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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-60 are the original claims filed 9/26/2023. In the Preliminary Amendment of 5/28/2024, Claims 2, 4-7, 9-11, 15-18, 45, and 49-50 are amended and Claims 3, 12-14, 19-44, 46-48, and 51-60 are canceled.
Claims 1-2, 4-11, 15-18, 45, and 49-50 are all the claims.
Election/Restrictions
2. Applicant’s election of Group I without traverse on in the reply filed on 6/22/2026 is acknowledged.
3. Claims 45 and 49-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 6/22/2026.
4. Claims 1-2, 4-11 and 15-18 are the claims under examination.
Priority
5. USAN 18/474,824, filed 09/26/2023, Claims Priority from Provisional Application 63/377,529, filed 09/28/2022.
Information Disclosure Statement
6. As of 8/19/2026, a total of one (1) IDS is filed: 6/22/2026. The corresponding initialized and dated 1449 form is considered and of record.
Objections
Drawings
7. The drawings are objected to because:
a) the use of the term G-Rex, GREX, Origen, LOVO, ATCC, AIM V, which is a trade name or a mark used in commerce, has been noted in several of the drawings. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) Figure 26 contains irrelevant text in the drawings that are unrelated to the invention:
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Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term G-Rex, GREX, Origen, LOVO, ATCC, AIM V, MEGALIGN, DNASTAR, Ficoll, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See [1885 and 1886]. Applicants are required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
c) The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Claim Objections
9. Claims 1-2, 4-11 and 15-18 are objected to because of the following informalities:
a) Amend Claim 1 to recite “… a tumor infiltrating lymphocyte (TIL)…”.
See the abstract of disclosure.
b) Amend Claims 2(d), 6 and 8 to recite “[such] the second period”, “wherein [such] the target cell…”, and “wherein [such] the negative control cell”, respectively.
c) Amend claims 6 and 15-17 in the corresponding Markush group to recite for purposes of consistency “or combinations thereof” or “and combinations thereof.”
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
10. Claims 1, 4, 6, and 15-18 are rejected under 35 U.S.C. 101 because the disclosed invention is inoperative and therefore lacks utility. Claims 1, 4, 6, and 15-18 are rejected under 35 U.S.C. 101 because the claims are drawn to a selection process (method of determining a TIL function (potency)) without setting forth a control (negative) step involved in the process. The determination of the potency for the TIL of the invention requires the presence of a negative control and a negative control cell against which control values for one or more markers on the TIL and/or secretion of one or more analytes by the TIL that establish a corresponding threshold value but that is omitted from the claims. The claimed invention is without merit for a practical utility without comparative data from negative control(s) to establish a threshold value(s) for potency (activation). See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131,149 USPQ 475 (D.D.C. 1966).
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.
11. Claims 1, 4, 6, 11, and 15-18 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.
a) Claims 1, 4, 6, and 15-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the determination of the potency for the TIL of the invention in the presence of a negative control and a negative control cell against which control values for one or more markers on the TIL and/or secretion of one or more analytes by the TIL establish a corresponding threshold value. The claimed invention is without merit for a practical utility without comparative data from negative control(s).
Inasmuch as Claim 17 recites “the control value for one or more of the analytes”, it does not mention a control for the markers on the TIL and further still, the claim is indefinite for separate reasons herein below.
b) Claim 11 is indefinite for the term “about”. The specification provides a broad definition for the term much less amongst the ranges encompassed thereby at to the extent the claim is rendered indefinite:
[0627] The terms “about” and “approximately” mean within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, more preferably still within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the terms “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Moreover, as used herein, the terms “about” and “approximately” mean that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.
c) Claim 17 recites the limitation "the control value". There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not include a limitation for a control value so does not provide the antecedent basis for the phrase in dependent claim 17.
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.
Written Description
12. Claims 1-2, 4-11 and 15-18 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.
Claim interpretation:
Claims 1, 4, 6, and 15-18 are drawn to the method of determining the potency of a TIL that after a 1 step culture/(harvest/extraction) against a target cell and based on expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL, classified in A61K 40/11. Generic claim 1 is silent for a control step.
Claims 2, 5, 7-11 depend from Claim 1 with additional steps that include a negative control comprising a negative control cell or anti-HLA-blocking antibody co-cultured with the TIL to assess expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL.
“potency”: the specification equates the meaning of potency to activation at
[0657] In some embodiments, the potency of expanded or formulated TILs, MILs, and PBLs is examined by a co-culture assay described herein. Examining the potency of the expanded or formulated TILs, MILs, and PBLs allows for characterization of TIL, MIL, or PBL product lots. The potency of TILs, MILs, or PBLs, also referred to as activation, is defined as increased expression of select surface markers expressed as percentage of marker-positive cells or mean fluorescence intensity (MFI) upon coculture of TILs, MILs, or PBLs with Raji cells, or derivatives, variants, modifications, or progeny thereof, compared to co-culture of TILs, MILs, or PBLs with K562 cells.
“analyte”: the specification defines numerous species of analytes with one species inclusive of a cytokine ([0660]) and yet defines a cell surface marker as an analyte at [0661]:
[0660] In an embodiment, the invention includes a method for determining the potency of a T cell product using a target cell capable of binding to a T cell receptor, wherein the secretion or expression of an analyte is detected using a detection method. In an embodiment, the analyte detected is a protein. In an embodiment, the analyte detected is a cytokine. In an embodiment, the analyte detected is an interferon. In an embodiment, the analyte detected is interferon-alpha, also referred to as IFN-α or IFNα. In an embodiment, the analyte detected is interferon-alpha, also referred to as IFN-β or IFNβ. In an embodiment, the analyte detected is interferon-gamma, also referred to as IFN-γ or IFNγ. In an embodiment, the analyte detected is granzyme B, also referred to as GzmB. In an embodiment, the analyte detected is perforin. In an embodiment, the analyte detected is tumor necrosis factor alpha, also referred to as TNF-α or TNFα. In an embodiment, the analyte detected is an interleukin. In an embodiment, the analyte detected is IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-14, IL-16, IL-17, IL-18, IL-22, IL-25, or IL-26. In an embodiment, the analyte detected is CD25. In an embodiment, the analyte detected is CD69. In an embodiment, the analyte detected is CD137 (4-1BB). In an embodiment, the analyte detected is CD134 (OX40). In an embodiment, the analyte detected is CCL4. In an embodiment, the analyte detected is CD150, also known as SLAM, SLAM F1, or signaling lymphocytic activation molecule 1. In an embodiment, the analyte detected is KLRG1. In an embodiment, the analyte detected is KLRG1. In an embodiment, the analyte detected is secreted MIP-1β.
[0661] In an embodiment, the invention includes a method for determining the potency of a T cell product using a target cell capable of binding to a T cell receptor, wherein the secretion or expression of an analyte is detected using a detection method, wherein the T cell product is a TIL product, and wherein the analyte is a cell surface marker selected from the group consisting of CD25, CD69, CD134, CD137, and CD150.
The POSA could reasonably conclude that the determination of observed values for TIL potency may comprise any analyte known-and-yet to be discovered and that is the same or different from a marker used for an alleged separate determinant in resolving a threshold value.
“marker”: the specification defines a limited number of markers on a TIL cell relevant to the potency evaluation at
[0042] In some embodiments, the one or more markers on the T cell product are selected from the group consisting of CD25, CD69, CD134, CD137, CD150, KLRG1, or combinations thereof.
[0576] TILs can generally be defined either biochemically, using cell surface markers, or functionally, by their ability to infiltrate tumors and effect treatment. TILs can be generally categorized by expressing one or more of the following biomarkers: CD4, CD8, TCR αβ, CD27, CD28, CD56, CCR7, CD45Ra, CD95, PD-1, and CD25. Additionally and alternatively, TILs can be functionally defined by their ability to infiltrate solid tumors upon reintroduction into a patient.
[0623] TILs can generally be defined either biochemically, using cell surface markers, or functionally, by their ability to infiltrate tumors and effect treatment. TILs can be generally categorized by expressing one or more of the following biomarkers: CD4, CD8, TCR αβ, CD27, CD28, CD56, CCR7, CD45Ra, CD95, PD-1, and CD25. Additionally, and alternatively, TILs can be functionally defined by their ability to infiltrate solid tumors upon reintroduction into a patient. TILs may further be characterized by potency—for example, TILs may be considered potent if, for example, interferon (IFN) release is greater than about 50 pg/mL, greater than about 100 pg/mL, greater than about 150 pg/mL, or greater than about 200 pg/mL.
The POSA could reasonably conclude that the determination of observed values for TIL potency may comprise any marker known-and-yet to be discovered in resolving a threshold value.
“negative control cell”: the definition is specific for a marker for a negative control cell, namely, its being MHC or HLA expressionless or negative
[0593] The terms “negative control,” “negative control cell,” and “negative control cell line” refers to a cell that is used as a negative control for a T cell assay, including a TIL, MIL, or PBL assay. In an embodiment, a target cell lacks MHC Class I and Class II expression. In an embodiment, a target cell lacks MHC Class I expression. In an embodiment, a target cell lacks MHC or HLA Class I expression. In an embodiment, a target cell expresses MHC or HLA Class I and/or Class II at a minimal level.
“target cell”: the specification provides a per se definition albeit with little information about the specific aspect(s) that confer TIL-specific recognition and activation with the target cell at
[0587] The terms “target cell” and “target cell line” refers to a cell that is the assay target of a T cell, such as a TIL, MIL, or PBL. In an embodiment, a target cell expresses MHC Class I and/or Class II. In an embodiment, a target cell includes a Raji cell and derivatives, variants, modifications, and progeny thereof, as well as other cells that express MHC Class I and/or Class II. In an embodiment, a target cell includes a Thp1 cell and derivatives, variants, modifications, and progeny thereof. In an embodiment, a target cell includes a Ramos cell and derivatives, variants, modifications, and progeny thereof. In an embodiment, a target cell includes a U937 cell and derivatives, variants, modifications, and progeny thereof. In an embodiment, a target cell includes a Daudi cell and derivatives, variants, modifications, and progeny thereof. In an embodiment, the target cell is irradiated. In an embodiment, the target cell is not irradiated. In an embodiment, the target cell line is a combination of any two of a Raji cell line, a Thp1 cell line, a Ramos cell line, a U937 cell line, and a Daudi cell line. In an embodiment, the target cell line is a combination of any three of a Raji cell line, a Thp1 cell line, a Ramos cell line, a U937 cell line, and a Daudi cell line. In an embodiment, the target cell line is a combination of any four of a Raji cell line, a Thp1 cell line, a Ramos cell line, a U937 cell line, and a Daudi cell line. In an embodiment, the target cell line is a combination of a Raji cell line, a Thp1 cell line, a Ramos cell line, a U937 cell line, and a Daudi cell line. In an embodiment, a target cell line is a mixed tumor target cell line. In an embodiment, a target cell line is an alloreactive target cell line. In an embodiment, a target cell line is a mixed tumor alloreactive target cell line. In an embodiment, a target cell line is a mixed tumor alloreactive target cell line comprising a combination of at least two of the following cell lines: a Raji cell line, a Ramos cell line, a Thp1 cell line, a U937 cell line, and a Daudi cell line.
“derivatives, variants, modifications, or progeny thereof” as regards the scope of this genus is any target cell with any structure.
For example, the species of U937 cell and derivatives, variants, modifications, or progeny thereof (claim 6) can be a cell programmed into an induced pluripotent stem cell (iPSC) that can then be programmed into any cell type with any structure. Isogai et al. (PTO 892) teaches monocytes can be reprogrammed into induced pluripotent stem cells (Figure 1; Materials and Methods “Preparation of IPS cells”). Therefore derivatives, variants, modifications and progeny of the U937 cells can be induced into pluripotent stem cells.
Furthermore, Braganca et al. (PTO 892) teaches iPCs have the potential to differentiate into cells of the three germ layers (ectoderm, endoderm and mesoderm) and to originate virtually all cells of adult organisms (Introduction; p. 2). Therefore, derivatives, variants, modifications and progeny of the U937 cells can be virtually all cells.
Even further, the breadth encompasses any derivatives, variants, modifications and progeny of any target cell of the invention. AS such the breadth of the claimed target cell is enormously broad with an unfathomable number of structurally divergent and diverse cells.
Scope of the Invention
The interpretation encompasses methods comprising infinite combinations of different parameters in a co-culture system defined by generic terms “a target cell”, “one or more markers on a TIL”, “one or more analytes secreted from a TIL”, “a negative control”, “a negative control cell”, “HLA blocking antibody” with steps comprising “a first period” and “a second period” wherein the outcome yields “one or more observed values” in determining whether a TIL is potent or activated.
Because applicants seek patent protection for all such generic methods the claimed genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed.
Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Regents of the University of California v. Juno Therapeutics, Inc. (Fed. Cir. 2021) When claims recite functionally defined selection reagents (e.g., scFvs that bind to a "selected target"), merely stating the function or naming a boundless class is insufficient if the specification fails to disclose either a representative number of species or common structural features. If the binding/selection mechanism is unpredictable and the structural variety within the reagent genus is vast, the specification must provide concrete structural or biological characterization to prove possession.
Centocor Ortho Biotech, Inc. v. Abbott Labs. (Fed. Cir. 2012) The court held that fully isolating or selecting functional binding reagents (like antibodies) to a target does not automatically satisfy written description unless the generation and selection of those specific variants are routine, or the specification adequately describes their structural signatures
One of skill in the art could reasonably conclude the specification fails to disclose a representative number of reagents used in the method steps that are correlated by structure with a function that yields the method endpoint for the potency (activation) of any TIL above a threshold value.
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.
12. Claim(s) 1-2, 4-6, 9-11 and 15-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wardell et al. (US 10398734 B2; published/issued 2019-09-03).
Claims 1-2, 4-11 and 15-18 are prima facie obvious over Wardell.
AS regards claims 1-2, 4 and 18, Wardell teaches a method for producing a therapeutic population of infiltrating lymphocytes (TILs), comprising: (a) obtaining a first population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments; (b) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, (c) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (target cells), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs which comprises an increased subpopulation of effector T cells and/or central memory T cells relative to the second population of TILs, wherein the second expansion is followed by a collection of assays (the assessing step in claim 1) for evaluating the quality of TILs (“critical quality attributes”, see for example para. [2112]).
Wardell teaches and appreciates the co-culturing step of TILs with a target antigen, for example, being evaluated for interferon-7 (IFN-7) secretion in response to stimulation either with OKT3 or co-culture with autologous tumor digest. Other suitable antigens may include, e.g., NY-ESO-1, TRP-1, TRP-2, tyrosinase cancer antigen, MAGE-A3, SSX-2, and VEGFR2, or antigenic portions thereof. TIL may also be rapidly expanded by re-stimulation with the same antigen(s) of the cancer pulsed onto HLA-A2-expressing antigen-presenting cells. Alternatively, the TILs can be further re-stimulated with, e.g., example, irradiated, autologous lymphocytes or with irradiated HLA-A2+ allogeneic lymphocytes and IL-2. In some embodiments, the re-stimulation occurs as part of the second expansion. In some embodiments, the second expansion occurs in the presence of irradiated, autologous lymphocytes or with irradiated HLA-A2+ allogeneic lymphocytes and IL-2.
Wardell teaches and appreciates unstimulated or negative controls in an assay for potency determination at FIG. 92: Potency assessment of TIL products following T-cell activation. IFNγ secretion after re-stimulation with anti-CD3/CD28/CD137 in TIL products assessed by ELISA in duplicate (n=5). IFNγ secretion by the TIL products was significantly greater than unstimulated controls using Wilcoxon signed rank test (P=0.02), and consistently >1000 pg/ml. IFNγ secretion>200 pg/ml is considered to be potent. p value<0.05 is considered statistically significant.
Wardell teaches throughout the specification any of the method steps comprising a period (of time) for co-culturing the reagents of the process, e.g., In some embodiments, steps (i) through (vii) are performed within a period of about 40 days to about 50 days. In some embodiments, steps (i) through (vii) are performed within a period of about 42 days to about 48 days. In some embodiments, steps (i) through (vii) are performed within a period of about 42 days to about 45 days. In some embodiments, steps (i) through (vii) are performed within about 44 days.
Under MPEP 2144.05 In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960) (MPEP 716.02(d)).
As regards claim 5, Wardell teaches administering the more potent TIL for treating a patient where “There is an urgent need to provide TIL manufacturing processes and therapies based on such processes that are appropriate for commercial scale manufacturing and regulatory approval for use in human patients at multiple clinical centers.”
As regards claim 6, Wardell teaches examples of target cells comprising “peripheral blood mononuclear cells” and “PBMCs” refers to a peripheral blood cell having a round nucleus, including lymphocytes (T cells, B cells, NK cells) and monocytes. Preferably, the peripheral blood mononuclear cells are irradiated allogeneic peripheral blood mononuclear cells. PBMCs are a type of antigen-presenting cell.
AS regards claims 9-10, Wardell teaches target:TIL ratios at
(95) In some embodiments, at step (d) the antigen presenting cells (APCs) are added to the cell culture of the second population of TILs at a APC:TIL ratio of 25:1 to 100:1.
(96) In some embodiments, the cell culture has a ratio of 2.5×10.sup.9 APCs to 100×10.sup.6 TILs.
(237) In some embodiments the antigen-presenting feeder cells (APCs) are PBMCs. In an embodiment, the ratio of TILs to PBMCs and/or antigen-presenting cells in the rapid expansion and/or the second expansion is about 1 to 25, about 1 to 50, about 1 to 100, about 1 to 125, about 1 to 150, about 1 to 175, about 1 to 200, about 1 to 225, about 1 to 250, about 1 to 275, about 1 to 300, about 1 to 325, about 1 to 350, about 1 to 375, about 1 to 400, or about 1 to 500. In an embodiment, the ratio of TILs to PBMCs in the rapid expansion and/or the second expansion is between 1 to 50 and 1 to 300. In an embodiment, the ratio of TILs to PBMCs in the rapid expansion and/or the second expansion is between 1 to 100 and 1 to 200.
As regards claims 9-10, Wardell teaches control:TIL ratios at
Example 24: Evaluating a Range of Allogeneic Feeder Cell:TIL Ratios from 100:1 to 25:1
(1124) This study tested the proliferation of TIL at 25:1 and 50:1 against the control of 100:1 allogeneic feeder cells.
Under MPEP 2144.05 In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960) (MPEP 716.02(d)).
AS regards claims 1 and 15, Wardell teaches the markers of expanded TILs include CD137, CD69, KLRG1 and CD25 at
(307) In an embodiment, expression of one or more regulatory markers is measured. In some embodiments, the regulatory marker is selected from the group consisting of CD137, CD8a, Lag3, CD4, CD3, PD-1, TIM-3, CD69, CD8a, TIGIT, CD4, CD3, KLRG1, and CD154. In some embodiments, the regulatory marker is selected from the group consisting of CD137, CD8a, Lag3, CD4, CD3, PD-1, and TIM-3. In some embodiments, the regulatory marker is selected from the group consisting of CD69, CD8a, TIGIT, CD4, CD3, KLRG1, and CD154. In some embodiments, regulatory molecule expression is decreased in thawed TILs as compared to fresh TILs. In some embodiments, expression of regulatory molecules LAG-3 and TIM-3 is decreased in thawed TILs as compared to fresh TILs. In some embodiments, there is no significant difference in CD4, CD8, NK, TCRαβ expression. In some embodiments, there is no significant difference in CD4, CD8, NK, TCRαβ expression, and/or memory markers in fresh TILs as compared to thawed TILs. In some embodiments, there is no significant difference in CD4, CD8, NK, TCRαβ expression between the TILs produced by the methods provided herein, as exemplified for example in FIG. 27, and/or TILs prepared using other methods than those provide herein including for example, methods other than those embodied in FIG. 27.
(315) In some embodiments, the TILs are being evaluated for various regulatory markers. In some embodiments, the regulatory marker is selected from the group consisting of TCR α/β, CD56, CD27, CD28, CD57, CD45RA, CD45RO, CD25, CD127, CD95, IL-2R−, CCR7, CD62L, KLRG1, and CD122. In some embodiments, the regulatory marker is TCR α/β. In some embodiments, the regulatory marker is CD56. In some embodiments, the regulatory marker is CD27. In some embodiments, the regulatory marker is CD28. In some embodiments, the regulatory marker is CD57. In some embodiments, the regulatory marker is CD45RA. In some embodiments, the regulatory marker is CD45RO. In some embodiments, the regulatory marker is CD25. In some embodiments, the regulatory marker is CD127. In some embodiments, the regulatory marker is CD95. In some embodiments, the regulatory marker is IL-2R−. In some embodiments, the regulatory marker is CCR7. In some embodiments, the regulatory marker is CD62L. In some embodiments, the regulatory marker is KLRG1. In some embodiments, the regulatory marker is CD122.
As regards claims 16-17, Wardell teaches a co-culture assay can be included to evaluate TILs for analyte (cytokine) release (IFN- gamma secretion) (para. [0452]). Wardell teaches IFN-gamma release is a marker for potency of TILs and can be measured with assays (para. [2397]).
(182) TILs can generally be defined either biochemically, using cell surface markers, or functionally, by their ability to infiltrate tumors and effect treatment. TILs can be generally categorized by expressing one or more of the following biomarkers: CD4, CD8, TCR αβ, CD27, CD28, CD56, CCR7, CD45Ra, CD95, PD-1, and CD25. Additionally, and alternatively, TILs can be functionally defined by their ability to infiltrate solid tumors upon reintroduction into a patient. TILS may further be characterized by potency—for example, TILS may be considered potent if, for example, interferon (IFN) release is greater than about 50 pg/mL, greater than about 100 pg/mL, greater than about 150 pg/mL, or greater than about 200 pg/mL.
(335) In some embodiments, TIL health is measured by IFN-gamma (IFN-γ) secretion. In some embodiments, IFN-γ secretion is indicative of active TILs. In some embodiments, a potency assay for IFN-γ production is employed. IFN-γ production is another measure of cytotoxic potential. IFN-γ production can be measured by determining the levels of the cytokine IFN-γ in the media of TIL stimulated with antibodies to CD3, CD28, and CD137/4-1BB. IFN-γ levels in media from these stimulated TIL can be determined using by measuring IFN-γ release. In some embodiments, an increase in IFN-γ production in for example Step D as provided in FIG. 27 TILs as compared to initially harvested TILs in for example Step A as provided in FIG. 27 is indicative of an increase in cytotoxic potential of the Step D TILs. In some embodiments, IFN-γ secretion is increased one-fold, two-fold, three-fold, four-fold, or five-fold or more. In some embodiments, IFN-γ secretion is increased one-fold. In some embodiments, IFN-γ secretion is increased two-fold. In some embodiments, IFN-γ secretion is increased three-fold. In some embodiments, IFN-γ secretion is increased four-fold. In some embodiments, IFN-γ secretion is increased five-fold. In some embodiments, IFN-γ is measured using a Quantikine ELISA kit. In some embodiments, IFN-γ is measured in TILs ex vivo. In some embodiments, IFN-γ is measured in TILs ex vivo, including TILs produced by the methods of the present invention, including for example FIG. 27 methods, as well as freshly harvested TILs or those TILs produced by other methods, such as those provided for example in FIG. 83 (such as for example process 1C TILs).
Two additional critical quality attributes of TIL are their ability to release IFN-γ and/or Granzyme B following cytokine (CD3/CD28/4-1BB) stimulation.
As regards claim 17, Wardell teaches analyte release and fold increase (335) In some embodiments, TIL health is measured by IFN-gamma (IFN-γ) secretion. In some embodiments, IFN-γ secretion is indicative of active TILs. In some embodiments, a potency assay for IFN-γ production is employed. IFN-γ production is another measure of cytotoxic potential. IFN-γ production can be measured by determining the levels of the cytokine IFN-γ in the media of TIL stimulated with antibodies to CD3, CD28, and CD137/4-1BB. IFN-γ levels in media from these stimulated TIL can be determined using by measuring IFN-γ release. In some embodiments, an increase in IFN-γ production in for example Step D as provided in FIG. 27 TILs as compared to initially harvested TILs in for example Step A as provided in FIG. 27 is indicative of an increase in cytotoxic potential of the Step D TILs. In some embodiments, IFN-γ secretion is increased one-fold, two-fold, three-fold, four-fold, or five-fold or more. In some embodiments, IFN-γ secretion is increased one-fold. In some embodiments, IFN-γ secretion is increased two-fold. In some embodiments, IFN-γ secretion is increased three-fold. In some embodiments, IFN-γ secretion is increased four-fold. In some embodiments, IFN-γ secretion is increased five-fold. In some embodiments, IFN-γ is measured using a Quantikine ELISA kit. In some embodiments, IFN-γ is measured in TILs ex vivo. In some embodiments, IFN-γ is measured in TILs ex vivo, including TILs produced by the methods of the present invention, including for example FIG. 27 methods, as well as freshly harvested TILs or those TILs produced by other methods, such as those provided for example in FIG. 83 (such as for example process 1C TILs).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method steps of Wardell to produce and select a TIL with potency (activation) above the threshold for a control using well understood assays for determining potency-related markers (e.g., CD137, CD69, KLRG1 and CD25) or potency-related analytes (measuring IFN-gamma or granzyme B) in the supernatant as suggested by Wardell with a reasonable expectation of success.
13. Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Wardell et al. (US 10398734 B2; published/issued 2019-09-03) as applied to claims 1-2 above, and in further view of Sarnaik et al. (US 2017/0044496 A1).
Although Wardell teaches the use of a negative control (para. [0215, 02406]), and regarding claim 2, Sarnaik teaches that blockade of HLA class 1 with an anti-HLA antibody (W6/32 anti-HLA-ABC) can inhibit the increased outgrowth and expansion of T cell products (para. 0150, 0153-154]; Figure 7A; para [0013]). Sarnaik evidences blockade of HLA class 1 with an anti-HLA antibody (W6/32 anti-HLA-ABC) can be used as a negative control (Figure 7A). Sarnaik teaches using the HLA blocking antibody at about 1-20 μg/mL (80 μg/mL; para. [0125]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention taught by Wardell to combine the HLA-blocking antibody of Sarnaik as a negative control. One of ordinary skill would have been motivated to do so as taught by Sarnaik because the HLA-blocking antibody would inhibit the increased outgrowth and expansion of the T cell products, and therefore not have a response, which is the purpose of a negative control. Regarding the reasonable expectation of success, Sarnaik demonstrates blockade of HLA class 1 with an anti-HLA antibody (W6/32 anti-HLA-ABC) can be used as a negative control (Figure 7A).
14. Claims 1-2 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Wardell et al. (US 10398734 B2; published/issued 2019-09-03) as applied to claims 1-2 above, and in further view of Veerapathran et al. (US 2018/0127715 A1) as evidenced by www.dsmz.de/collection/catalogue/details/culture/ACC-10 Product data sheet for K562).
Although Wardell teaches the use of a negative control cell (para. [0215, 02406]), and regarding claims 7-8, Veerapathran teaches the art-recognized use of the MHC-, K562 cell line and modifications thereof in TIL expansion yet with the caveats associated with the cell line at
[0004] Unfortunately, aAPCs developed for use in the expansion of TILs have suffered from poor performance when compared to PBMCs, including alterations of the phenotypic properties of the input TILs, as well as poor expansion performance and/or high variability in expansion results. Because of the large number of potential cells that might be adapted for use as aAPCs and the unpredictability of identifying suitable candidates, the focus of aAPC development for polyclonal TILs to date has been solely on the well-established K562 cell line. Butler and Hirano, Immunol. Rev. 2014, 257, 191-209. For example, K562 cells modified to express 4-1BBL (CD137L) were tested in pre-REP culture (but not in REP culture) to determine enhancement of TIL expansion from tumor digest, but PBMCs were still required to be used in conjunction with K562 cells to obtain TIL expansion. Friedman, et al., J. Immunother. 2011, 34, 651-661. Other engineered K562 cells modified to express CD64, CD86, and 4-1BBL were tested and achieved TIL expansion that was at best comparable to PBMCs, and most likely less than PBMCs, and also suffered from skewing of the polyclonal TIL phenotype to a less favorable CD8.sup.+/CD4.sup.+T cell ratio. Ye, et al., J. Translat. Med. 2011, 9, 131. Recently, K562 cells modified to express CD86, 4-1BBL (CD137L), high affinity Fc receptor (CD64) and membrane-bound IL-15 have also been shown to propagate TIL (post-REP) at equivalent numbers compared to PBMC feeders, but with the additional complexity of membrane-bound IL-15. Forget, et al., J. Immunother. 2014, 37, 448-60. Other systems developed have lacked critical costimulatory molecules, have led to unfavorable T cell phenotypic skewing, or have required additional interleukins (such as IL-21). Butler and Hirano, Immunol. Rev. 2014, 257, 191-209. Overall, K562 modified aAPCs have not been shown to provide for consistent expansion of TILs with acceptable variability while also performing better than PBMCs in other measures including overall expansion cell counts. Alternative aAPCs besides K562 cells have been successful in other cell expansion methods, but have not achieved the same performance as PBMCs with the unique polyclonal subset of cells that make up TILs. Maus, et al., Nat. Biotechnol. 2002, 20, 143-148; Suhoski, et al., Mol. Ther. 2007, 15, 981-988.
As evidenced by as evidenced by DSMZ product data sheet the K562 cell line is MHC negative.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention taught by Wardell to combine the K562 cell of Veerapathran as a negative control. One of ordinary skill would have been motivated to do so as taught by Veerapathran because the MHC- K562 cell was long recognized as suitable in the co-culture methods for TILs but with insufficient bioactivity on the TILs, and therefore would have been predictable that their use in the method of Wardell would not result in a response on TILs, which is the purpose of a negative control. Regarding the reasonable expectation of success, Veerapathran teaches the predictability of the neutral effect of K562 cell on TILs qualifies it as a negative control.
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 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.
15. Claims 1-2, 4-11 and 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12570961 in view of Wardell et al. (US 10398734 B2; published/issued 2019-09-03).
The ref claims are not afforded safe harbor under 35 USC 121 because the ref claims share no continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claim sets are drawn to a method of determining the potency of a TIL that after a 1 step culture/(harvest/extraction) against a target cell and based on expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL, with additional steps that include a negative control comprising a negative control cell or anti-HLA-blocking antibody co-cultured with the TIL to assess expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL. The ref patent teaches using U937 cells as a target cell that reads on, anticipates and renders obvious the species U937 cell in instant claim 6.
Ref claims:
1. A method of determining the potency of a tumor infiltrating lymphocyte (TIL) cell product comprising TIL cells, the method comprising the steps of: i. performing at least three co-cultures of U937 target cells with TIL cell product cells at different U937 target cell concentrations; ii. performing at least three co-cultures of U937 target cells with T cell reference standard cells at different U937 target cell concentrations; iii. extracting supernatants from each of the co-cultures; and iv. assessing the supernatants for interferon-gamma (IFN-γ) secreted from the TIL cell product cells and T cell reference standard cells to obtain U937 target cell dose-concentrations to determine the potency of the TIL cell product; wherein the U937 target cells express a major histocompatibility complex (MHC) and the TIL cells express a T cell receptor (TCR), wherein the TIL cells are activated via allogeneic MHC-TCR engagement between the MHC of the U937 target cells and the TCR of the TIL cells during the co-culture assay.
2. The method of claim 1, wherein the co-cultures are performed for a time period selected from the group consisting of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, and about 48 hours.
3. The method of claim 1, wherein four U937 target cell dose-concentrations of about 4×10.sup.5, about 2×10.sup.5, about 1×10.sup.5, and about 0.5×10.sup.5 U937 target cells per well and a single TIL cell concentration of about 1.5×10.sup.6 TIL per well are used.
4. The method of claim 1, wherein at least four co-cultures of U937 target cells with TIL cell product cells and at least four co-cultures of U937 target cells with T cell reference standard cells are used, parallel line analysis is performed, and one outlier U937 target cell dose-concentration is discarded.
5. The method of claim 1, wherein the method is a component of a potency assay matrix.
6. The method of claim 5, wherein the potency assay matrix comprises one or more assays selected from the group consisting of a bead- or plate-based assay using CD3, CD28, and/or CD137 stimulation and reporting interferon-γ, granzyme B, or tumor necrosis factor-α, an assay for total viable cells, an assay for percentage viable cells, an assay for CD4.sup.+ cell content, an assay for CD8.sup.+ cell content, an assay for T.sub.EM cell content, an assay for T.sub.CM cell content, an assay for LAG3.sup.+ cell content, and an assay for KLRG1.sup.+ cell content, an assay for CD101.sup.+ cell content, an assay for CD69.sup.+ cell content, an assay for T.sub.SCM cell content, an assay for T.sub.EMRA cell content, an assay for Treg cell content, an assay for PD-1.sup.+ cell content, an assay for TIM3.sup.+ cell content, an assay for CD25.sup.+ cell content, an assay for CD27.sup.+ cell content, an assay for CD28.sup.+ cell content, an assay for CD56.sup.+ cell content, an assay for CTLA-4.sup.+ cell content, an assay for TIGIT.sup.+ cell content, and an assay for CD57.sup.+ cell content.
7. The method of claim 1, wherein prior to step i, the method further comprises: (a) obtaining and/or receiving a first population of TILs from a tumor resected from a patient by surgical resection, needle biopsy, core biopsy, small biopsy, or other means by processing a tumor sample obtained from the patient into (i) multiple tumor fragments or (ii) a tumor digest; (b) adding the first population of TILs into a closed system; (c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system; (d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a therapeutic population of TILs, wherein the second expansion is performed for about 7-14 days, wherein the therapeutic population of-TILs comprises the TIL cell product, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system; (e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; (f) transferring the therapeutic population of TILs from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system; and (g) optionally cryopreserving the infusion bag comprising the therapeutic population of TILs from step (f).
8. The method of claim 7, wherein examining the potency and/or functionality of the TILs harvested occurs after cryopreservation, or optionally before and after cryopreservation.
9. The method of claim 7, wherein the patient has a tumor that is unresectable, metastatic, resistant, or refractory to a CTLA-4 inhibitor, PD-1 inhibitor, or a PD-L1 inhibitor, and optionally wherein the patient has been previously treated with a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.
10. The method of claim 7, wherein the second population of TILs in step (c) is at least 50-fold greater in number than the first population of TILs.
11. The method of claim 7, wherein the first expansion and/or the second expansion is performed over a period of about 10 to about 12 days.
12. The method of claim 7, wherein the first expansion and/or the second expansion is performed over a period of about 11 days or about 12 days.
13. The method of claim 7, wherein the IL-2 is present at an initial concentration of between 1000 IU/mL and 6000 IU/mL in the cell culture medium in the first expansion.
14. The method of claim 7, wherein in the second expansion step, the IL-2 is present at an initial concentration of between 1000 IU/mL and 6000 IU/mL and the OKT-3 antibody is present at an initial concentration of about 30 ng/ml.
15. The method of claim 7, wherein the patient has a cancer selected from the group consisting of melanoma, ovarian cancer, pancreatic cancer, endometrial cancer, thyroid cancer, cervical cancer, non-small-cell lung cancer (NSCLC), small-cell lung cancer, bladder cancer, breast cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)), glioblastoma, gastrointestinal cancer, renal cancer, sarcoma, and renal cell carcinoma.
16. The method of claim 1, wherein for at least one of the co-cultures in step (i), the ratio of TIL cell product cells: U937 target cell is about 15:1.
17. The method of claim 1, wherein for at least one of the co-cultures in step (ii), the ratio of T cell reference standard cells: U937 target cell is about 15:1.
18. The method of claim 1, wherein the co-cultures in step (i) and/or step (ii) are performed in a cell culture medium comprising IL-2.
19. The method of claim 18, wherein the cell culture medium comprises an IL-2 concentration of about 300 IU/mL.
20. The method of claim 1, wherein an HLA blocking antibody is used as a negative control in step (i) and/or step (ii), wherein the corresponding co-culture for the negative control is performed in the presence of the HLA blocking antibody.
21. The method of claim 20, wherein the HLA blocking antibody is at a concentration of about 1-20 μg/mL.
22. The method of claim 1, wherein no anti-CD3 antibody is added during any of steps i. to iv.
16. Claims 1-2, 4-11 and 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12553031 in view of Wardell et al. (US 10398734 B2; published/issued 2019-09-03).
The ref claims are not afforded safe harbor under 35 USC 121 because the ref claims share no continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claim sets are drawn to a method of determining the potency of a TIL that after a 1 step culture/(harvest/extraction) against a target cell and based on expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL, with additional steps that include a negative control comprising a negative control cell or anti-HLA-blocking antibody co-cultured with the TIL to assess expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL. The ref patent teaches using U937 cells as a target cell that reads on, anticipates and renders obvious the species U937 cell in instant claim 6.
Ref claims
1. A method for determining the potency and/or functionality of a tumor infiltrating lymphocyte (TIL) product comprising TIL cells, the method comprising: (a) measuring interferon gamma (IFN-γ) release from the TIL product by a co-culture assay, wherein the co-culture assay comprises (i) co-culturing TIL cells from the TIL product with U937 target cells, and (ii) detecting IFN-γ released by the TIL cells, wherein the U937 target cells express a major histocompatibility complex (MHC) and the TIL cells express a T cell receptor (TCR), wherein the TIL cells are activated via allogeneic MHC-TCR engagement between the MHC of the U937 target cells and the TCR of the TIL cells during the co-culture assay; (b) measuring IFN-γ release from the TIL product by a bead-based assay; and (c) measuring, using a flow cytometry assay, LAG3.sup.+ cell content, KLRG1.sup.+ cell content, the sum of CD4.sup.+ cell content and CD8.sup.+ cell content, total viable TCM and TEM cell population, and CD45.sup.+/CD3.sup.+ cell content of the TIL product.
2. The method of claim 1, wherein the bead-based assay comprises stimulating TIL cells from the TIL product with an anti-CD3 antibody, an anti-CD28 antibody, and/or an anti-CD137 antibody, and detecting IFN-γ released by the TIL cells.
3. The method of claim 1, wherein the co-culture assay for IFN-γ release comprises the steps of: a) co-culturing the U937 target cells with the TIL cells to provide a co-culture; b) extracting supernatant from the co-culture; and c) assessing the supernatant for IFN-γ.
4. The method of claim 3, wherein the co-culturing is performed for a time period selected from the group consisting of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, and about 48 hours.
5. The method of claim 3, wherein the ratio of TIL cell:U937 target cell is about 15:4, about 15:2, about 15:1, or about 30:1.
6. The method of claim 3, wherein the co-culturing is performed in a cell culture medium comprising IL-2.
7. The method of claim 6, wherein the cell culture medium comprises IL-2 at a concentration of about 300 IU/mL.
8. The method of claim 3, wherein an HLA blocking antibody is added in the co-culture as a negative control.
9. The method of claim 8, wherein the HLA blocking antibody is used at a concentration of about 1-20 μg/mL.
10. The method of claim 1, wherein the TIL product is produced by a method comprising: (i) performing a first expansion by culturing a first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs; (ii) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs; (iii) harvesting the therapeutic population of TILs obtained from step (ii); (iv) transferring the therapeutic population of TILs from step (iii) to an infusion bag; and (v) cryopreserving the infusion bag.
11. The method of claim 10, wherein steps (a)-(c) are performed after cryopreservation.
12. The method of claim 1, wherein the TIL product comprises CD8+ TILs and CD4+ TILs.
13. The method of claim 1, wherein the co-culture assay for IFN-γ release comprises the steps of: a) performing at least three different co-cultures of U937 target cells with the TIL cells at different U937 target cell concentrations; b) extracting supernatants from each of the co-cultures; and c) assessing the supernatants from each of the co-cultures for IFN-γ secreted from the TIL cells to determine the potency of the TIL product.
17. Claims 1-2, 4-11 and 15-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 8, 12-17, 19-20 and 23 of copending Application No. 18/477,810 (reference application US 20240082375). in view of Wardell et al. (US 10398734 B2; published/issued 2019-09-03).
The ref claims are not afforded safe harbor under 35 USC 121 because the ref claims share no continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claim sets are drawn to a method of determining the potency of a TIL that after a 1 step culture/(harvest/extraction) against a target cell and based on expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL, with additional steps that include a negative control comprising a negative control cell or anti-HLA-blocking antibody co-cultured with the TIL to assess expression of one or more markers on the TIL or one or more analytes in the supernatant that are used to obtain one or more values to determine the potency of the TIL. The ref teaches using U937 cells as a target cell that reads on, anticipates and renders obvious the species U937 cell in instant claim 6.
Ref claims
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
18. No claims are allowed.
19 Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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