, 38, and 39.
Regarding claim 31 and 39, given 1mL of PBMC comprises 300-1200 x 103 T cells and 50-200 x 103 B cells as evidenced by Puckrin (see Puckrin pg. 2 Table 1), MAIT cells comprise up to 5% of T cells as evidenced by Ussher (see Ussher pg. 195, Introduction 1st para), and PBMC samples are typically 10mL as evidenced by Millipore (see Millipore pg. 2, 1st col. 1st para) isolating T cells and B cells from a PBMC sample would comprise at least 106 MAIT and 106 B cells.
Regarding claims 32 and 40, Connell discloses purified MAIT cell cultures and the PBMC samples would inherently comprise “expanded MAIT and/or B cells” as these cells have been exposed to in vivo factors.
Regarding claims 33 and 41, the ordinary artisan would find it obvious to combine the MAIT cells and B cells before treatment with N-803 given both the B cells and N-803 are stimulants for MAIT cells and there is a limited number of combinations (i.e., same time, before, or after addition of the other).
Regarding claims 34 and 42, Connell teaches MAIT cells can be activated with cytokines such as IL-7, IL-12, IL-18, and IL-15 and that N-803 indirectly activates MAIT cells via IL-18R (see Connell pg. 1 para, pg. 2, 4-5th para). Therefore, the ordinary artisan would “further stimulate” the MAIT cells with an additional cytokine, (e.g., IL-18) given N-803 indirectly increases IL-18 production from monocytes which in turn activate MAIT cells via IL-18R and IL-18 is a known stimulant of MAIT cells.
Regarding claims 35 and 43, Connel discloses the MAIT cells were incubated for 24 hours with N-803 (see Connell pg. 2, 4th para).
Regarding claims 36 and 44, Connell suggests the N-803 treated MAIT cells can be administered as a vaccine (i.e., injection) adjuvant (see Connell pg. 14, 3rd para) as well as suspension in RPMI media with FBS (see Connell pg. 16, 4th para).
Regarding claim 37, Connell teaches using the N-803 treated MAIT cells could be used to target infection (see Connell pg. 14, 3rd para).
Conclusion
No claim allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HILARY ANN PETRASH whose telephone number is (703)756-4630. The examiner can normally be reached Monday-Friday 8:30-4:30 EST.
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/H.A.P./Examiner, Art Unit 1644
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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