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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-5, 7, 10-11, and 23-24, in the reply filed on June 2, 2026 is acknowledged. Claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-5, 7, 10-11, and 23-24 are under consideration in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of PCT/US2022/018290, which claims benefit to U.S. Provisional Application No. 63/156,269, filed March 3, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 30, 2024, March 5, 2025, April 25, 2025, June 24, 2025, August 20, 2025, January 28, 2026, and June 2, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figure 15B) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 1-5, 7, 10-11, and 23-24 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 1 is comprised of steps “contacting the plurality of mononuclear cells with hydrocortisone and N-802” and “incubating the plurality of mononuclear cells in the presence of the hydrocortisone and the N-803”. It is unclear if these are two distinct steps or whether the incubation simply occurs after the cells have already been contacted with the drug. As such, one of ordinary skill in the art could not determine the scope of the claim with reasonable certainty; the specification provides no further clarity. This distinction is important, because claim 2 states that “the plurality of mononuclear cells are cryopreserved before the step of incubating”; can the cells be frozen after contact with hydrocortisone and N-803 but prior to the incubation with hydrocortisone and N-803? In the interest of compact prosecution, the claim steps of contacting and incubating will be interpreted to be one step of incubating.
Claim 2-5, 7, 10-11, and 23-24 are included in this rejection for being dependent of a rejected base claim and for failing to cure the indefiniteness.
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 1-5, 7, 10, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO2021006876A1, published January 14, 2021 (“Duggal”; see IDS from 6/30/2024) in view of Moustaki et al, published June 26, 2011 (see IDS from 3/5/2025).
The claims are directed to a method of generating M-CENK cell, comprising the steps of obtaining mononuclear cells and contacting and incubating them with hydrocortisone and the IL-15 agonist N-803 to enrich for NK cells and inducing enriched NK cells to generate M-CENK cells with cytokine composition comprising IL-12, IL-15, or IL-18 or analogs thereof.
Regarding claims 1 and 23-24, Duggal teaches a method of generating cytokine induced memory like NK cells (abstract), comprising the steps of expanding NK cells and inducing expanded NK cells with a mixture of cytokines to form the cells (pg 3, para 10). The expansion of NK cells is performed with N-803 and the activation is performed with IL-12/IL-15/IL-18 or an IL-18/IL-12-TxM fusion protein complex (pg 3, para 10).
Duggal teaches that the biological fluids from which the NK cells are generated are frozen (pg 10, para 47), as in cryopreservation of the sample before the incubation step of instant claim 2.
Duggal teaches that the separated mononuclear cells are washed and resuspended in activation medium comprising N-803 [0043], as in instant claim 3.
The cells of Duggal are cultured for 3 weeks [0044], as in the 21 days of instant claim 4. At this time point, the culture contains 85% NK cells [0044], as in instant claim 5.
According to Duggal, the cytokine stimulation of enriched NK cells is performed for a period of between 4 and 24 hours [0042], which overlaps with the induction time of instant claim 7.
Duggal teaches that the CIML NK cells can be administered to an individual as a therapeutic (pg pg 7, para 20), as in the limitations of claim 10 drawn to collecting and formulating the NK cells for infusion.
Duggal does not teach a method comprising administration of N-803 with hydrocortisone.
Moustaki teaches a method to generate expanded NK cells from isolated peripheral-blood mononuclear cells (pg 1684, column 2, “Isolation of peripheral blood CD56+ cells”), the method comprising combining hydrocortisone and IL-15 treatments, thereby inducing an increase in the proliferation of peripheral blood NK cells, without any significant effect on their function, compared to IL-15 alone (abstract; pg 1684, para 4). The CD56+ cells were cultured medium comprising recombinant human IL-15 and hydrocortisone (pg 1685, column 1, para 0) (which reads on the incubating step of claim 1).
Given that Duggal teaches a method for generating cytokine-induced NK cells comprised of obtaining mononuclear cells, contacting the cells with the IL-15 agonist N-803, and inducing the enriched NK cells with cytokine composition comprising IL-12, IL-19, or IL-15, and further given that Moustaki teaches a method of promoting NK cell expansion and function with hydrocortisone and IL-15, if would have been obvious to one of ordinary skill at the time the invention was filed to modify the method of Duggal by administering hydrocortisone as taught by Moustaki. The motivation to do so comes from Jones’ express teaching that hydrocortisone works synergistically with IL-15 to increase proliferation of NK cells that retain their functional integrity and migratory potential, making the cells useful for adoptive transfer in NK cell-based cancer immunotherapy (abstract). The ordinary artisan would add hydrocortisone to the incubating step of the method of Duggal and have a reasonable expectation of successfully generating the claimed M-CENK cell. The ordinary artisan would have reasonably expected that incorporating hydrocortisone in the method of Duggal would improve the production of cells obtained by Duggal’s method, thereby achieving the predictable result of increased cell yield. Applying a known technique to improve a similar method in the same field is obvious and will yield predictable results (see MPEP 2143).
Furthermore, the court in Integra Life Sciences / Ltd. V. Merck KGaA, 50 USPQ2d 1846 (DC SCalif, 1999) held that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discovery of a particular property of one of the starting materials or end products. Because the only active method steps recited in claim 1 are the steps of obtaining a plurality of mononuclear cells, contacting the plurality of mononuclear cells with hydrocortisone and N-803, incubating the plurality of mononuclear cells in the presence of hydrocortisone and N-803, and inducing enriched NK cells cells with a cytokine compositions comprising IL-12, IL-15, or IL-18 agonists or analog thereof, and because Duggal in view of Moustaki teach this step, the references have inherently performed the presently claimed method and would thus the cultured cells would intrinsically produce M-CENK cells, as required by claim 1.
Claims 1-5, 7, 10, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO2021006876A1(“Duggal”) in view of Moustaki et al, as applied to claims 1-5, 7, 10, and 23-24 above, and further in view of Damodharan et al, published online June 11, 2020 (instant PTO-892).
The teachings of Duggal in view of Moustaki are discussed above. This combination of references does teach the step wherein the harvested M-CENK cells are cryopreserved before infusion, as required by claim 11.
Damodharan teaches the step of cryopreserving NK cells after expansion and activation with IL-15 (abstract; pg 451, column 1, para 1), thereby demonstrating that freezing is a conventional step in the preparation of expanded and activated NK cells.
Damodharan teaches that a limitation of expansion and activation methods for NK cells is the inability to administer multiple NK cell infusions without performing repeat apheresis and expansion; because NK cell activation and expansion can yield a high number of cells, it would be beneficial to cryopreserve the remaining aliquots for future infusions (pg 451, column 1, para 1).
Given that Duggal in view of Moustaki teach a method of making expanded memory NK cells and further given that Damodharan teaches the step of cryopreserving NK cells after expansion and activation, it would have been obvious to one of ordinary skill in the art to modify the invention of Duggal in view of Moustaki by cryopreserving the produced cells. The motivation to do so comes from Moustaki, who teaches that cryopreservation allows preservation of remaining aliquots for future infusions, thereby providing the recognized advantage of long-term storage and treatment flexibility and reduced manufacturing burden. Also, because Damodharan teaches successful cryopreservation in similar therapeutic cells, the ordinary artisan would have had a reasonable expectation of success in applying the freezing step to the method of Duggal in view of Moustaki. This modification represents application of a known storage technique to a known method of making cells for benefiting preservation of cells for later administration.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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