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 1, claims 46-61 and 63-66 in the reply filed on 02 March 2026 was previously acknowledged.
Claim 62 was withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02 March 2026.
Claim 62 was canceled by Applicant in the reply filed 07 August 2026.
Newly submitted claims 67-77 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Originally presented claims 46-61 and 63-66 are drawn to a cell therapy product comprising a population of CAR NK cells, classified in C12N 5/0646.
The newly submitted claims 67-77** are drawn to a method of cryopreserving NK cells, classified in A01N 1/125.
These two inventions are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the process for using could be practiced with a cryopreservation medium with a different composition. Additionally, the product, as claimed, could be used for treating a disease involving the genetically modified NK cells, such as treating a specific cancer.
**Claim 77 is listed as a product claim that depends from claim 70, a method claim. For the sake of compact prosecution, this claim is interpreted as containing a typographical error and depends from the method of claim 70.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 67-77 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Status
Claims 1-45 were previously canceled, claims 56-57 and 60-66 are newly canceled, claims 46, 54, and 59 have been amended, claim 67-77 are new, claims 67-77 have been withdrawn from consideration, and claims 46-55 and 58-59 have been considered on their merits.
Withdrawn Objections/Rejections
The claim objections have been withdrawn due to Applicant’s amendments to the claims.
The claim rejections under 35 USC § 102 have been withdrawn due to Applicant’s amendments to the claims.
The claim rejections under 35 USC § 103 have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration and new rejection has been set forth below.
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 46-53, 55, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Boissel et al. (US 2021/0260116 Al, published 26 August 2021, of record) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref., of record) and Chang et al. (Blood, volume 140, Issue supplement 1, 2022) as evidenced by Allen et al. (BMC Pediatrics, 2016, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. This rejection is substantially similar to the rejection of record, however, due to Applicant’s amendments to independent claim 46, this rejection is considered new in order to address the new limitations and modified scope of the claim. A response to Applicant' s traversal follows the reiterated rejection below.
Regarding claim 46, Boissel teaches NK-92 cells expressing a CD19 chimeric antigen receptor (CAR) (Abstract and Fig. 1). Boissel teaches NK cells may further be genetically modified to express one or more cytokines, to include IL-15 (para. [0122]).
Boissel is silent to a cryopreservation medium.
However, Reusch teaches cryopreserved NK cells preloaded with an antibody construct (Abstract). Reusch teaches CAR-NK cells are suitable for cryopreservation (p. 25, lines 9-10). Reusch teaches a cryo-solution may comprise basal medium, Plasma-lyte, human serum albumin (HSA), and 10% DMSO (p. 26, lines 25-27). Plasma-lyte is known to comprise sodium chloride, sodium gluconate, sodium acetate, potassium chloride, and magnesium chloride, as evidenced by Allen (p. 8, Abbreviations). Reusch teaches pharmaceutical compositions comprising the preloaded NK cells may comprise formulation materials for the purpose of modifying, maintaining, or preserving to include disaccharides, preferably trehalose (p. 30, lines 38-39 and p. 31, lines 23-24). Reusch teaches a method for reconstituting/preparing viable preloaded human NK cells from a cryopreserved state for an administration of said cells (p. 29, lines 37-41).
Regarding the limitation directed to wherein the cell therapy product is thawed from a cryopreserved state and is characterized by having greater than 90% cell viability, this clause reads as a product-by-process limitation. The process being wherein the cells are first cryopreserved in the disclosed medium flowed by a thawing process. This process then recites the intended result, which is a cell viability greater than 90%. This functional property would naturally flow from the prior art structure, therefore, the prior art reads on the intended result or functional property recitation. There is no requirement that the cited prior art expressly teach or suggest the intended result or functional property recitation, but only that the subject matter is, in fact, present in the cited prior art. See MPEP § 2113.
Regarding the intended results, MPEP § 2112 states, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). 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 § 2112.01(I) states when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the CAR-NK cells of Boissel in the cryopreservation medium of Reusch with a reasonable expectation of success because Reusch teaches CAR-NK cells are suitable for cryopreservation. One would be motivated to utilize the CAR-NK cells of Boissel in the cryo-solution of Reusch because Boissel teaches significant adverse reactions were observed for animals which received IV administration of freshly prepared CAR-NK cells; in addition, cryopreserved modified NK cells proved to be safe to animals after IV administration at a lower cells/dose level which showed significant efficacy in suppressing tumor growth (para. [0244]).
Even if the 90% cell viability did not naturally flow from the composition taught by Boissel in view of Reusch, this process would be considered a matter of routine optimization.
Chang teaches high-density (HD) cryopreservation of off-the-shelf CAR-NK cells for the purpose of on-demand treatment access (Abstract). Chang teaches to select the ideal cryopreservation formulation in HD-fill studies, iterative formulation screening were performed which were supported by orthogonal analytical characterizations looking at cell viability, proliferation capacity, and cytotoxicity function upon thaw and over time (p. 2). Chang teaches the tested HD-fills were produced using two induced NK (iNK) cells products, to include anti-CD19 CAR iNK cells (p. 2). Chang teaches standard dose concentration of 1.5E+07 viable cells/mL and HD-fill dose concentrations up to 1.1E+08 viable cells/mL in the top cryopreservation formulation using assessment parameters such as immediate post-thaw recovery and tolerance of hold-time (in-use stability), transgene expression, and potency (p. 2). Chang teaches the results demonstrated comparable recovery and viability immediately post thaw (>99.0%) as well as after 90 minutes hold time at room temperature (>95.0%) between standard density and HD-fill densities (p. 2).
MPEP 2144.05.II.A. states "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller,220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, it would have been obvious to one of ordinary skill in the art to have recognized that the formulation of the cryopreservation medium was a result effective variable because Chang teaches to select the ideal cryopreservation formulation in HD-fill studies, iterative formulation screening were performed which were supported by orthogonal analytical characterizations looking at cell viability, proliferation capacity, and cytotoxicity function upon thaw and over time. Since the goal of a cryopreservation study would be to achieve maximum viability and function, the formulation of the cryopreservation medium is recognized as a result effective variables, one of ordinary skill would have been motivated to optimize by routine experimentation to determine the optimal composition of the cryopreservation medium in order to achieve the maximum cell viability.
Regarding claims 47 and 48, Boissel teaches genetically modified NK cell carrying a membrane bound recombinant CAR comprising an extracellular domain, hinge domain, transmembrane domain, and a signaling domain (para. [0015]). Boissel teaches the extracellular domain comprise anti-CD19 single-chain variable fragment (scFv) (Fig. 1).
Regarding claims 49 and 50, Boissel teaches a sequence comprising the light chain variable region of the CD19 CAR, SEQ ID NO: 4 which comprises instant SEQ ID NO: 1 with 100% identity, see the attached sequence alignment. The alignment results are reproduced below for convenience:
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294
621
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Regarding claims 51 and 52, Boissel teaches the 3rd generation CAR with CD28/4-1BB/CD3z signaling domain has the nucleic acid sequence SEQ ID NO: 16 (para. [0137]). The nucleic acid sequence disclosed by Boissel encodes an amino acid sequence which comprises instant SEQ ID NO: 3 with a 100% identity, see the attached sequence alignment. The alignment results are reproduced below for convenience:
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589
788
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Regarding claim 53, Boissel teaches a sequence encoding a CD3z signaling domain, SEQ ID NO: 10, which is 96% identical to instant SEQ ID NO: 4, see the attached sequence alignment. The alignment results are reproduced below for convenience:
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316
683
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Regarding claim 55, Boissel teaches NK-92 cells were discovered in the blood of a subject suffering from a non-Hodgkins lymphoma (para. [0006]). Therefore, the NK-92 cells of Boissel reads as being derived from peripheral blood.
Regarding claim 59, Reusch teaches the concentration of the albumin in the cryo-solution may be in the range of 1% to 40% (v/v) (p. 26, lines 21-23).
It would have been obvious to one of ordinary skill in the art to select the concentration range (1.25% v/v to 15% v/v) of HSA for use in the teachings of Reusch because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists: selecting the specific HSA concentration range, is obvious. See MPEP § 2144.05. One would have had a reasonable expectation of successfully selecting the appropriate concentration range of HSA based on the species of cells being cryopreserved and the variables of the other components of the cryopreservation medium.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 07 August 2026 have been fully considered but they are not persuasive.
In response to applicant's argument that Reusch does not teach the thawed cryopreserved cells possess a greater than 90% viability, as discussed in the rejection above, this limitation is directed to a product-by-process limitation and an intended result of said process. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established.
Additionally, in response to applicant's argument that Reusch does not teach the limitations of the claims, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding the argument directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the rejection of claim 46 above does provide a motivation and a reasonable expectation of success to combine the cited references to arrive at the claimed invention.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Boissel et al. (US 2021/0260116 Al, published 26 August 2021, of record) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref., of record) and Chang et al. (Blood, volume 140, Issue supplement 1, 2022) as evidenced by Allen et al. (BMC Pediatrics, 2016, of record), as applied to claims 46-53, 55, and 59 above, and further in view of Rezvani et al. (WO 2022/251504 A2, published 01 December 2022, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant' s traversal follows the reiterated rejection below.
Regarding claim 54, Boissel teaches a sequence encoding a CD3z signaling domain, SEQ ID NO: 10, which is 96% identical to instant SEQ ID NO: 4, see the rejection of claim 53 above. Boissel does not teach a sequence encoding a CD3z signaling domain with 100% identity to instant SEQ ID NO: 4.
However, Rezvani teaches CAR-NK cells which express one or more cytokines (Abstract). Rezvani teaches transduced NK cells may be comprised in a media suitable for transfer to an individual and/or media suitable for preservation, such as cryopreservation (para. [0261]). Rezvani teaches SEQ ID NO: 4, which comprises a CD3z signaling domain with 100% identity to instant SEQ ID NO: 4, see sequence search result file US-18-361-790-4.rag, result 2.
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the CD3z signaling domain of Rezvani in the CAR-NK cells taught by Boissel with a reasonable expectation of success because both sequences encode a CD3z signaling domain thus would be expected to work in the same manner. Substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP § 2143(I).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Regarding the argument directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Boissel et al. (US 2021/0260116 Al, published 26 August 2021, of record) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref., of record) and Chang et al. (Blood, volume 140, Issue supplement 1, 2022) as evidenced by Allen et al. (BMC Pediatrics, 2016, of record), as applied to claims 46-53, 55, and 59 above, and further in view of Zhang et al. (Transfusion, Volume 43, 2003, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant' s traversal follows the reiterated rejection below.
Regarding claim 58, Boissel in view of Reusch teaches a cryopreservation medium comprising trehalose, yet are silent to the concentration of trehalose used in the cryopreservation medium.
However, Zhang teaches cryopreservation testing using various concentrations of trehalose, wherein tested concentrations of 0.05-0.5M (50mM-500mM) reported to be effective in preserving various types of cells (p. 271, Discussion). Zhang teaches the addition of trehalose at 1 to 10 percent significantly increased CFU recovery in a dose-dependent manner (p. 268, Results).
It would have been obvious to one of ordinary skill in the art to select the concentration range (10mM-100mM) of trehalose for use in the teachings of Reusch because in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists: selecting the specific trehalose concentration, is obvious. See MPEP § 2144.05. One would have had a reasonable expectation of successfully selecting the appropriate concentration of trehalose based on the species of cells being cryopreserved and the variables of the other components of the cryopreservation medium. Therefore, absent evidence to the contrary, Reusch in view of Zhang render obvious the concentration range of the trehalose found in the cryopreservation medium.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Regarding the argument directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Conclusion
No claims are allowed.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.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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