DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/07/2026 has been entered.
Status of the Claims
Claims 1, 4-5, 9, 12, 17, 32, 39, 41, 48, 50, 53-56, 66-69, 72-75, and 79 are pending.
Claims 1 and 4-5 are newly amended.
Claim 79 is newly added.
Claims 9, 12, 17, 66-69, and 72-75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/21/2025.
Claims 1, 4-5, 32, 39, 41, 48, 50, 53-56, and 79 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1, 4, 32, 39, and 41 under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Besser et al. (Cytotherapy, 2009, previously cited) is withdrawn in order to address the claimed as amended.
The rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Besser et al. (Cytotherapy, 2009, previously cited) as applied to claims 1 and 4 above, and further in view of in view of Kim et al. (US20180228844A1, 2018, previously cited) is withdrawn in order to address the claimed as amended.
The rejection of claims 48 and 50 under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Besser et al. (Cytotherapy, 2009) as applied to claim 1 above, and further in view of in view of He et al. (Chinese Journal of Cancer, 2012, previously cited) is withdrawn in order to address the claimed as amended.
The rejection of claims 53-55 under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Besser et al. (Cytotherapy, 2009, previously cited) as applied to claim 1 above, and further in view of in view of in view Thermo Fisher (Pen Strep, retrieved from Wayback Machine, 2017, previously cited) and Hass et al. (Cancer Immunology Research, 2019, previously cited) is withdrawn in order to address the claimed as amended.
The rejection of claim 56 under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Besser et al. (Cytotherapy, 2009, previously cited) as applied to claim 1 above, and further in view of in view of Lynn et al. (US20200101108A1, 2020, previously cited) is withdrawn in order to address the claimed as amended.
Claim Interpretation
Claim 1 as amended recites, “A seed cell culture medium . . . comprising the following components . . . a cytokine . . . wherein said cytokine comprises IL-2 and IL-7.” In isolation, the plain language could suggest a single cytokine that comprises IL-2 and IL-7 simultaneously. However, the claim further recites said IL-7 has a concentration of about 200 U/mL to about 1000 U/mL” and in later embodiments (claim 79),“IL-7 has a concentration of about 200 U/mL to about 1000 U/mL.”
Therefore, taken together, a person of ordinary skill in the art would have recognized that “a cytokine” is a broad, open-ended, term that can refer to multiple discrete cytokines, and therefore, does not arise to a specific rejection/objection.
It is noted that claim 4 also recites similar language “wherein said cytokine comprises IL-15, etc.”
However, it is noted that, for grammatical precision, Applicant could consider amending the claims to recite “at least one cytokine”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the EFFECTIVE filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the EFFECTIVE filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and EFFECTIVE filing dates of each claim that was not commonly owned as of the EFFECTIVE filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 32, 39, 41, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Frank et al. (WO2018081473A1), Sica et al. (International Journal of Cancer, 1993), and Prado-Garcia et al. (Cancer Immunol Immunother, 2012).
In regards to claims 1 and 79, Fang teaches a serum free (a cell ingredient) TIL culture medium comprising IL-2 (a cytokine) and anti-CTLA-4 (an immune checkpoint antibody) (Abstract; claims 1 and 3). Fang teaches that the concentration of IL-2 is 1000U/ml (which is the same as 1000 IU/mL of IL2) (claim 2).
While less than the claimed range of 2000-3000 IU/mL, as taught by Frank it was known in the art that media comprising about 2000 IU/mL, about 2500 IU/mL, and about 3000 IU/mL, specifically, which overlaps with the clamed ranges (paragraph [0186]) could be used to culture and expand TILs (paragraph [0008]).
It would have been predicably obvious to substitute concentrations because this was a known parameter for media for culturing TILs, as taught by Frank.
Moreover, a person of ordinary skill in the art could have arrived at the claimed concentration range by routine optimization and the disclosure does not point to a criticality in this concentration.
See MPEP 2144.05(II), 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 reAller, 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 the instant case, because the general conditions were taught by Fang above, and since Frank establishes that different concentrations of IL-2, including those which overlap with the claimed ranges, could be used to culture and expand TILs, and is thus, is a result-effective variable, a person of ordinary skill in the art could have arrived at a concentration of 2000-3000 IU/mL by routine optimization with predicable results and a reasonable expectation of success.
Fang does not explicitly teach that the medium comprises IL-7. However, a person of ordinary skill in the art would have been motivated to include IL-7 because as taught by Sica, in media, IL-7 promotes the proliferation of CD4+ and CD8+ TIL lines that have specificity for renal cell carcinoma (Abstract, p941; Fig. 1). Moreover, Sica teaches that these results were achieved with a concentration of 100 U/mL (Fig. 1, p943), which overlaps with the claimed range. Furthermore, because Sica demonstrates that TILs can be cultured with IL-7 ( Fig. 1, p953), a person of ordinary skill in the art could have added IL-7 to the composition of Fang with predicable results and a reasonable expectation of success.
In regards to the limitation wherein the seed cell medium “does not comprise an anti-CD3 antibody”, it is noted that the instant specification does not contain explicit disclosure of this embodiment. Instead, Applicant points to paragraph [0003] which identifies anti-CD3 (OKT3), together with high-dose IL-2 and feeder cells, as part of a conventional rapid expansion procedure (REP) for culturing TILs and also argues that anti-CD3 is not identified as a specific reagent in Tables 1-3 of the instant specification (see Remarks, p8, 08/07/2026).
It is also pointed out that according to paragraph [0290] of the instant specification, in an embodiment, a medium “was supplemented with a CD3 antibody (OKT3)” for the expansion of TILs.
Therefore, there it is determined that there implied disclosure of this limitation.
In this regard, Fang is silent on whether the media comprises or not comprise an anti-CD3 antibody (although, it is also noted that like the instant disclosure, Fang teaches that it is known in the art that CD3-antibody can be used to amplify subsets of TILs (p1, Background technology), and also does not disclose embodiments comprising anti-CD3).
However, Prado-Garcia teaches that anti-CD3 antibody promotes high levels of activation-indued cell death in CD8+ TIL T cell subsets (Title, Abstract, p1065; Fig. 2, p1070; see specifically, “in malignant pleural effusions, AICD compromises the antitumor functions of CD8+ T cells, p1066). Therefore, a person of ordinary skill in the art would have been motivated to specifically exclude anti-CD3 antibody in order to avoid apoptosis of the T cell subset. Furthermore, because Prado-Garcia demonstrates that CD8+ T cells can be cultured without anti-CD3 antibody (Fig. 2, 1070; Fig. 3, 1071) and because Sica also demonstrates that TILs can be expanded without anti-CD3 antibody (Fig. 2, p944) a person of ordinary skill in the art could have specifically excluded anti-CD3 antibody with predictable results and a reasonable expectation of success.
In regards to claim 4, Fang teaches that composition further comprises the cytokine IL-12 (claim 2).
In regards to claim 32, Fang teaches that the concentration of the CTLA-4 antibody is 3 µg/mL (claim 2), which overlaps with the claimed range of 1 µg/mL to 100 µg/mL.
In regards to claim 39, Fang teaches that the medium also comprises CD28 antibody (a costimulatory receptor antibody) (claim 1).
In regards to claim 41, Fang teaches that the concentration of anti-CD28 is 2 µg/mL (claim 2), which overlaps with the range of 3 µg/mL to 10 µg/mL as in claim 41.
Therefore, the combined teachings of Fang, Frank, Sica, and Prado-Garcia renders obvious the invention as claimed.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Frank et al. (WO2018081473A1), Sica et al. (International Journal of Cancer, 1993), and Prado-Garcia et al. (Cancer Immunol Immunother, 2012) as applied to claims 1 and 4 above, and further in view of in view of Kim et al. (US20180228844A1, 2018, previously cited).
In regards to claim 5, Fang teaches that the concentration of IL-12 is 7 pg/mL (claim 2). While it is unclear what this concentration is in U/mL, as taught by Kim, it was known in the art that T cells (of which TILs are a type) can be cultured be cultured in media comprising a range 150 IU/mL to 300 IU/mL IL-12 for the activation and expansion of those cells (paragraphs [0091-0092]),
It would have been predicably obvious to substitute for this concentration because this was a known parameter for media for culturing T cells, as taught by Kim.
Moreover, a person of ordinary skill in the art could have arrived at the claimed concentration range by routine optimization and the disclosure does not point to a criticality in this concentration.
See MPEP 2144.05(II), 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 reAller, 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 the instant case, because the general conditions were taught by Fang above, and since Kim establishes that different concentrations of IL-12, including those which overlap with the claimed ranges, could be used to culture and expand T cells, and is thus, is a result-effective variable, a person of ordinary skill in the art could have arrived at the claimed ranges by routine optimization with predicable results and a reasonable expectation of success.
Therefore, the combined teachings of Fang, Frank, Sica, Prado-Garcia, and Kim renders the invention unpatentable as claimed.
Claims 48 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Frank et al. (WO2018081473A1), Sica et al. (International Journal of Cancer, 1993), and Prado-Garcia et al. (Cancer Immunol Immunother, 2012) as applied to claim 1 above, and further in view of in view of He et al. (Chinese Journal of Cancer, 2012, previously cited).
In regards to claims 48 and 50, in regards to the limitation “The seed cell medium according to claim 1, wherein the serum-containing medium further comprises serum”, it is noted that claim 1 can be either a serum-containing medium or a serum-free medium. Therefore, claim 48 has been interpreted as requiring a serum-containing medium.
While, as discussed above, the medium as taught by Fang is serum-free, as taught by Fang, serum containing media is known in the art (p2 last paragraph to p3 top paragraph). A person of ordinary skill in the art would have been motived to use serum-containing conditions because serum contains growth factors and nutrients essential for cellular growth in vitro, and because He (cited by Fang at p2 last paragraph to p3 top paragraph) teaches that TILs can be effectively cultured in media comprising 5% serum (Generation of young TIL cultures, p288; a concentration of 5% serum lies within the concentration of 1% to 10%). Furthermore, because He teaches that TILs can be cultured in 5% serum, and because Fang cites He as teachings that it is known in the art that TILs can be cultured with serum, a person of ordinary skill in the art could have incorporated serum at a concentration between 1% and 10% into the composition of Fang, with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Fang, Frank, Sica, Prado-Garcia, and He renders the invention unpatentable as claimed.
Claims 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Frank et al. (WO2018081473A1), Sica et al. (International Journal of Cancer, 1993), and Prado-Garcia et al. (Cancer Immunol Immunother, 2012) as applied to claim 1 above, and further in view of in view of in view Thermo Fisher (Pen Strep, retrieved from Wayback Machine, 2017, previously cited) and Hass et al. (Cancer Immunology Research, 2019, previously cited).
In regards to claims 53-55, Fang does not explicitly teach that the medium comprises an antibiotic penicillin-streptomycin PS mixed solution. However, a person of ordinary skill in the art would have been motivated to use a penicillin-streptomycin PS mixed solution (Pen-Strep) in order to, as taught by Thermo Fisher prevent bacterial or fungal infections in culture (First page). A person of ordinary skill in the art would have been motivated to use a concentration that overlaps with the range of 1 U/mL to 200 U/mL because Haas teaches that T cells can be cultured in 1% (which is 100 U/mL) penicillin/streptomycin (Cell culture, pOF2) (see Thermo Fisher first page; stock Pen Strep has a concentration of 10,000 U/mL (first page); 1% x 10,000 U/mL = 100 U/mL). Furthermore, because Pen Strep is a well-known antibiotic for cell culture, and because Hass specifically teaches that T cell can be cultured in pen strep, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Fang, Frank, Sica, Prado-Garcia, Thermo Fisher, and Haas renders the invention unpatentable as claimed.
Claim 56 is rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (CN103374548, 2013, on IDS 11/28/2022, previously cited) in view of Frank et al. (WO2018081473A1), Sica et al. (International Journal of Cancer, 1993), and Prado-Garcia et al. (Cancer Immunol Immunother, 2012) as applied to claim 1 above, and further in view of in view of Lynn et al. (US20200101108A1, 2020, previously cited).
In regards to claim 56, Fang does not explicitly teach that the composition comprises a Treg inhibitor such as dasatinib. However, a person of ordinary skill in the art would have been motivated to include dasatinib because Lynn teaches that dasatinib prevents or reverses T cell exhaustion (paragraph [0013]. Furthermore, because Fang teaches that compositions for treating T cells can comprise dasatinib (claims 25 and 28), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Fang, Frank, Sica, Prado-Garcia, and Lynn renders the invention unpatentable as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4-5, 32, 39, 41, 48, 50, 53-56, and 79 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 9, 11-23 of copending Application No. 18/254,167 (reference application) in view of Prado-Garcia et al. (Cancer Immunol Immunother, 2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions are drawn to compositions or uses of compositions for culturing TILs comprising at least IL-2, IL-7 and a PD-1 antibody. The copending Application discloses a concentration of 200-6000 IU/mL of IL-2, which overlaps with the claimed range.
Additionally, the co-pending Application also discloses that the medium may be supplemented with IL-15, TNFα, GM-CSF, IFNγ, a CD137 antibody, and comprise serum, antibiotics (PS dual antibiotics), and RRx-001.
The claimed concentrations either overlap with the concentrations ranges of the co-pending Application, or could have been predicably optimized based on the disclosure of the co-pending and the disclosure does not point to a criticality in these concentrations (see MPEP 2144.045(II)(A), 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%).
While the co-pending Application does not explicitly exclude anti-CD3 antibody, Prado-Garcia teaches that anti-CD3 antibody promotes high levels of activation-indued cell death in CD8+ TIL T cell subsets (Title, Abstract, p1065; Fig. 2, p1070; see specifically, “in malignant pleural effusions, AICD compromises the antitumor functions of CD8+ T cells, p1066). Therefore, a person of ordinary skill in the art would have been motivated to specifically exclude anti-CD3 antibody in order to avoid apoptosis of the T cell subset. Furthermore, because Prado-Garcia demonstrates that CD8+ T cells can be cultured without anti-CD3 antibody (Fig. 2, 1070; Fig. 3, 1071), a person of ordinary skill in the art could have specifically excluded anti-CD3 antibody with predictable results and a reasonable expectation of success.
It is noted that while the composition of the copending Application may comprise anti-CD3 antibody (claims 2-3, 16-17, and 21), this is a selectable feature, the claims do not necessarily require anti-CD3 antibody, and it would have been predicably obvious to exclude anti-CD3 as discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-5, 32, 39, 41, 48, 50, 53-56, and 79 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 21 of copending Application No. 18/254,171 in view of Prado-Garcia et al. (Cancer Immunol Immunother, 2012).
Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions are drawn to compositions for culturing TILs comprising at least IL-2, IL-7 and a PD-1 antibody. The copending Application discloses a concentration of 200-6000 IU/mL of IL-2, which overlaps with the claimed range.
Additionally, the co-pending Application also discloses that the medium may be supplemented with IL-15, TNFα, GM-CSF, IFNγ, a CD137 antibody, and comprise serum, antibiotics (PS dual antibiotics), and RRx-001.
The claimed concentrations either overlap with the concentrations ranges of the co-pending Application, or could have been predicably optimized based on the disclosure of the co-pending and the disclosure does not point to a criticality in these concentrations (see MPEP 2144.045(II)(A), 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%).
While the co-pending Application does not explicitly exclude anti-CD3 antibody, Prado-Garcia teaches that anti-CD3 antibody promotes high levels of activation-indued cell death in CD8+ TIL T cell subsets (Title, Abstract, p1065; Fig. 2, p1070; see specifically, “in malignant pleural effusions, AICD compromises the antitumor functions of CD8+ T cells, p1066). Therefore, a person of ordinary skill in the art would have been motivated to specifically exclude anti-CD3 antibody in order to avoid apoptosis of the T cell subset. Furthermore, because Prado-Garcia demonstrates that CD8+ T cells can be cultured without anti-CD3 antibody (Fig. 2, 1070; Fig. 3, 1071), a person of ordinary skill in the art could have specifically excluded anti-CD3 antibody with predictable results and a reasonable expectation of success.
It is noted that while the composition of the copending Application may comprise anti-CD3 antibody, this is a selectable feature, the claims do not necessarily require anti-CD3 antibody, and it would have been predicably obvious to exclude anti-CD3 as discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues Fang does not teach each and every limitation of amended claim 1 (Remarks, p9). Specifically, Applicant argues that Fang does not disclose IL-7 in their medium formulation (Remarks, p9).
Applicant’s arguments filed 08/07/2026 have been fully considered but are not found persuasive.
In regards to IL-7, as discussed above, while Fang does not explicitly teach that the medium comprises IL-7, a person of ordinary skill in the art would have been motivated to include IL-7 because as taught by Sica, in media, IL-7 promotes the proliferation of CD4+ and CD8+ TIL lines that have specificity for renal cell carcinoma (Abstract, p941; Fig. 1). Furthermore, because Sica demonstrates that TILs can be cultured with IL-7 ( Fig. 1, p953), a person of ordinary skill in the art could have added IL-7 to the composition of Fang with predicable results and a reasonable expectation of success.
Thus, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In regards to Besser, Applicant argues that only in the REP (rapid expansion protocol) stage are multiple concentrations of IL-2 tested in the presence of OKT-3 (anti-CD3) and feeder cells, and given the differences between pre-REP and REP in TIL culture process, it is unlikely for a skilled artisan to be motivated to incorporate REP conditions into a pre-REP stage (Remarks, p9-10).
Applicant also argues that Besser discloses that 60-6000 IU/mL IL-2 produced massive expansion and high IFNγ, but recommends a regimen of 10-120 IU/mL (Remarks, p10).
Applicant argues that while the Final Action concludes that the range of 2,000-3,000 IU/mL as a routine selection from Besser’s broad 60-6000 IU/mL, the amended claim 1 presents a question substantially different from that addressed in the art – whether a skilled artisan would have selected that fixed range of IL-2 in an IL-7-containing seed medium that excludes anti-CD3 (Remarks, p10).
Applicant argues that Besser shows that IL-2 concentration changes the balance among expansion, IFN-γ production, direct cytotoxicity, and its preferred solution is temporal escalation rather than a fixed intermediate range (Remarks, p10).
Applicant argues that routine optimization requires both a reason to optimize under the relevant conditions and a reasonable expectation of success, which Applicant concludes are not established (Remarks, p10).
Applicant’s arguments filed 08/07/2026 have been fully considered but are moot because Besser is not relied upon for any teaching in the instant Office Action.
However, in regards to Applicant’s arguments regarding differences in a between pre-REP and REP in a TIL culture process, or differences in expansion, IFN-γ production or direct cytotoxicity of TILs, generally, Applicant’s arguments have been fully considered, but are not found persuasive.
The claims are drawn only to a composition not a method of using the composition in a pre-REP condition.
Furthermore, the composition is only a seed cell medium “for tumor-infiltrating lymphocytes”, which is an intended use and as long as a medium is capable of performing the intended use it meets the claim (see MPEP 2111.02, in re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner))).
In regards to the claimed concentration range, as discussed above, as taught by Frank it was known in the art that media comprising about 2000 IU/mL, about 2500 IU/mL, and about 3000 IU/mL, specifically, which overlaps with the clamed ranges (paragraph [0186]) could be used to culture and expand TILs (paragraph [0008]).
It would have been obvious to substitute concentrations because this was a known parameter for media for culturing TILs, as taught by Frank.
Moreover, a person of ordinary skill in the art could have arrived at the claimed concentration range by routine optimization and the disclosure does not point to a criticality in this concentration.
See MPEP 2144.05(II), 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 the instant case because the general conditions were taught by Fang above, and since Frank establishes that different concentrations of IL-2, including those which overlap with the claimed ranges, could be used to culture and expand TILs, and is thus, a result-effective variable, a person of ordinary skill in the art could have arrived at a concentration of 2000-3000 IU/mL by routine optimization with predicable results and a reasonable expectation of success.
Applicant argues that Kim does not cure the cited deficiencies and does not create the amended combination (Remarks, p10). Specifically, Applicant argues that Kim provides a generic list of IL-7, IL-12, IL-15, and IL-21 at about 150-300 IU/mL, but in actual experiments only uses 10 ng/mL IL-7 (Remarks, p10).
Applicant’s arguments filed 08/07/2026 have been fully considered but are not persuasive.
As above, Fang teaches that the concentration of IL-12 is 7 pg/mL (claim 2). While it is unclear what this concentration is in U/mL, as taught by Kim, it was known in the art that T cells (of which TILs are a type) can be cultured be cultured in media comprising a range 150 IU/mL to 300 IU/mL IL-12 for the activation and expansion of those cells (paragraphs [0091-0092]),
It would have been predicably obvious to substitute for this concentration because this was a known parameter for media for culturing T cells, as taught by Kim.
Moreover, a person of ordinary skill in the art could have arrived at the claimed concentration range by routine optimization and the disclosure does not point to a criticality in this concentration.
See MPEP 2144.05(II), 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 reAller, 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 the instant case, because the general conditions were taught by Fang above, and since Kim establishes that different concentrations of IL-12, including those which overlap with the claimed ranges, could be used to culture and expand T cells, and is thus, is a result-effective variable, a person of ordinary skill in the art could have arrived at the claimed ranges by routine optimization with predicable results and a reasonable expectation of success.
In regards to other embodiments as taught by Kim (e.g., other cytokines or concentrations), the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As discussed above, a concentration range of 150 IU/mL to 300 IU/mL IL-12 is explicitly a concentration taught by Kim (paragraph [0092]).
Continuing, in regards to IL-7, Applicant argues that Kim reports nearly identical growth for IL-2 and IL-2/IL-7 cultures (paragraph [0121]), lower IFN-γ stimulation indices in the IL-2/IL-7 cultures (paragraph [0122]), and generally similar melanoma-cell apoptosis (Remarks, p10-11). Thus, Applicant argues that Kim provides no experimental basis for expecting that selecting IL-7 from its list, adding it to Fang's anti-CD3-free TIL formulation, and independently replacing Fang's 1,000 U/mL IL-2 with a fixed 2,000-3,000 IU/mL range derived from Besser would predictably yield the claimed seed-cell medium (Remarks, p10-11).
Applicant’s arguments filed 08/07/2026 have been fully considered but are not persuasive.
Kim is not relied upon to provide a motivation to add IL-7 to the media of Fang.
Instead, as discussed above, a person of ordinary skill in the art would have been motivated to include IL-7 because as taught by Sica, in media, IL-7 promotes the proliferation of CD4+ and CD8+ TIL lines that have specificity for renal cell carcinoma (Abstract, p941; Fig. 1). Moreover, Sica teaches that these results were achieved with a concentration of 100 U/mL (Fig. 1, p943), which overlaps with the claimed range. Furthermore, because Sica demonstrates that TILs can be cultured with IL-7 ( Fig. 1, p953), a person of ordinary skill in the art could have added IL-7 to the composition of Fang with predicable results and a reasonable expectation of success.
However, in regards to Kim, the fact that Kim combines IL-7 and IL-2, as identified by Applicant, weights in favor of a conclusion that the medium could have added IL-7 with predictable results and a reasonable expectation of success.
Applicant argues that embodied mediums 3 or 1 yield greater numbers of cells compared to CM1 controls (citing paragraphs [0271-0273; Tables 1, 5, 8, and 10).
Continuing, Applicant argues that Examples 5-6 further show that seed cells produced using the disclosed media could be expanded downstream to 4x10¹⁰ and 5.2x10¹⁰ cells, respectively, and exhibited post-infusion persistence or robust lymphocyte proliferation without medicinal IL-2 after infusion (Remarks, p5).
Applicant argues that because the downstream REP in paragraph [0292] used OKT3, these results are cited only as confirmation of downstream suitability of the seed cells - not as an assertion that the entire manufacturing process avoided anti-CD3 or that clinical effects arose from the seed-medium variables alone. (Remarks, p5).
Applicant argues that the prior art teaches that a pre-REP (rapid expansion protocol) stage conventionally employs high-dose IL-2 together with anti-CD3 antibody, and that after adoptive transfer, patients receive repeated high-dose IL-2 infusions to sustain TIL in vivo, a regimen associated with substantial systemic toxicity and limited patient tolerability (citing instant paragraph [0003] and Sarnak et al. (J Clin Oncol, on IDS 08/07/2026).
However, continuing, Applicant argues that “the objective technical problem solved by the method of amended claim 1 can be formulated as to quickly obtain seed cells for tumor infiltrating lymphocytes with low contamination risk, high cell viability, and high clinical treatment safety” (Remarks, p12).
Applicant argues that the resulting TIL seed cells exhibit the unexpected property that, after subsequent expansion and adoptive transfer, persist and proliferate without requiring high-dose IL-2 therapy, activating superior therapeutic activity efficacy while avoiding the side effects associated with high dose IL-2 regimens (Remarks, p12).
Applicant’s arguments filed 08/7/2026 has been fully considered but is not found persuasive.
The examined claims are drawn to a composition not a method, and does not require using TILs whether for expanding those TILs or for any therapeutic use.
As discussed above, “A seed cell medium for tumor-infiltrating lymphocytes” is an intended use of the preamble, the claim only suggests that the medium is capable of being used for TILs.
As above, according to MPEP 211.02, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.
Additionally, in regards to the concentrations, as discussed above, Frank teaches media comprising about 2000 IU/mL, about 2500 IU/mL, and about 3000 IU/mL, specifically, which overlaps with the clamed ranges (paragraph [0186]) could be used to culture and expand TILs (paragraph [0008]).
Furthermore, the cited results only compare media with relatively high concentrations of IL-2 (6000 IU/mL IL-2, paragraph [0262]) and describes this as a “high-dose” concentration of IL-2 (paragraph [0003]), but the results do not compare other moderate-dose concentrations of IL-2 embodied in the art (e.g., the composition of Fang), and therefore, is not compared to the closest prior art.
Applicant argues that none of Kim, He, Thermo Fisher, Hass, or Lynn cure the above cited deficiencies of Fang (Remarks, p12).
Applicant’s arguments filed 08/07/2026 have been fully considered but are not persuasive because Fang is not deficient as discussed above.
Applicant requests that the double-patenting rejections be reconsidered in view of the claims as amended (Remarks, p13).
Applicant’s request has been noted and the co-pending rejections have been reconsidered in view of the claims as amended. However, the double-patenting rejections have been maintained as discussed above.
Applicant requests rejoinder (Remarks, p8-9).
Applicant’s request is noted. However, because the claims are still prima facie obvious as discussed above, rejoinder is premature at this time.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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