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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02 January 2026 has been entered.
Status of the Claims
Applicant’s submission filed 02 January 2026 has been entered. Claims 1, 3-4, 6-9, and 11-16 are pending. Claims 1, 4, and 6 have been amended, while claims 11-16 have been newly added. Therefore, prosecution on the merits continues for claims 1, 3-4, 6-9, and 11-16. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
The Examiner notes that support cannot be found within the Specification filed 21 September 2021 for the amendment to independent claim 1, as the phrase “in conjunction to” has a broader scope than “at the same time as”. See Page 9 of the Office action filed 07 July 2025.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 1, 4, and 6
Applicant’s amendments to instant claims 4 and 6 obviate the objections of record. In regards to
instant claim 1, Applicant’s amendments obviate all the objections of record except for (i) missing the addition of semicolon after “from a donor” in Line 3, and (ii) missing the addition of the comma before the recitation of “wherein the formulation of the immune cells is stocked” in Line 6.
Therefore, the objections to claims 4 and 6 are withdrawn, while the objection to claim 1 is maintained.
RE: Rejection of claims 1, 4, and 6-9 under 35 USC 102(a)(1) and 35 USC 102(a)(2) over Terunuma et al as evidenced by Gebo et al and Tonog et al
Applicant has amended independent claim 1 to require the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor. With that, Applicant has traversed the rejection, asserting in Pages 5-6 that Terunuma et al fail to distinctly state the timing of the sterility test with regards to the stocking of the formulation with immune type information.
In response, the Examiner respectfully submits that printed matter is only given patentable weight if a functional relationship exists between the printed matter and the associated substrate, and if the functional relationship between the printed matter and associated substrate is new and non-obvious. See MPEP § 211.05. In the instant case, the printed matter of immune type information stocked with the formulation comprising immune cells does not modify the formulation. Thus, no functional relationship between the label and the formulation exists, and the method step “wherein the formulation of immune cells is being stocked with immune type information” is not given patentable weight. Accordingly, the prior art will read on the method of the instant claims if the evaluation step is performed before prior to the selection of a formulation or identification of a recipient for a formulation.
The Examiner respectfully notes that since Terunuma et al disclose that the contamination
testing is performed at the end of the culturing step prior to the refrigeration or freezing of the enriched NK cells and subsequent administration to a patient in need thereof (Paragraphs [0106]- [0115], [0125], [0169]-[0172]), Terunuma et al still read on the method of the instant claim.
Furthermore, the Examiner also respectfully submits that, even if patentable weight is given to the method step “wherein the formulation of immune cells is being stocked with immune type information”, changes in the sequence of adding ingredients is prima facie obvious. See MPEP § 2144.04(IV)(C).
Therefore, the rejection of record is maintained and amended to encompass the claims as currently written.
RE: Rejection of claims 1, 4, and 6-9 under 35 USC 103 over Terunuma et al in view of Perry et al as evidenced by Gebo et al and Tonog et al
Applicant’s amendment to independent claim 1 requiring the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor obviates the rejection of record. It is of note that Applicant’s amendment narrows the scope of a previously presented limitation.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 3-4, and 6-9 under 35 USC 103 over Terunuma et al in view of Perry et al as evidenced by Gebo et al and Tonog et al, and further in view of Ohachi et al
Applicant’s amendment to independent claim 1 requiring the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor obviates the rejection of record. It is of note that Applicant’s amendment narrows the scope of a previously presented limitation.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 3-4, and 6-9 over claims 5 and 7 of US Patent No. 11,723,924 B2 in view of Terunuma et al and/or Ohachi et al, as evidenced by Gebo et al and Tonog et al
Applicant’s amendment to independent claim 1 requiring the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor obviates the rejection of record. It is of note that Applicant’s amendment narrows the scope of a previously presented limitation.
Therefore, the rejection is withdrawn.
RE: Provisional rejection of claims 1, 3-4, and 6-9 over claims 1 and 5 of copending Application No. 18/196779 in view of Terunuma et al and/or Ohachi et al, as evidenced by Gebo et al and Tonog et al
Applicant’s amendment to independent claim 1 requiring the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor obviates the rejection of record. It is of note that Applicant’s amendment narrows the scope of a previously presented limitation, and that copending Application No. 18/196779 is now US Patent No. 12329817 B2.
Therefore, the rejection is withdrawn.
RE: Provisional rejection of claims 1, 3-4, and 6-9 over claims 1, 9, and 11 of copending Application No. 16/808989 in view of Terunuma et al and/or Ohachi et al, as evidenced by Gebo et al and Tonog et al
Applicant’s amendment to independent claim 1 requiring the evaluation test to be performed at the same time as the step wherein the formulation of immune cells is being stocked with immune type information of the donor obviates the rejection of record. It is of note that Applicant’s amendment narrows the scope of a previously presented limitation, and claims 1, 9, and 11 have been cancelled in copending Application No. 16/808989.
Therefore, the rejection is withdrawn.
New/Maintained Grounds of Rejection
Claim Objections
Claims 1 and 14 are objected to because of the following informalities:
Regarding claim 1: The instant claim requires a semicolon after “from a donor” in Line 3. The instant claim also requires a comma between the words “formulation” and “wherein” in Line 6.
Appropriate correction is required.
Regarding claim 14: The instant claim is objected to for failing to recite “further” prior to “comprising” within Line 1.
Appropriate correction is required.
Claim Interpretation
Independent claim 1 is broadly directed to a method for isolating immune cells from a donor:
A method for providing immune cells obtained from a non-recipient donor to a recipient,
which comprises the following steps:
proliferating and/or activating immune cells collected from a donor;
preparing a formulation of the immune cells collected from the donor in a unit suitable for administration;
refrigerating or freezing the formulation, wherein the formulation of the immune cells is stocked with immune type information of the donor;
performing an evaluation test on the formulation at the same time as the step wherein the formulation of the immune cells is being stocked, wherein the evaluation test includes a sterility test;
and subsequent to the sterility test,
selecting a formulation for the recipient from stocked formulations for which the sterility test has been completed,
or
identifying a recipient for one selected stocked formulation for which the sterility test has been completed on the basis of immune type information of the donor and immune type information of the recipient.
The claim requires refrigerating or freezing the formulation comprising the immune cells, wherein the formulation of the immune cells is stocked “with immune type information”.
The instant Specification teaches “immune type information” at Paragraph [0028]:
Immune type information refers to information relating to immunity, such as that concerning ABO blood type, RH blood type, HLA type, and KIR type. Immune type information is used for the selection of stock formulations described below. A formulation containing immune cells obtained from a certain donor should be stocked in such a manner that the immune type information obtained from the same donor is associated with the formulation. They can be associated by, for example, assigning a unique number to each donor, and assigning that number to both the formulation and the immune type information. The immune type information and the number can be documented or digitized. The information to be attached to the formulation to be stocked may also include the results of the evaluation test described below.
Thus, the broadest reasonable interpretation of the immune type information of the claimed formulation encompasses a label (i.e. printed matter) with written immune type information. However, printed matter is only given patentable weight if a functional relationship exists between the printed matter and the associated substrate, and if the functional relationship between the printed matter and associated substrate must be new and non-obvious (MPEP § 211.05). In the instant case, the printed matter of immune type information stocked with the formulation comprising immune cells does not modify the formulation. Thus, no functional relationship between the label and the formulation exists, and the method step “wherein the formulation of immune cells is being stocked with immune type information” is not given patentable weight. Accordingly, the prior art will read on the method of the instant claims if the evaluation step is performed before prior to the selection of a formulation or identification of a recipient for a formulation.
To the extent Applicant argues a functional relationship of the printed material associated with the formulation exists, labeling formulations with immune cells is not new. See, for example, the Food and Drug Administration reference (HPC Labelling, 2016), which discloses blood fractions comprising cells in biobanks are stored in vials which are labeled (Pages 1, 3-4, 10).
With that, It is of note that changes in the sequence of adding ingredients is prima facie obvious. See MPEP § 2144.04(IV)(C).
Claim 6 utilizes the term “includes”. It is of note that the transitional term “includes” is synonymous with "comprises", which is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP § 2111.03(I).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 6-9, and 11-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 is directed to a method for providing immune cells obtained from a non-recipient donor to a recipient, which comprises the following steps: proliferating and/or activating immune cells collected from a donor; preparing a formulation of the immune cells collected from the donor in a unit suitable for administration; refrigerating or freezing the formulation, wherein the formulation of the immune cells are is stocked with immune type information of the donor; and performing an evaluation test on the formulation at the same time as the step wherein the formulation of the immune cells is being stocked, wherein the evaluation test includes is a sterility test; and subsequent to the sterility test, selecting a formulation for the recipient from stocked formulations for which the sterility test has been completed, or identifying a recipient for one selected stocked formulation for which the sterility test has been completed on the basis of immune type information of the donor and immune type information of the recipient (emphasis added). A review of the Specification shows that Applicant has failed to provide support for performing an evaluation test on the formulation “at the same time” as the step wherein the formulation of the immune cells is being stocked. More specifically, Applicant instead utilizes the phrase “in conjunction to” within Paragraph [0029] of the Specification filed 21 September 2021, which has a broader scope than “at the same time as”. See Page 9 of the Office action filed 07 July 2025, and the Thesausus.com reference, of record. Therefore, the subject matter of claim 1 can be considered an addition of new matter. See MPEP § 608.04(a), Waldemar Link, GmbH & Co. v. Osteonics Corp., 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1114 (Fed. Cir. 1991) (A written-description question often arises when an applicant, after filing a patent application, subsequently adds "new matter" not present in the original application.); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).
Instant claims 3-4, 6-9, and 11-16 are included because they depend from a rejected claim.
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.
Claim 16 is 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.
Regarding claim 16: The instant claim recites the limitation "the injectable formulation" in Line 2. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of an injectable formulation within the instant claim, or parent claim 1. It is of note that the recitation of “a unit suitable for administration” is broader than “an injectable formulation”, and not an inherent feature of the “unit suitable for administration”.
Appropriate correction is required.
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 1, 4, 6-9, 13, and 16 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Terunuma et al (US 2016/0075996 A1, of record) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record).
The following rejection follows the Claim Interpretation above, wherein a functional relationship between the label comprising the immune type information and the formulation does not exist, and the method step “wherein the formulation of immune cells is being stocked with immune type information” is not given patentable weight.
Terunuma et al disclose methods for producing a natural killer (NK) cell-enriched blood preparation (Abstract).
As such, Terunuma et al disclose a method wherein peripheral blood containing NK cells is collected from a donor, activated with a NK cell growth-stimulating factor that enriches for NK cells, and cultured to increase the number of NK cells (Paragraphs [0064]-[0065], [0074], [0092]-[0093], [0106]). Terunuma et al further disclose that the NK cell growth-stimulating factors that enrich for NK cells are an anti-CD16 antibody, an anti-CD137 antibody, OK432, and cytokines (Paragraphs [0075]-[0081], [0108]).
Terunuma et al further disclose that the cultured NK cells are then subject to cytotoxicity assays – wherein the cytotoxic activity of the activated and cultured NK cells is measured by activation marker expression – and then either immediately administered to a patient or stored at a temperature of 0°C to 8°C, or -80°C for later use (Paragraphs [0124]-[0125]). Terunuma et al further disclose that, since the enriched NK cells are activated prior to being stored, the stored NK cells can be administered in a necessary amount to a subject at the time of need via injection (Paragraphs [0127]-[0128], [0153]).
Terunuma et al further disclose that a contamination test must be performed on the NK cells at the end of the culturing step prior to the refrigeration or freezing of the enriched NK cells and subsequent administration to a patient in need thereof (Paragraphs [0106]-[0115], [0125], [0169]-[0172]). It is of note that Terunuma et al further disclose that the patient may be a cancer patient (Paragraphs [0118], [0150], [0159]).
Terunuma et al further disclose that the blood is preferably collected from a donor having a human leukocyte antigen (HLA) genotype compatible with that of a recipient (Paragraph [0065]).
Accordingly, Terunuma et al anticipate the claims as follows:
Regarding claims 1, 6, and 8: As aforementioned in the Claim Interpretation section above, no functional relationship between the label comprising the immune type information and the formulation exists. Therefore, the prior art is not explicitly required to recite the labelling of the cells with immune type information, so long as the resulting formulation comprises the pertinent immune type information itself. In addition, as mentioned in the Claim Interpretation section above, so long as the performance of the sterility test occurs before the selection of the immune cell formulation for a recipient, then the prior art will read on the method of the instant claims.
Accordingly, Terunuma et al disclose a method of generating an NK cell-enriched blood preparation, wherein peripheral blood containing NK cells is collected from a donor, activated with an NK cell growth-stimulating factor and cultured to increase the number of NK cells, assessed for activation marker expression and cytotoxic activity (claim 6), evaluated for any contamination within the NK cells via a contamination test and stored at a temperature of 0°C to 8°C, and then selected for an HLA-matched cancer patient (claim 8). As HLA genotype information is considered immune type information (see instant Specification, Paragraph [0028]) and a contamination test is synonymous with a sterility test (see Gebo et al: Page 2, Paragraph 2; Figure 1), this therefore reads on the method of instant claim 1 given the aforementioned claim interpretation.
It is of note that Gebo et al is cited solely as evidence to show that the contamination test of Terunuma et al is inherently a sterility test as claimed. See MPEP § 2112.
Regarding claim 4: Following the discussion of claim 1, Terunuma et al further disclose that one dose – or unit – of the NK cell-enriched blood preparation can be a volume containing NK cells in the range of 20 x 107 to 5x109 cells (Paragraph [0154]). As this dosage lies within the claimed range, this therefore reads on the method of the instant claim. See MPEP § 2131.03.
Regarding claim 7: Following the discussion of claim 1, Terunuma et al further disclose that NK cell-enriched blood preparation can be diluted with normal saline and administered to a patient via an intravenous drip (Paragraphs [0123], [0153]). As normal saline is inherently an isotonic solution (see Tonog et al: Page 2, 0.9% Sodium Chloride (Normal Saline), this therefore reads on the method of the instant claim.
It is of note that Tonog et al is cited solely as evidence to show that the normal saline of Terunuma et al is inherently an isotonic solution as claimed. See MPEP § 2112. Furthermore, although the publication date of Tonog et al is 2022, MPEP §2124 establishes references which show inherency need not antedate the filing date.
Regarding claim 9: Following the discussion of claim 1, Terunuma et al disclose that the donor is a healthy human (Paragraph [0177]). This therefore reads on the method of the instant claim.
Regarding claim 13: Following the discussion of claim 1, Terunuma et al further disclose that, since the enriched NK cells are activated prior to being stored, the stored NK cells can be administered in a necessary amount to a subject at the time of need via injection. As Terunuma et al is silent to the re-expansion and/or re-activation of the stored NK cells upon administration, this therefore reads on the method of the instant claim.
Regarding claim 16: Following the discussion of claim 1, Terunuma et al further disclose that the NK cell growth-stimulating factors that enrich for NK cells are an anti-CD16 antibody, an anti-CD137 antibody, OK432, and cytokines. This therefore reads on the method of the instant claim.
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, 4, 6-9, 13-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Terunuma et al (US 2016/0075996 A1, of record) in view of Food and Drug Administration (HPC Labelling, 2016) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record).
Terunuma et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). The Food and Drug Administration (FDA) reference is considered prior art under 35 USC 102(a)(1).
The following rejection follows the Claim Interpretation above, wherein Applicant argues that a functional relationship between the label comprising the immune type information and the formulation does exist, and the method step “wherein the formulation of immune cells is being stocked with immune type information” is given patentable weight.
Regarding claims 1, 6, and 8: Terunuma et al disclose methods for producing a natural killer (NK) cell-enriched blood preparation (Abstract).
As such, Terunuma et al disclose a method wherein peripheral blood containing NK cells is collected from a donor, activated with a NK cell growth-stimulating factor that enriches for NK cells, and cultured to increase the number of NK cells (Paragraphs [0064]-[0065], [0074], [0092]-[0093], [0106]). Terunuma et al further disclose that the cultured NK cells are then subject to cytotoxicity assays – wherein the cytotoxic activity of the activated and cultured NK cells is measured by activation marker expression – and then either immediately administered to a patient or stored at a temperature of 0°C to 8°C, or -80°C for later use (Paragraphs [0124]-[0125]). Terunuma et al further disclose that a contamination test must be performed on the NK cells at the end of the culturing step prior to the refrigeration or freezing of the enriched NK cells and subsequent administration to a patient in need thereof (Paragraphs [0106]-[0115], [0125], [0169]-[0172]). It is of note that Terunuma et al further disclose that the patient may be a cancer patient (Paragraphs [0118], [0150], [0159]).
Although Terunuma et al further disclose that the blood is preferably collected from a donor having a human leukocyte antigen (HLA) genotype compatible with that of a recipient (Paragraph [0065]), Terunuma do not explicitly disclose stocking the NK cell-enriched blood preparation with immune type information at the same time as the contamination testing, nor the selection of a final NK cell-enriched blood preparation for a patient based on that immune type information, as required by instant claim 1.
The FDA reference, however, discloses procedures for the procurement, storage, and use of blood and the cells comprised within (Page 1). As such, the FDA reference discloses the labeling of the obtained blood samples with pertinent information, including the HLA type of the sample (Pages 3, 10). The FDA reference further discloses that quality control tests must be performed and documented on the samples, including the results of sterility testing (Pages 6, 18-19).
Therefore, it would have been prima facie obvious to modify the method of Terunuma et al to label the NK cell-enriched blood preparation with at least the donor HLA genotype information and sterility testing results, and then select a NK cell-enriched blood preparation to administer to a patient that is appropriately HLA-matched to the receiving patient, as is detailed in the FDA reference. One of ordinary skill before the effective filing date of the invention would have been motivated to ensure that the immune type information – particularly the HLA genotype – of the donor and recipient are appropriately recorded and taken into account, as administering a NK cell-enriched blood preparation that is HLA-matched reduces the possibility of an adverse immune reaction within the recipient (Terunuma et al: Paragraphs [0065], [0155]). The ordinary artisan also would have been motivated to ensure that the obtained blood sample is sterile – or contamination-free – and appropriately labelled on the sample along with the immunotype information, as contaminated blood samples cannot be utilized for downstream therapies (FDA reference: Page 6). Furthermore, the ordinary artisan would have had a reasonable expectation of success based on the detailed protocols and consideration of the immune type information and sterility of the samples already outlined in Terunuma et al (Paragraphs [0064]-[0065], [0074], [0092]-[0093], [0106]-[0115], [0124]-[0125], [0169]-[0172]) coupled with the labeling protocols outlined in the FDA reference (Pages 3, 6, 10, 18-19). See MPEP § 2143(I)(G) and 2144.04(IV)(C).
Consequently, Terunuma et al as modified by the FDA reference render obvious a method of generating an NK cell-enriched blood preparation, wherein peripheral blood containing NK cells is collected from a donor; activated with a NK cell growth-stimulating factor and cultured to increase the number of NK cells; assessed for activation marker expression and cytotoxic activity (claim 6); labelled with at least the donor HLA genotype information, evaluated for any contamination within the NK cells via a contamination test, and stored at a temperature of 0°C to 8°C, or -80°C; and then selected for an HLA-matched cancer patient (claim 8). As HLA genotype information is considered immune type information (see instant Specification, Paragraph [0028]) and a contamination test is synonymous with a sterility test (see Gebo et al: Page 2, Paragraph 2; Figure 1), this therefore renders obvious the method of instant claim 1.
It is of note that Gebo et al is cited solely as evidence to show that the contamination test of Terunuma et al is inherently a sterility test as claimed. See MPEP § 2112.
Regarding claim 4: Following the discussion of claim 1, Terunuma et al further disclose that one dose – or unit – of the NK cell-enriched blood preparation can be a volume containing NK cells in the range of 20 x 107 to 5x109 cells (Paragraph [0154]). As this dosage lies within the claimed range, this therefore reads on the method of the instant claim. See MPEP § 2131.03.
Regarding claim 7: Following the discussion of claim 1, Terunuma et al further disclose that NK cell-enriched blood preparation can be diluted with normal saline and administered to a patient via an intravenous drip (Paragraphs [0123], [0153]). As normal saline is inherently an isotonic solution (see Tonog et al: Page 2, 0.9% Sodium Chloride (Normal Saline), this therefore reads on the method of the instant claim.
It is of note that Tonog et al is cited solely as evidence to show that the normal saline of Terunuma et al is inherently an isotonic solution as claimed. See MPEP § 2112. Furthermore, although the publication date of Tonog et al is 2022, MPEP §2124 establishes references which show inherency need not antedate the filing date.
Regarding claim 9: Following the discussion of claim 1, Terunuma et al disclose that the donor is a healthy human (Paragraph [0177]). This therefore reads on the method of the instant claim.
Regarding claim 13: Following the discussion of claim 1, Terunuma et al further disclose that, since the enriched NK cells are activated prior to being stored, the stored NK cells can be administered in a necessary amount to a subject at the time of need via injection (Paragraphs [0127]-[0128], [0153]). As Terunuma et al is silent to the re-expansion and/or re-activation of the stored NK cells upon administration, this therefore reads on the method of the instant claim.
Regarding claim 14: Following the discussion of claim 8, the FDA reference discloses that HLA matching of donor samples to recipient is recommended, as it helps prevent graft failure and leads to a faster recovery of the cells within the recipient (Pages 2-3, 5, 11). Therefore, it would have been prima facie obvious to modify the method of Terunuma et al such that NK cell-enriched blood preparations from multiple donors having a variety of HLA types are formulated and stored. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to comprise a wide array of HLA types, as it is recommended that at least 4 of 6 HLA-A antigens, HLA-B antigens, and HLA-DRB1 alleles match between donor and recipient (FDA reference: Page 3), and would have had a reasonable expectation of success given that the disclosure of Terunuma et al is concerned with the HLA typing of the collected samples (Paragraph [0065]). See MPEP § 2143(I)(G).
Consequently, Terunuma et al as modified by the FDA reference render obvious a method of generating an NK cell-enriched blood preparation, wherein NK cell-enriched blood preparations having a variety of HLA types are maintained and stored. This therefore renders obvious the method of the instant claim.
Regarding claim 16: Following the discussion of claim 1, Terunuma et al further disclose that the NK cell growth-stimulating factors that enrich for NK cells are an anti-CD16 antibody, an anti-CD137 antibody, OK432, and cytokines (Paragraphs [0075]-[0081], [0108]). This therefore reads on the method of the instant claim.
Claims 1, 3-4, 6-9, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Terunuma et al (US 2016/0075996 A1, of record) in view of Food and Drug Administration (HPC Labelling, 2016) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record), and further in view of Yoshikawa et al (US 2014/0087465 A1).
The discussion of Terunuma et al in view of the FDA reference as evidenced by Gebo et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Terunuma et al in view of the FDA reference as evidenced by Gebo et al and Tonog et al render obvious claims 1, 4, 6-9, 13-14, and 16. Yoshikawa et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 3: Following the discussion of claim 1 above, Terunuma et al further disclose that the NK cells are collected within peripheral blood in a blood collection bags (Paragraph [0069]).
The combination of Terunuma et al and the FDA reference fail to teach that the blood collection bags are resin bags, as required by instant claim 3.
Yoshikawa et al, however, disclose the culture of adherent cells within polyolefin resin bags (Abstract; Paragraphs [0003], [0017]-[0018], [0027]-[0034], [0046]-[0049]).
Therefore, it would have been prima facie obvious to have substituted the blood collection bag of Terunuma et al with the cell culture bag of Yoshikawa et al, as doing so would have been a simple substitution of one culture bag for another. See MPEP § 2143(I)(B). One of ordinary skill before the effective filing date of the invention would have recognized that the two culture bags are functionally comparable, as they both allow for the culture of adherent cells comprised within the bag, and thereby would have been able to substitute the culture bags with predictable results.
Consequently, Terunuma et al as modified by the FDA reference and Yoshikawa et al render obvious a method of generating an NK cell-enriched blood preparation, wherein the NK cells are held within a culture bag constructed from polyolefin resin. This therefore renders obvious the method of the instant claim.
Regarding claim 15: Following the discussion of claim 1 above, Terunuma et al further disclose that the NK cells are collected within peripheral blood in a blood collection bags (Paragraph [0069]).
The combination of Terunuma et al and the FDA reference fail to teach that the blood collection bags are inverted during the proliferation and/or activation of the NK cells within the blood sample, as required by instant claim 15.
Yoshikawa et al, however, disclose the culture of adherent cells within polyolefin resin bags, wherein the cells adhere to at least one inner surface of the culture bag during expansion by reversing – or inverting – the culture bag (Abstract; Paragraphs [0003], [0012]-[0013], [0017]-[0019], [0027]-[0034], [0039], [0046]-[0049]).
Therefore, it would have been prima facie obvious to have modified the method of Terunuma et al in view of the FDA reference such that the collection bags are inverted during the proliferation and/or activation of the NK cells within the blood sample, as detailed in Yoshikawa et al. One of ordinary skill before the effective filing date of the invention would have been motivated to ensure that the NK cells are expanding to their full potential by adhering and proliferating upon both sides of the collection bag (Yoshikawa et al: Paragraph [0049]), and would have had a reasonable expectation of success given that the disclosures of Terunuma et al and Yoshikawa et al are both concerned with the culture and expansion of cells within culture bags. See MPEP § 2143(I)(G).
Consequently, Terunuma et al as modified by the FDA reference and Yoshikawa et al render obvious a method of generating an NK cell-enriched blood preparation, wherein the collection bags housing the NK cells are inverted during the proliferation and/or activation of the NK cells within the blood sample. This therefore renders obvious the method of the instant claim.
Claims 1, 4, 6-9, 11-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Terunuma et al (US 2016/0075996 A1, of record) in view of Food and Drug Administration (HPC Labelling, 2016) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record), and further in view of Koehl et al (Oncoimmnuology, 2015).
The discussion of Terunuma et al in view of the FDA reference as evidenced by Gebo et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Terunuma et al in view of the FDA reference as evidenced by Gebo et al and Tonog et al render obvious claims 1, 4, 6-9, 13-14, and 16. Koehl et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 11: As aforementioned in the discussion of claim 1 above, Terunuma et al as modified by the FDA reference renders obvious a method of generating a NK cell-enriched blood preparation, wherein HLA immunotype information is labelled on the sample.
The combination of Terunuma et al and the FDA reference fail to teach that the labelled immunotype information include KIR type, as required by instant claim 11.
Koehl et al, however, disclose that typing of KIR and HLA are important sample features to consider when selecting an NK cell donor sample for administration to a recipient (Pages 3-4, 7).
Therefore, it would have been prima facie obvious to have modified the method of Terunuma et al in view of the FDA reference such that KIR typing information is included with the HLA typing information on the sample label, as detailed in Koehl et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to include the KIR typing information on the sample label, as it is critical for selecting an auspicious NK cell donor (Koehl et al: Page 7), and would have had a reasonable expectation of success given the KIR typing protocols outlined in Koehl et al (Pages 3-4). See MPEP § 2143(I)(G).
Consequently, Terunuma et al as modified by the FDA reference and Koehl et al render obvious a method of generating an NK cell-enriched blood preparation, wherein the KIR typing information of the NK cell-enriched blood preparation is included on the sample label. This therefore renders obvious the method of the instant claim.
Regarding claim 12: Following the discussion of claim 11, Koehl et al further disclose that selecting an NK cell donor sample for administration to a recipient is based on KIR mismatch (Pages 3-4). This therefore renders obvious the method of the instant claim for the same reasons as discussed in the rejection of instant claim 11.
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, 3-4, 6-9, and 11-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 7 of U.S. Patent No. 11,723,924 in view of Terunuma et al (US 2016/0075996 A1, of record) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record), and further in view of Yoshikawa et al (US 2014/0087465 A1) and Koehl et al (Oncoimmnuology, 2015).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims. More specifically, the patented claims are not identical because no single patented claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are disclosed by separate patented claims, or rendered obvious by the accompanying prior art. The fact that each of the elements were claimed in the patent application, just not in a single claim, still renders obvious the instant invention because each of the features, though separately claimed, can be physically combined into a single embodiment.
As such, it is first of note that instant claim 1 encompasses a method of isolating immune cells as a formulation, refrigerating or freezing the cells, stocking the formulation with “immune type information” of the donor at the same time an evaluation test is performed – wherein the evaluation test is a sterility test, and selecting cells suitable for the recipient. However, the method step wherein the formulation of immune cells is being stocked with “immune type information” is not given patentable weight. See Claim Interpretation section above.
Therefore, instant claim 1 is an obvious variant of the claims of the cited patent in view of the art:
Patent claim 5 is directed to a method for preparing the population according to claim 1, which comprises the following steps: collecting peripheral blood monocytes from a healthy volunteer using Ficoll; adding CD3 beads to the obtained peripheral blood monocytes, and incubating the monocytes and the beads at 4° C for 15 minutes; adding a separation buffer to the monocytes and the beads to obtain a suspension, and centrifuging the suspension at 300×g for 10 minutes; removing a supernatant from the centrifuged suspension to obtain a residue, suspending the residue in a separation buffer, and adding the resulting suspension to LD Column wetted beforehand with the separation buffer; collecting an eluate from the LD Column, and centrifuging the eluate at 500×g for 5 minutes; removing a supernatant from the centrifuged eluate to obtain resultant cells, and suspending the resultant cells in NK medium I at a density of 5×105 cells/mL which are collected as primary NK cells (reads on a formulation of immune cells from a donor); culturing the primary NK cells (reads on “immune type information of the donor”) in a medium in a CO2 incubator at 37° C under 5% CO2 atmosphere; collecting the cells on day 14 of the culturing step as the population; and wherein the medium is COSMEDIUM 008 containing 5% of human AB type serum which is obtained by inactivation at 56° C for 30 minutes.
Patent claim 7 is directed to a pharmaceutical composition comprising the NK cells according to claim 1 (reads on formulating the primary NK cells for administration).
The combination of patent claims 5 and 7 fail to disclose that the cultured NK cells are refrigerated or frozen, as well as the selection of a formulation comprising immune cells suitable for a recipient after performing a sterility test on the formulation.
However, refrigerating or freezing and storing isolated formulations comprising immune cells, and selecting such formulations for recipients that have undergone a sterility test was known in the art from Terunuma et al.
Terunuma et al disclose a method of generating a NK cell-enriched blood preparation, wherein peripheral blood containing NK cells is collected from a donor, activated with a NK cell growth-stimulating factor and cultured to increase the number of NK cells, assessed for activation marker expression and cytotoxic activity, stored at a temperature of 0°C to 8°C or -80°C and evaluated for any contamination within the NK cells via a contamination test, and then selected for an HLA-matched cancer patient.
Therefore, it would have been prima facie obvious modify the claims of the earlier filed patent to arrive at the claimed invention, as refrigerating or freezing and storing isolated formulations comprising immune cells, and selecting such formulations that have undergone a sterility test for recipients was known in the art at the time of the invention. One of ordinary skill before the effective filing date of the invention would have been motivated to ensure that the immune type information – particularly the HLA genotype – of the donor and recipient are appropriately recorded and taken into account, as administering a NK cell-enriched blood preparation that is HLA-matched reduces the possibility of an adverse immune reaction within the recipient (Paragraphs [0065], [0155]).
Consequently, patent claims 5 and 7 as modified by Terunuma et al render obvious instant claim 1.
With that, instant claims 3-4, 6-9, and 11-16 are known from the prior art and can be further incorporated into the method rendered obvious by patent claims 5 and 7 as modified by Terunuma et al:
Terunuma et al as evidenced by Gebo et al and Tonog et al further teach the limitations recited in instant claims 4, 6-9, 13-14, and 16.
Yoshikawa et al teach the limitations recited in instant claims 3 and 15.
Koehl et al teach the limitations recited in instant claims 11-12.
Claims 1, 3-4, 6-9, and 11-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 12,329,817 in view of Terunuma et al (US 2016/0075996 A1, of record) as evidenced by Gebo et al (J Clin Microbiol, 2020, of record) and Tonog et al (StatPearls, 2022, of record), and further in view of Yoshikawa et al (US 2014/0087465 A1) and Koehl et al (Oncoimmnuology, 2015).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the instant claims. More specifically, the patented claims are not identical because no single patented claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are disclosed by separate patented claims, or rendered obvious by the accompanying prior art. The fact that each of the elements were claimed in the patent application, just not in a single claim, still renders obvious the instant invention because each of the features, though separately claimed, can be physically combined into a single embodiment.
As such, it is first of note that instant claim 1 encompasses a method of isolating immune cells as a formulation, refrigerating or freezing the cells, stocking the formulation with “immune type information” of the donor at the same time an evaluation test is performed – wherein the evaluation test is a sterility test, and selecting cells suitable for the recipient. However, the method step wherein the formulation of immune cells is being stocked with “immune type information” is not given patentable weight. See Claim Interpretation section above.
Therefore, instant claim 1 is an obvious variant of the claims of the cited patent in view of the art:
Patent claim 1 is directed to a population of NK cells, wherein the population is obtained from the following steps: collecting peripheral blood mononuclear cells from a healthy volunteer using Ficoll; adding CD3 beads to the obtained peripheral blood mononuclear cells, and incubating the mononuclear cells and beads at 4° C for 15 minutes; adding a separation buffer to the mononuclear cells and the beads to obtain a suspension, and centrifuging the suspension at 300×g for 10 minutes; removing a supernatant from the centrifuged suspension to obtain a residue, suspending the residue in a separation buffer, and adding the resulting suspension to LD Column wetted beforehand with the separation buffer; collecting an eluate from the LD Column, and centrifuging the eluate at 500×g for 5 minutes; removing a supernatant from the centrifuged eluate to obtain resultant cells, and suspending the resultant cells in NK medium I at a density of 5×105 cells/mL which are collected as primary NK cells (reads on a formulation of immune cells from a donor), and culturing the primary NK cells (reads on “immune type information of the donor”) in a CO2 incubator at 37° C under 5% CO2 atmosphere; collecting the cells on day 14 of the culturing step as the population; and wherein the NK medium I is COSMEDIUM 008 containing 5% of human AB type serum which is obtained by inactivation at 56° C for 30 minutes.
Patent claim 5 is directed to a pharmaceutical composition comprising the NK cells according to patent claim 1 (reads on formulating the primary NK cells for administration).
The combination of patent claims 1 and 5 fail to disclose that the cultured NK cells are refrigerated or frozen, as well as the selection of a formulation comprising immune cells suitable for a recipient after performing a sterility test on the formulation.
However, refrigerating or freezing and storing isolated formulations comprising immune cells, and selecting such formulations for recipients that have undergone a sterility test was known in the art from Terunuma et al.
Terunuma et al disclose a method of generating a NK cell-enriched blood preparation, wherein peripheral blood containing NK cells is collected from a donor, activated with a NK cell growth-stimulating factor and cultured to increase the number of NK cells, assessed for activation marker expression and cytotoxic activity, stored at a temperature of 0°C to 8°C or -80°C and evaluated for any contamination within the NK cells via a contamination test, and then selected for an HLA-matched cancer patient.
Therefore, it would have been prima facie obvious modify the claims of the earlier filed patent to arrive at the claimed invention, as refrigerating or freezing and storing isolated formulations comprising immune cells, and selecting such formulations that have undergone a sterility test for recipients was known in the art at the time of the invention. One of ordinary skill before the effective filing date of the invention would have been motivated to ensure that the immune type information – particularly the HLA genotype – of the donor and recipient are appropriately recorded and taken into account, as administering a NK cell-enriched blood preparation that is HLA-matched reduces the possibility of an adverse immune reaction within the recipient (Paragraphs [0065], [0155]).
Consequently, patent claims 1 and 5 as modified by Terunuma et al render obvious instant claim 1.
With that, instant claims 3-4, 6-9, and 11-16 are known from the prior art and can be further incorporated into the method rendered obvious by patent claims 1 and 5 as modified by Terunuma et al:
Terunuma et al as evidenced by Gebo et al and Tonog et al further teach the limitations recited in instant claims 4, 6-9, 13-14, and 16.
Yoshikawa et al teach the limitations recited in instant claims 3 and 15.
Koehl et al teach the limitations recited in instant claims 11-12.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633