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
Claims 1-20, 22, and 24-26 are pending.
Claims 21 and 23 are canceled.
Claim 1 is currently amended.
Claims 1-20, 22, and 24-26 are under examination on the merits.
Rejections Withdrawn
35 U.S.C. 103
The rejection of claims 1-14, 20, and 24-26 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS) is withdrawn in view of the claim amendments, dated 11/05/2025.
The rejection of claims 15 and 16 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) and Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), as applied to claims 1-14 and 20, and further in view of Maeurer (WO 2015/189356, international publication date: 12/17/2015, IDS) is withdrawn in view of the claim amendments, dated 11/05/2025.
The rejection of claim 17 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) and Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), as applied to claims 1-14 and 20, and further in view of Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS) is withdrawn in view of the claim amendments, dated 11/05/2025. Claim 21 is canceled.
The rejection of claims 18 and 19 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) and Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), as applied to claims 1-14 and 20, and further in view of Bozzetti et al. (J Thorac Oncol., 3:18-22, 2008) is withdrawn in view of the claim amendments, dated 11/05/2025.
The rejection of claim 22 under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) and Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), as applied to claims 1-14 and 20, and further in view of Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010) is withdrawn in view of the claim amendments, dated 11/05/2025.
Nonstatutory Double Patenting
The nonstatutory double patenting rejections of record have been maintained.
Response to Arguments
In Applicant Arguments, dated 11/05/2025, Applicant asserts that “[t]he Examiner makes the unfounded assumption that lowering the expansion time would have a beneficial effect on TIL expansion outcome. This assumption is unfounded based on the prior art, which teaches: 1. larger starting materials from tumor resections (e.g., 2 cm starting size) and 2. Longer TIL culture times. Absent such recognition in the prior art, the optimization rationale under In re Aller relied upon by the Examiner does not apply here… neither Dudley nor Ochoa identifies compressing each expansion step to approximately 3-11 days (or completing the overall process in approximately 17-22 days) as a parameter that predictably delivers the claimed therapeutic outcome-namely, therapeutic-scale TIL numbers with preserved phenotype within the restricted total timeline. Dudley teaches a long pre-REP followed by an approximately 14-day REP from large tumor fragments, while Ochoa involves PBLs, not FNA-derived TILs. Thus, the very relationship the Examiner asserts-that step duration controls the claimed product/result specifically in this FNA TIL expansion process-is not recognized in the cited art.”
These arguments have been fully considered but are not sufficient to overcome the obviousness rejections of record. The Non-Final Rejection, dated 08/06/2025, does not state that lowering the expansion time would have a beneficial or deleterious effect on TIL expansion outcome. The action makes the argument that one of ordinary skill in the art would have been motivated to experiment with different expansion times in order to determine which expansion time provides an optimal or desired number of TILs. Culture time is a critical variable for any cell expansion protocol. Furthermore at [0026], Dudley et al. state that while 14 days is a preferable culture time for the second expansion step, i.e., the rapid expansion step, Dudley also states that rapid expansion of TILs generally occurs over a range from about 10 to about 14 days, which overlaps with the 3-11 day range recited in claim 1. - “An embodiment of the method comprises expanding cultured T cells. The cultured T cells are pooled and rapidly expanded. Rapid expansion provides an increase in the number of antigen-specific T-cells of at least about 50-fold (e.g., 50-, 60-, 70-, 80-, 90-, or 100-fold, or greater) over a period of about 10 to about 14 days, preferably about 14 days. More preferably, rapid expansion provides an increase of at least about 200-fold (e.g., 200-, 300-, 400-, 500-, 600-, 700-, 800-, 900-, or greater) over a period of about 10 to about 14 days, preferably about 14 days. Most preferably, rapid expansion provides an increase of at least about 1000-fold over a period of about 10 to about 14 days, preferably about 14 days. Preferably, rapid expansion provides an increase of about 1000-fold over a period of about 14 days (emphasis added).” Additionally the teaching in Dudley et al. that that rapid expansion of TILs generally occurs over a range from about 10 to about 14 days suggests that expansion time is a variable that requires at least a measure of optimization. This assertion is further supported by [0025] of Dudley et al., which indicates that primary tumor sample cultures are incubated until confluence, which may take between 5 and 21 days - “An embodiment of the method comprises culturing autologous T cells. Tumor samples are obtained from patients and a single cell suspension is obtained. The single cell suspension can be obtained in any suitable manner, e.g., mechanically (disaggregating the tumor using, e.g., a gentleMACS.TM. Dissociator, Miltenyi Biotec, Auburn, Calif.) or enzymatically (e.g., collagenase or DNase). Single-cell suspensions of tumor enzymatic digests are cultured in interleukin-2 (IL-2), e.g., in multiple wells. The cells are cultured until confluence (e.g., about 2.times.10.sup.6 lymphocytes), e.g., from about 5 to about 21 days, preferably from about 10 to about 14 days. For example, the cells may be cultured from 5 days, 5.5 days, or 5.8 days to 21 days, 21.5 days, or 21.8 days, preferably from 10 days, 10.5 days, or 10.8 days to 14 days, 14.5 days, or 14.8 days.”
Applicant further asserts that “[t]he skilled artisan would not have a reasonable expectation of successfully obtaining enough TILs for therapeutically relevant application by simultaneously reducing both the prior art's suggested TIL expansion time and starting material amount.”
This argument has been fully considered but is not sufficient to overcome the obviousness rejections of record. The only claim that appears to recite a starting material amount is claim 17, which requires a fine needle aspirate (FNA) tumor biopsy of at least 400,000 TILs. As indicated in the Non-Final Rejection, dated 04/17/2025, given that the FNA-based method of Carrasco et al. yielded 200,000 cells per tube, which suggests more than one tube, it is submitted that the method of the prior art renders bvious an FNA tumor biopsy of at least 400,000 TILs.
With respect to the teachings of Carrasco et al. and Singh et al., Applicant asserts that “Carrasco is a diagnostic cytology/flow cytometry paper on testing samples for, e.g., breast cancer expression profiles. It specifies collecting samples with 22-gauge needles into CytoLyt and processing them into single-cell suspensions (mesh filtration, RBC lysis, and fixatives) to enable FACS immunophenotyping, not to generate viable, clinical-grade TIL products via pre-REP/REP. Nothing in Carrasco suggests (a) two-step TIL expansion, (b) 3-11-day step windows, (c) an overall 17-22-day cycle, or (d) obtaining samples through FNA to support therapeutic-scale TIL manufacturing as presently claimed… Similarly, Singh is a diagnostic/assay platform. It lists FNA among many possible sample types for antibody-based assays (e.g., HER2 pathway profiling) and repeatedly treats FNA as limited-material diagnostic input. It has no disclosure or suggestion that FNA or small biopsies as presently claimed could be used as a starting sample for TIL pre-REP/REP manufacturing. Thus, the skilled artisan reading Carrasco or Singh would not have a reasonable suggestion that utilizing a fine needle aspirate with 25-18 gauge needles or a small biopsy with 16-11 gauge needles would provide enough viable cells for TIL expansion.”
These arguments have been fully considered but are not sufficient to overcome the obviousness rejections of record. It is initially noted that “[o]ne cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).” With respect to the teachings of Carrasco et al., this reference does not teach obtaining FNA samples for TIL manufacturing; however the reference clearly teaches that tumor samples may be obtained via FNA. The claimed (a) two-step TIL expansion, (b) 3-11 day step windows, and (c) an overall 17-22 day cycle are suggested by the prior art as indicated in the 35 U.S.C. 103 rejections detailed below. Furthermore it is noted that Singh et al. provide “no disclosure or suggestion that FNA or small biopsies as presently claimed could be used as a starting sample for TIL pre-REP/REP manufacturing.” However as indicated in the 35 U.S.C. 103 rejections detailed below, TIL pre-REP/REP manufacturing and tumor sampling via FNA is taught by the prior art.
With respect to the nonstatutory double patenting rejections of record, Applicant asserts that “the presently amended claims are not an obvious variant over these patents and co-pending applications at least because the claims of these applications and patents do not specify that the tumor sample be cultured from a FNA or small biopsy that is obtained with either a 25-18 or 16-11 gauge needle for use in TIL manufacturing processes.”
These arguments have been fully considered but are not deemed persuasive. The reference applications and patents, in view of the cited references, would render the instant claims obvious, as indicated in the claim rejections under 35 U.S.C. 103 detailed below. As such the nonstatutory double patenting rejections of record have been maintained.
New Grounds of Rejection
35 U.S.C. 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 1-14, 17, 20, 22, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010).
Dudley et al. teach “a method of promoting regression of a cancer in a mammal comprising (i) culturing autologous T cells; (ii) expanding the cultured T cells using. OKT-3 antibody, IL-2, and feeder lymphocytes, wherein the cultured T cells are enriched for CD8+ T cells prior to expansion of the T cells; (iii) administering to the mammal nonmyeloablative lymphodepleting chemotherapy; and (iv) after administering nonmyeloablative lymphodepleting chemotherapy, administering to the mammal the expanded T cells…” At [030] and [0031], Dudley et al. teach that said method may be performed using “young” tumor-infiltrating lymphocytes (TILs) - “Young T cell cultures that are administered to the mammal in accordance with an embodiment of the invention advantageously have features associated with in vivo persistence, proliferation, and antitumor activity. For example, young T cell cultures have a higher expression of CD27 and/or CD28 than T cells that are about 44 days old. Without being bound to a particular theory, it is believed that CD27 and CD28 are associated with proliferation, in vivo persistence, and a less differentiated state of T cells (the increased differentiation of T cells is believed to negatively affect the capacity of T cells to function in vivo). T cells expressing higher levels of CD27 are believed to have better antitumor activity than CD27-low cells. Moreover, young T cell cultures have a higher frequency of CD4+ cells than T cells that are about 44 days old… In addition, young T cell cultures have a mean telomere length that is longer than that of T cells that are about 44 days old. Without being bound to a particular theory, it is believed that T cells lose an estimated telomere length of 0.8 kb per week in culture, and that young T cell cultures have telomeres that are about 1.4 kb longer than T cells that are about 44 days old. Without being bound to a particular theory, it is believed that longer telomere lengths are associated with positive objective clinical responses in patients and persistence of the cells in vivo.”
At [0063] - [0066], Dudley et al. teach the generation of “young” TILs may be initiated by first obtaining a tumor sample from a patient and preparing single-cell suspensions. Five days following initiation, IL-2 was added to the cells (first expansion). 10-18 days following initiation, rapid expansion (second expansion) was performed by culturing the cells in IL-2 with an anti-CD3 antibody and peripheral blood mononuclear cells (PBMCs). As indicated above, Dudley et al. teach that TILs may be expanded using the anti-CD3 antibody, OKT-3. On day 14 of the rapid expansion, “young” TILs were produced with an average expansion of over 300-fold. It is noted that day 14 meets the limitation of “about 12 days.” At [006], Dudley et al. teach that there are multiple options for the initial cell preparation for culturing TILs, including a fine needle aspirate from tumor tissues.
Therefore Dudley et al. teach a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs; however Dudley et al. do not teach or suggest a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs. Dudley et al. also do not teach or suggest FNA biopsies obtained with 25-18 gauge needles or small biopsies obtained with 16-11 gauge needles. These deficiencies are remedied by Ochoa et al., Carrasco et al., and Singh et al.
Ochoa et al. teach methods of in vitro culturing of lymphocytes to illicit killer activity, see column 1. At Example 3, Ochoa et al. teach that the initial culturing of TILs isolated from patients may be supplemented with IL-2 and an anti-CD3 antibody, such as OKT-3 (see Example 1). Ochoa et al. teach that TILs initially cultured with IL-2 and OKT-3 demonstrated a greater increase in cell number compared to TILs initially cultured in IL-2 alone, and Ochoa et al. further teach that TILs cultured with OKT-3 appeared to exhibit a greater degree of cytotoxicity per culture compared to TILs cultured without OKT-3.
Carrasco et al. teach a method of obtaining tumor samples via FNA – “A multidirectional fine-needle aspiration biopsy (FNAB) from the tumor was performed with a 22-gauge needle connected to a 20 ml plastic syringe that was attached to a metal holder. The aspirate was resuspended and fixed in CytoLyt solution (Cyto Corporation, Boxborough, MA), maintained at 4° C, and analyzed within 24-48 hr. The cells which were resuspended in the CytoLyt solution were then passed through a 35-mm nylon mesh, centrifuged at 500 g, and resuspended and permeabilized in PBS (phosphate buffered saline) containing 0.1% BSA (bovine serum albumin) and 0.2% saponin (PBSAP). 200,000 cells/ tube were incubated for 1 hr at room temperature in 100 ml PBSAP… (emphasis added).”
At [0593], Singh et al. teach that tumor biopsy samples may be surgically extracted using either 14 or 16 gauge needles, and at [0613]-[0616], Singh et al. teach that said tumor cells isolated from biopsy may be subsequently cultured with growth factors.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Dudley et al. with the teachings of Ochoa et al., Carrasco et al., and Singh et al. to develop a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle. One of ordinary skill in the art would have been motivated to do so, because Dudley et al. teach a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs. Furthermore Ochoa et al. teach that TILs initially cultured with IL-2 and OKT-3 demonstrated a greater increase in cell number compared to TILs initially cultured in IL-2 alone, and Ochoa et al. further teach that TILs cultured with OKT-3 appeared to exhibit a greater degree of cytotoxicity per culture compared to TILs cultured without OKT-3. Therefore one of ordinary skill in the art would have been motivated to modify the invention of Dudley et al. to comprise a first expansion in step (ii) that is supplemented with OKT-3, because the resultant method would have reasonably been expected to increase the number of TILs obtained in culture as well as cytotoxicity per culture, thereby providing an improvement over the method of Dudley et al.
Carrasco et al. teach that tumor samples may be isolated via FNA using a 22-gauge needle. One of ordinary skill in the art would have therefore been motivated to modify the TIL expansion protocol of Dudley et al. and Ochoa et al. to comprise the step of acquiring an FNA sample from a tumor using a 22-gauge needle, because such a method would be expected to provide sufficient cells for expansion. Additionally given that the method of Carrasco et al. yielded 200,000 cells per tube, which suggests more than one tube, it is submitted that the method of Dudley et al., Ochoa et al., and Carrasco et al. is capable of yielding at least 400,000 cells (claim 17).
Furthermore at [0593], Singh et al. teach that tumor biopsy samples may be surgically extracted using either 14 or 16 gauge needles, and at [0613]-[0616], Singh et al. teach that said tumor cells isolated from biopsy may be subsequently cultured with growth factors. Absent evidence to the contrary, the biopsy of Singh et al. meets the limitations of a “small biopsy.” One of ordinary skill in the art would appreciate that either FNA samples or small biopsies may be used to isolate tumor cells that may then be cultured into TILs for therapeutic purposes. The invention of Dudley et al., Ochoa et al., Carrasco et al. and Singh et al. meets the limitations of claims 1-3, 10, 17, 20, and 22.
With respect to claim 4, at [0081], Dudley et al. teach that TILs may be cryopreserved and thawed for later use.
With respect to claims 5-8, as indicated above, both the first expansion, pre-REP, and the second expansion, REP, may be performed for about 12 days each, and as such steps (i) and (ii) of claim 1 may be performed in 24 days, which meets the limitations of about 22 days.
With respect to claim 9, given that the prior art teaches or suggests the claimed invention, one of ordinary skill in the art would reason that the method of the prior art and the instant method yield identical results. As such absent evidence to the contrary, one of ordinary skill in the art would reason that TILs from the method of Dudley et al. and the instant method express similar levels of CD4, CD8, and αβ TCR.
With respect to claims 11 and 12, given that the method of Dudley et al. is identical to the instant claims, one of ordinary skill in the art would reason that the method of Dudley et al. and the instant method yield identical results. As such absent evidence to the contrary, one of ordinary skill in the art would reason that 1) the REP method of Dudley et al. results in an enrichment of effector or central memory T cells and 2) effector T cells yielded from the method of Dudley et al. would be expected to exhibit increased CD57 expression and decreased CD56 expression.
With respect to claim 13, at [0089], Dudley et al. teach that feeder cells of the invention may be autologous or allogenic.
With respect to claim 14, at [0032], Dudley et al. teach that “[t]he T-cells can be administered by any suitable route as known in the art. Preferably, the T-cells are administered as an intra-arterial or intravenous infusion… (emphasis added).”
With respect to claim 24, one of ordinary skill in the art would appreciate that the REP protocol of Dudley et al., Ochoa et al., Carrasco et al. and Singh et al. could be repeated as many times as necessary to generate a desired number of TILs for therapeutic use.
With respect to claims 25 and 26, it is noted that the cited references do not teach particular TIL dosages; however Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation, which states that:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, effective TIL dosages, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed effective TIL dosages are akin to the variables discussed in the cited MPEP passage, because said TIL dosages are an optimizable variable that would affect the efficacy of TIL-based cancer treatment. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize TIL dosages in the treatment of cancer, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to effective TIL dosages, and this variable achieves a recognized result, such as efficacy in the treatment of cancer. Accordingly the recited TIL dosages are a result-effective variable that achieves a recognized result, such as efficacy in the treatment of cancer, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variable, the recited TIL dosages were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010), as applied to claims 1-14, 17, 20, 22, and 24-26, and further in view of Maeurer (WO 2015/189356, international publication date: 12/17/2015, IDS).
As indicated above Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. teach or suggest a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle. These references do not teach or suggest TIL culture supplemented with IL-15. This deficiency is remedied by Maeurer.
At p. 5, Maeurer teach a T cell expansion protocol that is “based on the finding that a composition comprising cytokines interleukin-2 (IL-2), interleukin-15 (IL-15) and/or interleukin- 21 (IL-21) leads to a superior stimulation and expansion of lymphocytes in particular clinically relevant lymphocytes. The expansion and stimulation procedure with the cytokine mixture is highly sensitive and allows the preparation of the population of clinically relevant lymphocytes even if the starting concentration in the sample is very low.” At p. 14, Maeurer teaches that “[t]he inventors have found that a combination of the interleukins IL-2, IL-15 and IL- 21 provides significant improvements for immunotherapy with lymphocytes. One major advantage is that the expansion and stimulation of lymphocytes derived from a patient with the composition of a combination of at least two types of cytokines selected from IL-2, IL-15 and IL-21 specifically favors the generation of lymphocytes, in particular T-cells, which are clinically relevant.” At p. 5 and 6, Maeurer teaches “a method of preparing a population of clinically relevant lymphocytes, comprising the steps of: obtaining a body sample from a mammal, in particular a tissue sample or body liquid sample, comprising at least one lymphocyte and optionally separating the cells in the body sample, culturing the body sample in vitro to expand and/or stimulate lymphocytes in the sample, wherein the culturing comprises using IL-2, IL-15 and/or IL-21, and optionally determining the presence of clinically relevant lymphocyte in the cultured sample. The method of the second aspect of the invention leads to the formation of population of lymphocytes, which includes a population of clinically relevant lymphocytes.”
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. with those of Maeurer to develop a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle, wherein the TIL culture is supplemented with IL-15. One of ordinary skill in the art would have been motivated to do so, because Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. teach or suggest a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle. Furthermore Maeurer teaches that cytokine combinations, including the combination of IL-2 and IL-15, “specifically favors the generation of lymphocytes, in particular T-cells, which are clinically relevant.” Therefore one of ordinary skill in the art would have been motivated to modify the invention of Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. to comprise first (ii) and/or second expansion steps that are further supplemented with IL-15, because the resultant method would be expected to provide an improvement over the method of Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. by specifically favoring the generation of clinically relevant lymphocytes.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Dudley et al. (US 2011/0052530, publication date: 03/03/2011, IDS) in view of Ochoa et al. (US PAT 5,443,983, publication date: 08/22/1995, IDS), Carrasco et al. (WO 0165998, international publication date: 09/13/2001, IDS), and Singh et al. (US PG PUB 2010/0167945, publication date: 07/01/2010), as applied to claims 1-14, 17, 20, 22, and 24-26, and further in view of Bozzetti et al. (J Thorac Oncol., 3:18–22, 2008).
As indicated above Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. teach or suggest a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle. These references do not teach or suggest that the FNA tumor biopsy is from a lung tumor, such as non-small cell lung carcinoma (NSCLC). This deficiency is remedied by Bozzetti et al.
At p. 21, second column, last full paragraph, Bozzetti et al. teach that FNA biopsies of NSCLC metastatic lesions are an excellent source of fresh material for a variety of uses.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. with the teachings of Bozzetti et al. to develop a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle, and wherein the FNA tumor biopsy is derived from a lung cancer (NSCLC) patient. One of ordinary skill in the art would have been motivated to do so, because Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. teach or suggest a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising: (i) performing a first expansion (Pre-Rapid Expansion Process, pre-REP) of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, OKT-3, and antigen presenting cells (APCs), and wherein the first expansion is performed for about 12 days; and (ii) performing a second expansion (Rapid Expansion Process, REP) by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs (PBMCs), to produce a third population of TILs, wherein the second expansion is performed for about 12 days, wherein the third population of TILs is the therapeutic population of TILs, and wherein the first population of TILs is obtained via fine needle aspirate (FNA) with a 25-18 gauge needle or a small biopsy with a 16-11 gauge needle. Furthermore Bozzetti et al. teach that FNA biopsies of NSCLC metastatic lesions are an excellent source of fresh material for a variety of uses. One of ordinary skill in the art would have been motivated to modify the invention of Dudley et al., Ochoa et al., Carrasco et al., and Singh et al. to comprise performing FNA biopsies of NSCLC lesions, because the resultant method would provide a means of acquiring NSCLC samples for generating TIL populations that may be used in the treatment of NSCLC.
Therefore the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references.
Conclusion
No claims are allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
Prosecution Insights