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 is acknowledged.
Claim 62 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 Status
Claims 1-45 have been cancelled, claim 62 has been withdrawn, and claims 46-61 and 63-66 have been considered on their merits.
Claim Objections
Claim 54 is objected to because of the following informalities: the limitation of the claim referencing the “CD3z transmembrane domain” is being interpreted as a typo, as the instant specification points to the exemplary CD28 transmembrane sequence as being shown in SEQ ID NO: 3 and the exemplary CD3z signaling domain as being shown in SEQ ID NO: 4 (para. [0027]). Since claim 53 is directed to a CD3z signaling domain, claim 54 is interpreted as, “The cell therapy produce of claim 53, wherein the CD19 CAR comprises a CD3z signaling domain of SEQ ID NO: 4.”
Claim 60 is objected to because of the following informalities: the claim limitation “2.35% w/v HSA” is believed to read “2.35% v/v HSA” as the instant specification repeatedly discusses the HSA percentages in the form of v/v, not w/v. Therefore, the claim is interpreted as comprising the limitation “2.35% v/v HSA”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 46-61 and 63-66 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.
Claims 46, 63, and dependent claims contain the trademark/trade name PLASMA-LYTE. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an isotonic solution and, accordingly, the identification/description is indefinite.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
The term “transmembrane domain” in claim 54 is used by the claim to mean “signaling domain,” while the accepted meaning is “transmembrane domain.” The term is indefinite because the specification does not clearly redefine the term. Additionally, SEQ ID NO: 4 does not comprise the sequence for a transmembrane domain. The instant specification points to the exemplary CD28 transmembrane sequence as being shown in SEQ ID NO: 3 and the exemplary CD3z signaling domain as being shown in SEQ ID NO: 4 (para. [0027]). Since claim 53 is directed to a CD3z signaling domain, claim 54 is interpreted as, “The cell therapy produce of claim 53, wherein the CD19 CAR comprises a CD3z signaling domain of SEQ ID NO: 4.”
Regarding claim 59, the language of the claim is unclear. It is not clear to what the 25% w/v limitation is referring, either the HSA or the cryopreservation medium. Looking to the specification for guidance, the specification only refers to the HSA in terms of v/v, for example, at paragraph [0012], “the HSA is at a concentration of between about 1.25% v/v to 15% v/v…”. Therefore, it is unclear how to interpret the claim. Thus, the claim is interpreted as requiring the HSA is at a concentration between about 1.25% v/v to 15% v/v.
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.
Claim 61 is 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 61 recites the limitation further requiring a cryoprotectant, wherein the cryoprotectant is DMSO. This limitation does not further limit the claim as claim 46, from which claim 61 depends, requires CS10. CS10 comprises 10% DMSO.
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.
Claims 63-66 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref.) and evidenced by Allen et al. (BMC Pediatrics, 2016).
Regarding claims 63 and 64, Reusch et al. teach cryopreserved NK cells (immune cells) (Abstract). Reusch et al. teach a cryopreservation medium may comprise basal medium, Plasma-lyte, human serum albumin (HSA), and 10% DMSO (a cryoprotectant) (claim 64) (p. 26, lines 25-27). Reusch et al. teach 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 et al. does not specifically name Plasma-Lyte A, however, isotonic Plasma-Lyte it is known in the art to have different naming conventions and different publications may refer to Plasmalyte A, Plasmalyte, or Plasmalyte 148 (Allen et al., p. 2 Background). Therefore, the Plasma-Lyte of Reusch et al. is being interpreted the same as Plasma-Lyte A.
Regarding claims 65 and 66, Reusch et al. teach suitable formulations for the cryopreservation medium may include amino acids (which are metabolites), antioxidants, buffers, sugar alcohols, and glutathione (an antioxidant) (claim 66) (pp. 30-32). The limitation regarding HEPES and dextran are considered optional because HEPES at 0 mM and dextran at 0% v/v would not be present in the medium, thus is interpreted as an intentional omission from then medium.
Thus, the reference anticipates the subject matter of claims 63-66.
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, 55-57, 59, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Boissel et al. (US 2021/0260116 Al, published 26 August 2021) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref.) and evidenced by Allen et al. (BMC Pediatrics, 2016).
Regarding claim 46, Boissel et al. teach NK-92 cells expressing a CD19 chimeric antigen receptor (CAR) (Abstract and Fig. 1). Boissel et al. teach NK cells may further be genetically modified to express one or more cytokines, to include IL-15 (para. [0122]).
Boissel et al. is silent to a cryopreservation medium.
However, Reusch et al. teach cryopreserved NK cells preloaded with an antibody construct (Abstract). Reusch et al. teach CAR-NK cells are suitable for cryopreservation (p. 25, lines 9-10). Reusch et al. teach a cryo-solution may comprise basal medium, Plasma-lyte, human serum albumin (HSA), and 10% DMSO (p. 26, lines 25-27). Reusch et al. teach 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 et al. do not specifically state the utilization of CS10, however, CS10 is known to comprise 10% DMSO. The instant specification states CS10 is commercially available and includes DMSO among other things (para. [0104]). Reusch et al. does not specifically name Plasma-Lyte A, however, isotonic Plasma-Lyte it is known in the art to have different naming conventions and different publications may refer to Plasmalyte A, Plasmalyte, or Plasmalyte 148 (Allen et al., p. 2 Background). Therefore, the Plasma-Lyte of Reusch et al. is being interpreted the same as Plasma-Lyte A.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the CAR-NK cells of Boissel et al. in the cryopreservation medium of Reusch et al. with a reasonable expectation of success because Reusch et al. teach CAR-NK cells are suitable for cryopreservation. One would be motivated to utilize the CAR-NK cells of Boissel et al. in the cryo-solution of Reusch et al. because Boissel et al. teach 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]).
Regarding claims 47 and 48, Boissel et al. teach 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 et al. teach the extracellular domain comprise anti-CD19 single-chain variable fragment (scFv) (Fig. 1).
Regarding claims 49 and 50, Boissel et al. teach 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 et al. teach 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 et al. 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 et al. teach 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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Greyscale
Regarding claim 55, Boissel et al. teach 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 et al. read as being derived from peripheral blood.
Regarding claims 56 and 57, Reusch et al. teach cryo-solution may further comprise an isotonic solution such as Plasma-lyte, wherein the concentration of the isotonic solution may be 40% (v/v) (p. 26, lines 9-19).
Regarding claim 59, Reusch et al. teach 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 et al. 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.
Regarding claim 61, Reusch et al. teach a cryopreservation medium comprising DMSO (p. 26, lines 25-27).
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.
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) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref.) and evidenced by Allen et al. (BMC Pediatrics, 2016), as applied to claims 46-53, 55-57, 59, and 61 above, and further in view of Rezvani et al. (WO 2022/251504 A2, published 01 December 2022).
Regarding claim 54, Boissel et al. teach 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 et al. does not teach a sequence encoding a CD3z signaling domain with 100% identity to instant SEQ ID NO: 4.
However, Rezvani et al. teach CAR-NK cells which express one or more cytokines (Abstract). Rezvani et al. teach 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 et al. teach 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 et al. in the CAR-NK cells taught by Boissel et al. 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.
Claims 58 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Boissel et al. (US 2021/0260116 Al, published 26 August 2021) in view of Reusch et al. (WO 2020/043670 A1, published 05 March 2020, IDS ref.) and evidenced by Allen et al. (BMC Pediatrics, 2016), as applied to claims 46-53, 55-57, 59, and 61 above, and further in view of Zhang et al. (Transfusion, Volume 43, 2003).
Regarding claim 58, Boissel et al. in view of Reusch et al. teach a cryopreservation medium comprising trehalose, yet are silent to the concentration of trehalose used in the cryopreservation medium.
However, Zhang et al. teach 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 et al. teach 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 et al. 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.
Regarding claim 60, Reusch et al. teach cryopreservation medium may further comprise an isotonic solution such as Plasma-lyte, wherein the concentration of the isotonic solution may be in the range of 1% to 60% (v/v) (p. 26, lines 9-19). Reusch et al. in view of Zhang et al. teach a cryopreservation medium comprising trehalose in the concentration range of 50mM-500mM. Reusch et al. do not specifically state the utilization of CS10, however, CS10 is known to comprise 10% DMSO. The instant specification states CS10 is commercially available and includes DMSO among other things (para. [0104]). Reusch et al. is not specific to the percent of the cryopreservation medium which comprises the 10% DMSO solution/CS10. Reusch et al. teach the concentration of the human albumin in the cryopreservation medium may be in the range of 1% to 40% (v/v) (p. 26, lines 21-23).
Regarding the percentage of Plasma-Lyte and HSA, it would have been obvious to one of ordinary skill in the art to select the specific concentration, Plasma-Lyte at 37.7% and HSA at 2.35% v/v for use in the teachings of Reusch et al. 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 Plasma-Lyte and HSA concentration, is obvious. See MPEP § 2144.05. One would have had a reasonable expectation of successfully selecting the appropriate concentration Plasma-Lyte and HSA based on the species of cells being cryopreserved and the variables of the other components of the cryopreservation medium.
Regarding the concentration of trehalose, while Reusch et al. in view of Zhang et al. teach a concentration of trehalose close to 30mM, this specific concentration was not disclosed. However, it would have been obvious to one of ordinary skill in the art to arrive at the claimed concentrations through routine optimization. Reusch et al. and Zhang et al. provide sufficient information to permit the skilled artisan to manipulate the concentrations that will yield appropriate physical and chemical properties to support the formulation of the cryopreservation medium. See MPEP § 2144.05. Thus, the claimed concentrations are considered prima facie obvious over the disclosure of Reusch et al. and Zhang et al.
Regarding the percentage of CS10 in the cryopreservation medium, Reusch et al. is silent to the percentage of CS10/DMSO. However, it would have been obvious to one of ordinary skill in the art to arrive at the claimed percentage through routine optimization. Reusch et al. provide sufficient information to permit the skilled artisan to manipulate the percentages of the components of the cryopreservation medium that will yield appropriate physical and chemical properties to support the formulation of said cryopreservation medium. See MPEP § 2144.05. Thus, all of the claimed percentages are considered prima facie obvious over the disclosure of Reusch et al. in view of Zhang et al.
Therefore, absent evidence to the contrary, Reusch et al. in view of Zhang et al. make obvious the composition 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.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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