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 .
Status of the Claims
Applicant’s submission filed 02 December 2025 has been entered. Claims 1, 3-5, 9, and 11-12 are pending. Claims1, 3-5, and 9 have been amended, while claims 2, 6-8, and 10 have been cancelled without prejudice or disclaimer and claims 11-12 have been newly added. Therefore, prosecution on the merits continues for claims 1, 3-5, 9, and 11-12. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to the drawings
The replacement drawing sheets filed 02 December 2025 are acknowledged and entered into the application file. With that, the replacement drawing sheets are filed in black and white, thus obviating the objection of record.
Therefore, the objection is withdrawn.
RE: Objection to claims 2 and 4-6
The cancellation of claims 2 and 6 renders the objections moot for those claims. For the remaining claims, Applicant has removed the bullet points from claims 4-5 and corrected the recitation of “following” within claim 4. However, Applicant has failed to add contextual language to claim 4.
Therefore, the objections are withdrawn for claims 2 and 5-6 and maintained for claim 4.
RE: Rejection of claims 3-5 and 8 under 35 USC 112(b)
The cancellation of claim 8 renders the rejection moot for that claim. For the remaining claims, Applicant’s amendments correcting the antecedent basis of each claim obviate the rejection of record.
Therefore, the rejections are withdrawn.
RE: Rejection of claim 7 under 35 USC 112(d)
The cancellation of claim 7 renders the rejection moot for that claim. Therefore, the rejection is withdrawn.
RE: Rejection of claims 1 and 3-9 under 35 USC 102(a)(2) over Rezvani et al as evidenced by Baxter Healthcare Corporation
Applicant has amended independent claims 1 and 9 such that the methods each respectively require a treatment with a medium supplemented with any selected from the group consisting of a bile acid and phenylbutyric acid within method step (1) – which was previously recited in now cancelled claims 2 and 10 – as well as the in vitro-activated cells to be NK cells having a cytotoxic activity of 50% or higher when the NK cells are used as effector cells for K562 cells as target cells in co-culture at a mixing ratio of 1:1. As previous claims 2 and 10 were not included within the rejection of record, and the newly presented limitations have not previously been considered, Applicant’s amendments obviate the rejection.
Therefore, the rejection is withdrawn.
It is of note that Applicant has made no assertions against Baxter Healthcare Corporation within the Remarks filed 02 December 2025.
RE: Rejection of claims 1-10 under 35 USC 103 over Rezvani et al as evidenced by Baxter Healthcare Corporation in view of Wammers et al
Applicant has amended independent claims 1 and 9 such that the methods each respectively require the in vitro-activated cells to be NK cells having a cytotoxic activity of 50% or higher when the NK cells are used as effector cells for K562 cells as target cells in co-culture at a mixing ratio of 1:1. As these are newly presented limitations that have not previously been considered, Applicant’s amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
It is of note that Applicant has made no assertions against Baxter Healthcare Corporation within the Remarks filed 02 December 2025.
RE: Provisional rejection of claims 1-3 and 9-10 on the grounds of nonstatutory double patenting over claim 7 of copending Application No. 18/689568 in view of Rezvani et al and Wammers et al
Applicant has amended independent claims 1 and 9 such that the methods each respectively require a treatment with a medium supplemented with any selected from the group consisting of a bile acid and phenylbutyric acid within method step (1) – which was previously recited in now cancelled claims 2 and 10 – as well as the in vitro-activated cells to be NK cells having a cytotoxic activity of 50% or higher when the NK cells are used as effector cells for K562 cells as target cells in co-culture at a mixing ratio of 1:1. As these amendments include newly presented limitations that have not previously been considered, Applicant’s amendments obviate the rejection of record.
Therefore, the provisional rejection is withdrawn.
New/Maintained Grounds of Rejection
Claim Objections
Claims 1, 4-5, and 9 are objected to because of the following informalities:
Regarding claims 1 and 9: The instant claims are each objected to for reciting “the vitro-activated cells” instead of “the in vitro activated-cells” in Line 7 and Line 8, respectively.
Appropriate correction is required.
Regarding claim 4: The instant claim is objected to for reciting capital letters within the claim other than at the beginning of the sentence, especially since the listed terms are not proper nouns. See MPEP § 608.01(m).
The instant claim also requires the addition of contextual claim language in regards to the molarity concentrations of the listed items. The Examiner recommends that the limitation reads as “sodium chloride at a concentration of 9.00 to 108 mM, sodium gluconate at a concentration of 2.30 to 27.7 mM, …”, or the like.
Appropriate correction is required.
Regarding claim 5: The instant claim is objected to for reciting capital letters within the claim other than at the beginning of the sentence, especially since the listed terms are not proper nouns. See MPEP § 608.01(m).
Appropriate correction is required.
Claim Interpretation
The transitional phrase of “containing” is synonymous with “comprising”. See MPEP § 2111.03(I).
In addition, instant claims 1 and 9 are directed to a method for treating cells, or making a pharmaceutical composition, comprising
(1) collecting in vitro-activated cells in a medium for cell culture;
(2) suspending the collected cells in a solution for cryopreservation; and
(3) freezing the suspended cells,
wherein the step (1) includes a treatment with a medium supplemented with any selected from the group consisting of a bile acid and phenylbutyric acid, and
the in vitro-activated cells are active NK cells having cytotoxic activity of 50% or higher when the NK cells are used as effector cells (E) for K562 cells as target cells (T) in co-culture at a mixing ratio (E:T) of 1:1.
The new limitation wherein…. “the in vitro-activated cells are active NK cells having cytotoxic activity of 50% or higher when the NK cells are used as effector cells (E) for K562 cells as target cells (T) in co-culture at a mixing ratio (E:T) of 1:1” is not an active step in the claims. Rather, the phrase is a contingent limitation within the claim, and the last active step of the claims is freezing the cells – or method step (3).
It is of note that claim scope is not limited by claim language that suggests, or makes optional but does not require, steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP § 2111.04.
The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A.
As such, instant claims 1 and 9 are interpreted to encompass the structure and steps through the freezing step, or method step (3).
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 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, 3-5, 9, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO 2017/066530 A1, of record on IDS filed 30 November 2022) as evidenced by Baxter Healthcare Corporation (PLASMA-LYTE A Technical Document, 2019, of record) in view of Nishigaki et al (Dig Dis Sci, 1996).
Zhang et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Nishigaki et al is considered prior art under 35 USC 102(a)(1). Baxter Healthcare Corporation is considered prior art under 35 USC 102(a)(1).
Regarding claims 1, 9, and 11-12: Zhang et al disclose methods of producing natural killer (NK) cells using a three-stage expansion and differentiation method with media comprising stem cell mobilizing factors (Abstract).
As such, Zhang et al disclose a method of producing NK cells, wherein hematopoietic stem or progenitor cells are serially cultured in three separate mediums to produce activated natural killer cells that are CD56+, CD3-, and CD11a+ (Paragraphs [0014], [0038]-[0046], [0049], [0060], [0358]). Zhang et al further disclose that the NK cells are expanded and suspended within a cryopreservation solution and cryopreserved (Paragraphs [0053], [00117], [00407]-[00411], [00414], [00420]-[00422], [00498]).
Although not required by the instant claims, Zhang et al further disclose that the CD11a+ NK cells have an in vitro cytotoxicity of 50% when co-cultured with K562 cells at a mixing ratio of 1:1 (Paragraphs [00138], [00533]; Figure 22).
Zhang et al do not disclose that the NK cells are treated with a bile acid or a phenylbutyric acid prior to being cryopreserved, as required by instant claims 1 and 9.
Nishigaki et al, however, disclose the in vitro treatment of NK cells with ursodeoxycholic acid (UDCA) and taurine-conjugated UDCA (TUDCA), wherein the treatments with UDCA and TUDCA allow for an enhanced expansion of NK cells (Pages 1488-1490, 1492; Figures 5-6).
Therefore, it would have been prima facie obvious to have modified the method of Zhang et al such that the CD11a+ NK cells are contacted with TUDCA, as detailed in Nishigaki et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to treat the NK cells with an agent known to enhance the proliferation of NK cells, and would have had a reasonable expectation of success given that the disclosures of both Zhang et al and Nishigaki et al are concerned with the expansion of NK cells. See MPEP § 2143(I)(G).
Consequently, Zhang et al as modified by Nishigaki et al render obvious a method of cryopreserving NK cells, wherein in vitro-activated CD11a+ NK cells are cultured and expanded in a culture medium supplemented with TUDCA (claims 11-12), collected and suspended in a cryopreservation solution, and cryopreserved. As the CD11a+ NK cells have an in vitro cytotoxicity of 50% when co-cultured with K562 cells at a mixing ratio of 1:1, this therefore renders obvious the methods of instant claims 1 and 9.
Regarding claims 3-4: Following the discussion of claim 1, Zhang et al further disclose thawing the cryopreserved NK cells and suspending them in a Plasma-Lyte A culture medium (claim 3) (Paragraphs [00421], [00497]). As the Plasma-Lyte A culture medium inherently comprises sodium chloride at a concentration of 90.00 mM, sodium gluconate at a concentration of 23.02 mM, sodium acetate at a concentration of 27.43 mM, potassium chloride at a concentration of 4.96 mM, and magnesium chloride at a concentration of 1.48 mM – as is evidenced by Baxter Healthcare Corporation – this therefore reads on the method of instant claim 4. See Page 1 of Baxter Healthcare Corporation in conjunction with the molarity formula, wherein
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For instance, in regards to the calculation of the molarity of sodium chloride, the Examiner divided the mass of sodium chloride in the Plasma-Lyte A culture medium – 526 mg – divided by the product of the reference volume of medium – 100 mL – and molar mass of sodium chloride – 58.44 g/mol. See Page 1 of Baxter Healthcare Corporation. This therefore equates to a molarity of 90.00 mM. The same computations were conducted for the remaining components of the Plasma-Lyte A medium.
Regarding claim 5: Following the discussion of claim 1, Zhang et al as evidenced by Baxter Healthcare Corporation further disclose that the Plasma-Lyte A solution does not comprise any of calcium ions or lactate. See Page 1 of Baxter Healthcare Corporation, which shows Plasma-Lyte A culture medium does not comprise any of the claimed components. This therefore reads on the method of the instant claim.
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, 3-5, 9, and 11-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of copending Application No. 18/689568 in view of Zhang et al (WO 2017/066530 A1, of record on IDS filed 30 November 2022) as evidenced by Baxter Healthcare Corporation (PLASMA-LYTE A Technical Document, 2019, of record) in view of Nishigaki et al (Dig Dis Sci, 1996).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claim renders obvious the instant claims. More specifically, the copending claim is not identical because no single copending claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are rendered obvious by the accompanying prior art.
Copending claim 7 is directed to a method for providing a pharmaceutical composition for infusion containing cells for administration to humans, the method comprising:
(1) washing the cells with a medium for animal cell culture;
(2) optionally washing and suspending the cells in a cryopreservation solution;
(3) freezing and preserving (stocking) the suspended cells in the cryopreservation solution;
(4) thawing the cryopreserved cells; and
(5) suspending the thawed cells in the solution according to claim 1 to prepare a pharmaceutical composition for infusion.
It is of note that the solution of copending claim 1 contains potassium ions, has a pH of 6.4 or higher, does not contain chloride ions at a concentration of 135 mEq/L or higher, does not contain calcium ions at a concentration of 0.423 mM or higher, and has an osmolarity of 200 to 396 mOsm.
Copending claim 7 does not disclose that the cells are in vitro-activated NK cells having a cytotoxicity of 50% when co-cultured with K562 cells at a mixing ratio of 1:1, nor that the in vitro-activated NK cells are contacted with a bile acid or phenylbutyric acid.
Zhang et al, however, disclose the expansion and cryopreservation of in vitro--activated CD11a+ NK cells, wherein the CD11a+ NK cells have an in vitro cytotoxicity of 50% when co-cultured with K562 cells at a mixing ratio of 1:1 (Paragraphs [0014], [0038]-[0046], [0049], [0053], [0060], [00117], [00138], [00358] [00407]-[00411], [00414], [00420]-[00422], [00498], [00533]; Figure 22).
With that, Nishigaki et al disclose the in vitro treatment of NK cells with ursodeoxycholic acid (UDCA) and taurine-conjugated UDCA (TUDCA), wherein the treatments with UDCA and TUDCA allow for an enhanced expansion of NK cells (Pages 1488-1490, 1492; Figures 5-6).
It therefore would have been prima facie obvious to have modified the method of copending claim 7 such that the cells are in vitro-activated NK cells having a cytotoxicity of 50% when co-cultured with K562 cells at a mixing ratio of 1:1, and have been expanded in culture medium supplemented with TUDCA, as a person of ordinary skill in the art before the effective filing date of the invention would have been motivated to expand the cells prior to cryopreserving them. This therefore renders obvious the method of instant claims 1, 3, 5, 9, and 11-12.
Furthermore, although the copending application does not disclose the limitations from instant claim 4, the subject matter is known from the prior art and can be further incorporated into the method rendered obvious by copending claim 7 and Rezvani et al:
Zhang et al as evidenced by Baxter Healthcare Corporation teach the limitation in instant claim 4.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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 ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633