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 .
Priority
This application is a 371 of PCT/EP2023/064344 filed on 29 May 2023, which claims priority to EP 22305788.6 filed 30 May 2022.
Claim Status
Claims 3-11 and 13-14 are currently amended, claim 15 was previously canceled, and claims 1-14 have been considered on their merits.
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 4, 6, 7, and 12-14 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.
Regarding claims 4, 6, 7, and 12, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. MPEP § 2173.05(d) states, description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.
Claim 13 recites the limitation “replacing 20-80% of the culture medium used in the preceding steps with a culture medium comprising IL-15" in the last line of the claim. There is insufficient antecedent basis for this limitation in the claim. It is unclear to which preceding steps claim 13 is referring. The claim discloses a method for obtaining iNKT cells according to claim 1, which describes culturing PBMCs in a culture medium comprising α-GalCer and IL-15. Since claim 13 depends from claim 1, and claim 1 only discloses one culture medium, it is not clear to which preceding steps claim 13 is referring. Thus, the scope of claim is unclear.
The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973).
For the purposes of compact prosecution, claim 13 is interpreted as the method according to claim 1, wherein said method further comprises a step of replacing 20-80% of the culture medium with a culture media comprising IL-15.
Claim 14 is included in the rejection because it does not remedy the issue.
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 1-2 and 4-14 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Li et al. (CN 113642646 A, published 01 October 2021) as evidenced by Lonza (Dendritic Cell (DC) and T Cell Assay from Matched PBMCs Instructions for use, published 2023).
CN 113642646 A was published in Chinese, an English machine translation, obtained from Espacenet, was utilized for reference purposes.
Regarding claims 1-2, 5-8, and 10, Li teaches an optimized lymphocyte culture medium, which is prepared by adding cell agonists and cytokines to the basic lymphocyte culture medium, wherein, the cell agonist is α-galactosylceramide (α-GalCer), preferably at a concentration of preferably 100 ng/mL (claim 6) (p. 2). Li teaches the basal lymphocyte culture medium is X-VIVO 15 containing fetal calf serum (FCS), which reads on fetal bovine serum (FBS), X-VIVO 15 comprises L-glutamine, as evidenced by Lonza at page 4 (claim 8) (p. 2). Li teaches preferably the NKT cells are iNKT cells (p. 3). Li teaches the lymphocyte culture medium comprises IL-15, with a working concentration of preferably 5 ng/mL (claim 5) (p. 3). Li teaches the initial concentration of the cells during the culture is 1x106/mL (claim 7) to 50x106/mL at culture conditions of 37°C and 5% CO2 (claim 10) (p. 3). Li teaches the culture medium is changed every other day and the liquid change is a half liquid change (p. 3). Li teaches the source of the sample is PBMCs isolated from peripheral blood (p. 3). Li teaches experimental results wherein the final iNKT cell expansion was 2,595 times (p. 7). The cell expansion factor of 2,595 reads as higher than 100 (claim 1) and higher than 500 (claim 2).
Regarding claim 9, Li teaches the basal lymphocyte culture medium is X-VIVO 15 containing 5% FBS. The claim does not require all of the elements from claim 8, from which it depends, merely what the concentrations of whichever one(s) are in the medium. Thus, the X-VIVO 15 of Li reads on a medium comprising 5% FBS.
Regarding claims 4 and 11, Li teaches inducing iNKT cells by first resuspending PBMCs in lymphocyte culture medium at a cell concentration of 2x106/mL and adding 100 ng/mL α-GalCer and placed in an incubator at 37°C and 5% CO2 (p. 6, Example 1). Li teaches changing half of the medium every other day and analyzing the phenotype of iNKT cells by flow cytometry (p. 6, Example 1). Li teaches activating and expanding iNKT cells, wherein, on the 10th day of culture (claim 4), purified cells are resuspended in a lymphocyte culture medium containing 5 ng/mL IL-15 and incubated at 37°C and 5% CO2(p. 7, Example 1). The method of Li reads as the PBMCs are first cultured in the presence of α-GalCer prior to adding IL-15.
Regarding claim 12, Li teaches activating and expanding iNKT cells wherein the sorted iNKT cells are plated on pre-coated antibody plates, followed by administration of IL-15 on day 10 (pp. 6-7, Example 1), the 10th day of culture reads as the IL-15 is introduced in the culture medium after 1 to 5 days of culture.
Regarding claim 13, as disclosed in the 112b rejection above, for the purposes of compact prosecution, claim 13 is interpreted as the method according to claim 1, wherein said method further comprises a step of replacing 20-80% of the culture medium with a culture media comprising IL-15. Li teaches changing half of the medium every other day and analyzing the phenotype of iNKT cells by flow cytometry (p. 6, Example 1). Changing half of the medium reads as 50%, thus falls withing the range of 20-80%. Li teaches replating the iNKT cells wherein the cells are replated for activating and expanding, wherein, on the 10th day of culture, purified cells are resuspended in a lymphocyte culture medium containing 5 ng/mL IL-15 and incubated at 37°C and 5% CO2 (p. 7, Example 1). Resuspending the purified cells in a lymphocyte culture medium containing 5 ng/mL IL-15 reads as the replacement medium comprises IL-15.
Regarding claim 14, Li teaches replacing 50% of the culture medium every other day, thus, the media would have been changed on days 6 and 8.
Thus, the reference anticipates the subject matter of claims 1-2 and 4-14.
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (CN 113642646 A, published 01 October 2021) as evidenced by Lonza (Dendritic Cell (DC) and T Cell Assay from Matched PBMCs Instructions for use, published 2023) as applied to claims 1-2 and 4-14 above, and further in view of Biasi et al. (Frontiers in Immunology, November 2016, Vol. 7, Article 555, published 30 November 2016).
Li anticipate the subject matter of claims 1-2 and 4-14, and thus, also render them obvious.
Regarding claim 3, Li teaches magnetic beads sorting iNKT cells, however, is silent to specifically screening for CD4- iNKT cells.
Biasi teaches iNKT cells belong to the family of innate-like lymphocytes; they are T lymphocytes characterized by the expression of NK cell markers and an invariant alpha chain and represent less than 1% of circulating T lymphocytes (p. 2, Introduction). Biasi teaches iNKT cells are a specialized lymphocyte subset, which expresses an invariant Vα24Jα18 T-cell receptor and recognizes as cognate antigens self and foreign lipids presented by CD1d (p. 2, Introduction). Biasi teaches on the basis of CD4 and CD8 expression, mature iNKT cells can be divided into functionally distinct subsets, i.e., CD4+CD8-, CD4-CD8-, and CD4-CD8+ (p. 2, Introduction). Biasi teaches in a study of cytokine production of different subsets of iNKT cells in both controls and MS patients, all cells, both from patients and controls, presented the same phenotype, i.e., >50% DN, about 33% CD8+, and few CD4+; almost all cells were CD161++ (p. 4, 2nd column). Biasi teaches a gating strategy to identify iNKT cells expressing CD4, or CD8, or double negative (DN) cells using flow cytometry (p. 4, Results and Fig. 1). Biasi teaches subsets of iNKT cells have different immunological properties: CD4+ iNKT cells release Th1 and Th2 cytokines, while CD8+ and CD4−, CD8− cells exhibit Th1 phenotypes and cytotoxic activity (p. 2, Introduction).
Therefore, absent evidence of criticality, iNKT cells only comprise 3 main categories, CD8+, CD4+, and CD4/CD8 double negative. One of ordinary skill would immediately envision the choice of screening and isolating CD4- iNKT cells in the method of Li because Biasi teaches the majority of iNKT cells are CD4- and depending on the use case, double negative iNKT cells may be prefered. MPEP 2144.08.II.4(a) states that a genus may be so small that, when considered in light of the totality of the circumstances, it would anticipate the claimed species or subgenus. For example, it has been held that a prior art genus containing only 20 compounds and a limited number of variations in the generic chemical formula inherently anticipated a claimed species within the genus because “one skilled in [the] art would... envisage each member” of the genus. In re Petering, 301 F.2d 676, 681, 133 USPQ 275, 280 (CCPA 1962) (emphasis in original).
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.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lin et al. (Cytokine 76 (2015), pp. 348-355)
Lin teaches the effects of IL-15 on α-GalCer-expanded iNKT cell functions from umbilical cord blood and adult peripheral blood mononuclear cells.
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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